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Physiology and Pharmacology of Vomiting

Physiology and Pharmacology of Vomiting

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Department of Pharmacology,


AND College



S. C. WANG of Medicine,


of Utah New York OF





and Department

of Physiology,


of Physician8










194 196







Introduction Apomorphine and Cardiac Glycosides





Quinine and Quinidine Veratrum Alkaloids Pilocarpine, Posterior Tartar Emetic





212 217 217 217 218 220






Nicotine Ergot Alkaloids Atropine

Aconitine Staphylococcus Miscellaneous


222 223 223 223



224 224


The which vomiting approaching regardless versal the

vomiting animals can are occur


is defies


of The



primitive variety follow

protective of circumstances simple

functions under overeating

with which or signal




It may

death. It of the route appearance and and act

often represents by which the great the emetic clinical action

one of the chief drug is administered. importance, of many the drugs are


of drug toxicity In spite of its unimechanism well understood. of

nervous not


‘this review is limited almost exclusively to the results of animal experimentation concerned with the mechanism of vomiting. Clinical studies on vomiting are included only insofar as they elucidate physiologic processes. The article on vomiting written by Hatcher (97) in 1924 represents the
Original investigations by research grants Diseases and Blindness,

by the authors, reported in this review, were supported in B-64 and B-31 from the National Institute of Neurological National Institutes of Health, Public Health Service. 2Editor’s Note: The John J. Abel Prize in Pharmacology was awarded to Dr. Borison in April 1953 by the American Society for Pharmacology and Experimental Therapeutics, for an essay on his research in the field reviewed in this article. part 193









latest authoritative survey of the subject ture. During the last generation, Hatcher investigators in the field of emetics. In most by experiments this group. review the U. was principles In on emesis, 1948, reported DuToit and up

to be found in the accessible and his coworkers were the large measure, the interpretations to 1949, Christensen rested (64) on the ideas completed a

literaleading of compre-

expounded “restricted” on emetic

hensive use by substances cological

of the literature S. Government. collected expressed agreement parts by by

on emetics (629 references) for While a great fund of information these authors, them on the of the are the basically physiological the of the same various The as


pharmathose terms preused defini-

sented by Hatcher (97). There is no universal to describe tions able only mouth. the component are presented at the measure of uniformity to the R&hing forceful

definitions syndrome.



outset to reduce ambiguity in the subsequent text. of the labored gastrointestinal rhythmic as the

and to establish a reasonVomiting or emesis applies contents activity of the vomiting. consequence retching The since mouth through respiratory Vomiting is of it. Moveretching opens is not irnmedithe


is defined

musculature which neither synonymous ments ordinarily suggestive accompanied

usually precedes or accompanies with retching nor an invariable are by not equivalent of the to mouth. opening

of vomiting

ately preceding the evacuation of the stomach or labored. If the mouth is opened widely but this act, together with the assumption gestive of vomiting. Nausea may or may not be associated whether nausea is experienced sistent by are tion many observed. and, appearance investigators However, therefore,

whether vomiting is projectile no expulsion of vomitus occurs, posture, is considered sug-

of a typical

is a psychic experience of human beings which with vomiting. It is impossible to determine by experimental animals. Nevertheless, the conemetic nausea of these prodromata is experienced signs are still positive

of certain that most cannot


prompted when such elicitable

the after

assumption signs decerebra-


be considered


of nausea.




the a portion apornorphine







the dog by destroying itiated vomiting with vomiting wide and peated Thumas’ oral and center 5 mm.

of the medulla oblongata applied locally. He structures through of the

from which he inconcluded that the area, work 2 mm. was’ re-

was located long, which

in deeper extended

a midline obex. This

somewhat results with chloride

refined by Hatcher apomorphine, but in dogs which were

and Weiss they were refractory

(100, able to

101). They confirmed to elicit emesis with apomorphine. induced cinerea, to as with which On the either they investiof ad-


other hand, apomorphine considered to gators, Thumas ventitious

Hatcher and or mercuric be the site erroneously to the

Weiss (101) prevented chloride by destroying of the vomiting implicated closely situated center. midline ala cinerea.

vomiting the ala According structures

these a result







195 of the aforemenwas demon-









tioned investigators. determined primarily strated, tivity effective

Only acute preparations were on the basis of drug application. lesions was Thus, the in

used and Koppanyi

localization (121)

in dogs with chronic to parenteral apomorphine by the oral ala route. cinerea has been to by (97)).

the ala cinerea, that reduced while irritant hypothesis that the

the emetic sensiemetics remained vomiting center for for aporeflex is

embodied in the The contention morphine, vomiting emetic existence referred (see specificity of the no The claim are

was placed in serious doubt. made that there are two some workers as automatic, surprising in

centers-one and view another of the



is not


of apomorphine. vomiting center, single for experiment a center

Most physiologists and not to its precise suffices must both be to held demonstrate in abeyance and

have agreed only to the location, in the medulla the until morphologically existence the of to have of an emetic can very well be considered of the given a

oblongata. Probably center.


in question



an integrating function. Most center, on the basis of ablation apply to receptor elements. An valid function, Borison tion of the only if it encompasses and and lateral when Wang it has (18, reticular 26) stood

arguments or even hypothesis the elicited of the prior and test

advanced in support stimulation experiments, for a neural center can concerned of time in the and in the immediate trial. cat by regulation

all aspects

vomiting in the

electrical of the

stimulafasciculus responses. latency reof 5 to 15 cessation 183) ala found cinerea cardiac of



solitarius. No other portion Vomiting was elicited without quired for maximal inspiration, seconds stimulation. that superficial the abolished. of stimulation. In a study medullary emetic response The in

lower brain stem retching, following it was continuous ceased dogs, with immediately and Wang minimal

yielded such the short for a period upon Borison to and the (180, the

vomiting chronic lesions


to intravenous

apomorphine to oral reticular as the to vomiting and trigger


glycosides without deeper lesions which responsiveness These the the results dorsal medullary to were portion surface

disturbing the response also involved the lateral oral copper lateral sulfate to mean reticular as well that interpreted of the

copper sulfate, whereas formation impaired the intravenous center that zone apomorphine. is situated there which exists in in


a specialized



as a receptor site for certain central emetic agents. However, the critical experiment to settle the question as to whether the superficially situated chemoreceptor trigger zone is merely a receptor area or has integrative functions is one in which the lateral reticular ventricular structures intact. This seeds inserted through the dorsum 78). in the surface The experiments, performed lateral reticular formation, structures, elevated the formation is destroyed while leaving penwas accomplished with the use of radon of the flexed cervical spinal cord (27, 182, in with thresholds chronic no dogs, demonstrated detectable of emetic that lesions histologically to a variety damage to agents includ-

196 ing intravenous that








apomorphine neither studies how Thumas of their deep








is un-

fortunate histological way work tion Borison cat slightly cardiac Wislocki recently of

(172) nor experimental the destruction

Hatcher and Weiss (101) lesions. Consequently, extended and, that the lateral It has been and abolish area that the the ala

had reported there is no in the by in the to by more of the forma-


particularly reticular demonstrated zone, cinerea has (35, been 36)

of Hatcher and Weiss and fasciculus solitarius and or Brizzee is situated not and by at Putnam Brizzee and may help universal all The (19, by 20, at least, in the

(101), it is possible were damaged. 31) area that postrema which of the (120), light of the

chemoreceptor emetic


is damaged studied and study

lesions King (32).



morphology (189), Neal


Cam.mermeyer on the emetic these animals

A comparative


area postrema However, the stimuli of the area

to shed some refractoriness trait is more formation

inactivity of rodents. to emesis-provoking with some property proper than of the

suggests that this brain stem reticular postrema.

probably associated and vomiting center








literature wish 1891. site






adequately work were



(97) the reviewers (172), reported in that time. scriptonius vomiting Furthermore, He and not later pointed Thumas as the was

to give special attention A number of noteworthy

here to the conclusions tip that

of Thumas reached at

placed great emphasis on the caudal of the vomiting center. He showed transection that the of making of the brain emetic center lesions stem at is located one

of the calamus the function of

intact after he indicated out the futility

the acoustic stniae. in deep structures. side of the medulla

in only

specifically mentioned abolish drug-induced report by Hatcher

that unilateral destruction of the ala cinerea does emesis; this statement directly conflicts with the and Weiss (101) that “certain” destruction of the ala emetic stimuli. between the these of they the rewhich hypercan be of as

cinerea Thumas activities centers Borison centers remain spiratory showed ventilation. abolished, properly continuity narcosis Several

on one side abolishes the vomiting initiated by various discussed certain physiologic similarities and relationships of the vomiting and the respiratory are identical. His conclusion has and Wang (26), who showed that are located in close mutual separate entities. Grimm and emetic centers are that vomiting However, is impossible there is ample been centers, borne the

but he denied that out by experiments respiratory and



proximity in the reticular formation, (91) and Greve (90) claimed that identical on the basis of experiments during proof the apnea (180, which 182) that results from vomiting

without significant placed lesions in the of and the apnea. two (128, centers 176)

impairment of respiration, medulla. It is not surprising that have they failed react to elicit similarly emesis

as a consequence from the morphologic to by such electrical influences stimula-








tion of the dorsal vagal nucleus. ing but not emesis on stimulation elicited vestibular retching root. movements These pentobarbital. stimulation produced of the cats. Most formation necessary mechanism localization special lateral latter but

Miller and Sherrington of the inferior fovea. not vomiting were on stimulation performed only

(148) elicited swallowBorison et al. (23, 17) of the mostly on descending cats anesseries and in dein the It is of the

experiments Vomiting experiments

thetized with of medullary Wang stimulation cerebrate reticular therefore regulatory The assumes (2

was elicited in anesthetized and formation points localized structure center region important respiratory vasomotor in of the

once in a large cats (26). Borison with oblongata

vomiting reticular


consistently medulla


of the responsive but a few were to of include this of vomiting. the vomiting when this

were found to be situated in the fasciculus solitarius. and the its nucleus lateral in as reticular a part

formation refunctions. inspiratory salivatory of the


is viewed visceral center center


morphological somatic (b) the (d) the

lationship to neuronal These loci include (a) and expiratory (177), centers nuclei systems these

loci regulating the spasmodic (158), (c) the

and (17), (187),

(e) the vestibular (140). The locus for foci. activities and Luckardt concomitantly that are

nuclei, and (f) the bulbofacilitatory vomiting is strategically situated of the vomiting act shows in its motor expression. described the cardiovascular Crittenden and Ivy

and inhibitory in the core that all


A consideration involved (33) have with associated nausea,

represented Brooks occurring

changes (43)

in dogs examined


the cardiac irregularities Their results indicate cutaneous injection cardiac rhythm and auricular The intravenous irregularities. associated and there vomiting Ivy with (43) and

with nausea and vomiting in dogs and man. retching and vomiting induced by the subin normal unanesthetized dogs may cause arrest, and ventricular occur during retching. inhibits the cardiac rate, bradycardia. vagal passages. nerves with the However, of the agreed of the occurring biliary nausea usually Crittenden so that nausea,

of apomorphine

irregularities such as heart block, cardiac ectopic beats. They are most likely to injection of atropine almost completely There a claimed pain are that incidence elicited by also marked and icterus of cardiac distention changes retching sensitizes of the in with the cardiac a cardiac tachycardia

is an increased



apparent synergism was not quantitated. Although the exact roles and sequence elements 152, 153, of the respiratory 171), there is no apparatus, question

of action

in vomiting,

are not completely as to the importance

upon (82, respiratory the and both

contribution to the vomiting emesis elicited by electrical that thoracic sponse The tion it was initiated at the and abdominal fell slightly but vocal indicated accompaniment that the

act. Borison stimulation peak

and Wang (26) have centrally was projectile inspiration pneumographic ejection of the occurred under during positive The the

shown that in type, recorded by

of a maximal

pneumographs. continuously during which thoracic occasionally viscera

inspiratory regastric contents. central stimuladuring the



198 period of vomiting. was observed prior on the cessation sive respiratory ular root. On this between distinction








No rhythmic hyperactivity to, during or following the On elicited and and

of the respiratory musculature vomiting episode which terminated rhythmic and explothe descending vestibmade exemplified a physiologic clinically (2) is

of stimulation. activity was basis, Borison vomiting

the other hand, strong, by Borison (17) from Wang (26, 179, These 182) retching. are


by (1) projectile vomiting which is often associated with elevated cerebrospinal fluid pressure and which occurs without preliminary retching, and the fatiguing and unproductive retching referred to as “dry heaves”. There no doubt and the that nature the particular gastric form contents. of vomiting Furthermore, is largely the related influence to the of the amount stomach of the

contents must be considered and perhaps more important, oblongata of sensory impulses improbable participation vomiting The and on the attitude for the postural that act. characterization system regulation in vomiting interaction tone. In this the character spasmodic by in the and of the regard, of postural of the

not only from the mechanical viewpoint but also, from the viewpoint of the effect on the medulla originating in the gastrointestinal wall. It is not of such impulses center and stem Our only his task and coworkers here may the determine vomiting (140) is to point of casts out the center relative in the respiratory Magoun brain tone.

a facilitatory a new the light postural formation regulating been shown




the favorable architecture of the reticular vomiting center with neuronal complexes it is interesting that apomorphine has

by Vernier and Unna (174, 175) to an action on the brain stem reticular its emetic action since apomorphine which manifest emetic refractoriness receptor trigger zone (178). Hatcher after direct tributed the has tion shown medullary application effect to in the emetic

reduce tremor and postural tone through formation. This action is independent of produces muscular relaxation in dogs as a result of lesions placed in the chemo(97) has described muscular but he contrast, relaxation at(53) to the a reducdepression the obex, action. In application evokes apomorphine apparently Dordoni without causes

of apomorphine to a peripheral muscular dog whereas that trigger local zone parenteral

decerebrate chemoreceptor rigidity,

of apomorphine vomiting

in decerebrate

of the muscular induced changes lary lesions was vomiting morphine action the formation. Hess (108-110, respiration center affects

rigidity in addition to vomiting. The fact that apomorphine in respiration without causing vomiting in dogs with medulone of the chief arguments offered by Thumas (172) that the is not identical with the respiration without causing on postural directly 113) tone by acting 112, on a limited respiratory emesis that region center. Just how apois not known. The central this of the the drug brain may stem influence reticular and other

of apomorphine


stimulated unanesthetized vomiting. accompanied

electrically cat The by the

diencephalon licking, consisted of vomitus,

forebrain structures ing, retching and mic retching

in the occasionally

and observed vomiting act expulsion

swallowof rhythand it







199 as long as 2 minutes with the experiof the medulla reabruptly medullary stimulation. activities, conclusion on cessaemetic The occurs is in-


ments suited

a short

occurred after some seconds of stimulation or even period of stimulation. This is to be contrasted of Borison and Wang (18, 26) in which stimulation immediate projectile These to the that in the vomiting which terminated authors vomiting vomiting, decerebrate

tion of stimulation. center is essential critical without escapable oblongata. that there fact remains diminution

agree with Hess that the induced by diencephalic with all animal. of its associated the Therefore,

that the basic Nevertheless, are

integrating mechanism for emesis resides in the medulla the experiments of Hess (1 10) demonstrate admirably neuronal loci which not only initiate vomiting downstream but probably affect the center with impulses of subliminal 165, 185) hypothalamic (1 18) of the part described various stimulation, observed lateral rhythmic hypothalamic orbital cortex attention foci the which responses changes but they spitting area and (160, control elicited retchmicturiof these thor(137) Al-


by sending effective barrages of impulses reflex excitability of the medullary emetic effect. Several in gastrointestinal have in the nearby 141, certain not reported workers (14, motility vomiting 107, 1 18, 143, resulting from responses. of the cortex structures 154, to rostral Kabat

as a result

of stimulation

cat. The cerebral rhinencephalic 9, 111, activities related

and more particularly the have received considerable 155, 117) and as supraregulatory eating. Among

6, 7, 8, 2, 71,


by electrical ing, biting, tion, and activities oughly that the

stimulation of these regions are sniffing, sneezing, coughing, chewing, licking, lapping, swallowing, salivation, defecation, changes in gastrointestinal motility. The representation basal by and medial portions of the Kaada (117). Furthermore, plays an described cortex, has been important as an no report encountered role cerebral it has cortex been

in the reviewed

has been proposed expression.


in emotional

though retching has been stimulation of the cerebral vomiting by this technic

occasional response to of the direct elicitation by the reviewers. With

electrical of frank regard

to vomiting produced by psychic stimulation, it is not clear time whether this is mediated directly through corticobulbar whether it is the result of impulses relayed through subcortical On the pilocarpine basis and of experiments in posterior pituitary which injected emetic into responses the lateral

at the present connections or structures.

were elicited with ventricles of man,

Cushing (44-47) postulated a direct hypothalamic nuclei (see page 218). tion that the chemoreceptor trigger of apomorphine pilocarpine and of analogous tain permit subcortical the in the posterior neuronal construction level. has been medulla, pituitary ependymal loci. In it

action of these drugs on subependymal However, in light of the recent demonstrazone constitujes the specific site of action seems more may induce which theory as for event, reasonable vomiting act the data action to postulate that through stimulation with insufficient of drugs at resulting certo the are


receptors any

in conjunction


of a convincing observed in cats

diencephalic Vomiting

a behavioral


from approach occurs exposure in certain to









conditioning the factors humans.

stimuli concerned

(65). in the


is perhaps


way which


experimentally Burns they From use Talmud sprayed stomach



psychoneurotic (159) obtained the of the

Riddle and pigeon which hydrochloride. in the repeated method. to alcohol the with (85) emesis reflex However, of washing some et al. cussed responses Gold

have described after 3 to same birds for

a conditioned emetic 8 oral administrations this assay observation of digitalis the

reflex in the of yohimbine is important by the pigeonemetic of CuSO4. procedure dishand, conditioned other in a number



(170) failed to produce into the mouth after the vomiting prior occasionally to attempts as the the development the by administration other

in dogs a conditioned oral administration following of workers stimulus. CuSO4. to obtain On vomiting the the

conditioned poorly




apomorphine reported

unconditioned administration (60) noted

of conditioned

of dogs after a few days of successive In a large series of animals, Dresbach one cat following the injection viewers with been observed other hand, Defecation drug-induced chronic administration no instance of frank conditioned salivation often accompanies vomiting. At the the

of digitalis glycosides. conditioned emesis in only In the experience of the re-

of strophanthidin.

of emetics to dogs and cats, there has vomiting as a conditioned response ; on the occurred vomiting in a number act. This of Hatcher, of cases. is particularly Koppanyi (121) true studied for


the central site of action of “evacuant” drugs. defecation by the local application of picrotoxin, floor of the fourth ventricle, and he abolished the by making lesions in the vicinity of the to this region. Because of the concomitant as apomorphine, experiments the vomiting vomiting question resulting established center. center logically each but the Since from these existence it is now the

He succeeded heroine and evacuant effect or

in producing codeine to the of these drugs morphine agents such that vicinity not on zone, his of the the both rein

ala cinerea refractoriness

by applying to emetic concluded in the acts trigger zone



of a defecation center known that apomorphine medullary same chemoreceptor elements in this there the whether does

on a specialized whether

arises of vomiting of these


the functions ceptors for the reticular brain stem observation in dogs struction between according

and defecation or functions. Furthermore,

exist separate vomiting center

formation or does the by Wang to receptors of central the

have a defecation counterpart elsewhere in the lower lateral reticular formation integrate both functions? The (178) that apomorphine is capable of eliciting defecation the eetic for (121), action trigger vomiting the facts of this zone and that for drug clearly defecation. produces for vomiting with organs. apomorphine as a result establishes On nausea and the frequently of surgical a distinction other hand, produces de-



to Koppanyi

defecation and that codeine tion suggests the possibility acted upon depending by essentially largely upon the the

almost invariably that the centers

before defecadefecation are response 109, 110)

same kind of stimuli, state of the peripheral

the ultimate Hess (112,






201 in the diencephalon vomiting. Kaada of the (160). are cerebrum. It is posin motion coordinated defecation of and Tyler evoke factor

elicited in the (117) Retching sible, at the

the defecation cat in a manner evoked has therefore, defecation also that been

act by electrical similar to that by elicited frequently However, level. the stimulation from

stimulation by which of the this region study

of points he obtained basal of the cortex cortex functions

associated no


a supramedullary decerebrate Because of much analysis According

of drug-induced

animal has come to the the tremendous economic research of the to these has been pertinent authors, by other labyrinthine

reviewers’ attention. and military importance disorder made by which

sickness, hensive (173).

done on this functional literature has been the vomiting induced stimuli and stimulation

a compreand Bard seems to be emesis. in the eighth Bard central fore-

by motion

entirely like that produced It appears certain that etiology cranial

conditions is the


of motion sickness. Either labyrinthectomy nerves renders animals immune to the emetic for in a chronic decerebrate motion sickness operates of the of the examine prevented nodulus, midbrain. vestibular this structure vomiting uvula and

or section of the effects of motion. essential of the

et al. (11) demonstrated nervous mechanism brain and suprasegmental led Bard motion-induced by removing tected These the control animals symptoms lingula and experiments the et al.

dog that the independently The fact receptors

rostral portion representation (11, 12) to emesis. They the cerebellar showed were flocculi, Bard

that the best known lies in the cerebellum factor in dogs pro-

as a participating

in previously susceptible pyramis. However, the

mild salivation and considered as possibly whose and role in motion coworkers

licking in the absence due to the functional sickness 12) found remains that (11,

of panting. integrity of uncertain. ablation of In all of the vomitmech-

parts of the vermis pyramis and a few ing. These workers anisms Wang (173, to the morphine

between the primary fissure and pyramis or removal folia of the uvula failed to prevent motion-induced concluded that the nodulus and uvula contain neural

which are prepotently involved in the genesis of motion sickness in dogs. and Chinn (184) recently confirmed this conclusion. It is well known 97) that total decerebellation does not reduce the sensitivity of animals emetic by to action that ablation the emetic of apomorphine. animals of the action zone sickness.


contrast, to

Wang the

and emetic

Chinn action


have of apo-




the concerned

medullary emetic chemoreceptor trigger zone are of swinging motion. This finding indicates that is in the direct pathway of the vestibular reflex

chemoreceptor in motion














are mainly somatic and their connections are well known. As for the importance of visceral efferents in the execution of emesis, there is no essential difference in the vomiting act performed by normal and gut-denervated animals. The role of the visceral efferent nerves in gastrointestinal motility will be considered

202 as has itiated from pathway. stimulation the been Afferent from the need arises. pathways almost source, With same








The are any regard to

subject very site the to

of the in the difficult

extrinsic to study

motor (42, 194, because may these occur may

innervation 5, 133, vomiting of impulses, over induce system many more 134,

of the 135, may than be

gut inone by by



literature body. chemicals,


in the emetic

Transmission center central of sites.

originating vomiting or perhaps such receptor

vomiting of the

of receptors

in or out

nervous Probably

acting simultaneously at a multiplicity sites remain to be discovered. In this section, emphasis will tion to the intricacies in activity anisms of emetic action of drugs cology. Sutton and King (168) described be

placed of emetic are given vomiting


nerve pathways without attensubstances. Details of the mechbelow, in the section on pharmain dogs as a result of compression

of the coronary vessels. They found pain but it prevented a fall in blood The effect of vagotomy of the left stellate on induced ganglion Removal

that section of the vagi did not abolish pressure following coronary compression. nausea abolished and the vomiting sensation was not reported. but salivaof pain

tion continued. Walton et al. suiting from the

(176) studied intraperitoneal

the pathways in the injection of E. coli.

vomiting of peritonitis reThey found that impulses

passed to the emetic center by way of afferent fibers in both the vagal and the sympathetic nerves. They maintained that, since neither sympathectomy nor vagotomy alone abolished the vomiting of peritonitis, the afferent emetic impulse transverses either pathway with equal facility. Actually this conclusion with regard to relative transmissibility is not justified since these workers could not to quantitate cause vomiting in their after experiments each of the the nerve threshold sections. level of irritation parallel induced suffice to necessary situaby oral transmit demonA somewhat

tion was found copper sulfate. emetic impulses

by Wang Either the to the

and Borison (181) vagi or abdominal center.

in the vomiting sympathetics these pathway, occurred occurred observation remained and




strated that the vagus is the more important the emetic threshold level of copper sulfate alone, whereas a two-fold increase in threshold Walton et al. (176) made the very interesting somatic did not innervation cause vomiting to the after arrived vomiting parietal abdominal peritoneum

since no change in after sympathectomy after vagotomy alone. that although the intact, thoracic visceral of the in peritonitis. peritonitis vagotomy. afferent visceral fibers rather Whether are of the vagi.


From this fact, they are important in the than the parietal

at the conclusion that only act, and that it is irritation which causes vomiting that the that the other mustard the conclusion In studying On


these investigators are justified in their not concerned in vomiting is debatable. mustard, sensory vomiting Miller (146) was unable impulses from movements the gastric induced by mucosa. intragastric

somatic afferents local emetic action splanchnics transmit hand, he prevented by division of the

to demonstrate






203 by of electrical intestinal


addition Herrin and

he induced of the Meek resulted showed of the central

salivation ends (105) reported

and of the

a modified vagal that closely vomiting, prevented branches continuous


of emesis stomach. distention


of the

fistulae in dogs tion. The dogs Denervation testinal nerves tion.

in a condition anorexia and mesenteric pedicle

simulating acute but no indication these

bowel obstrucof acute pain. of in-


distention. and described Vagotomy did

Subsequently the same authors (106) their respective roles in the syndrome not abolish the vomiting or anorexia. vomiting abolished is entirely in the by

identified the afferent of intestinal obstrucBilateral abdominal Combined vathe vomiting is transmitted on Pennington of an without the

sympathectomy abolished the gotomy and sympathectomy induced by intestinal distention centrally other et al. isolated evidence hand, via afferent apparently fibers

but not the anorexia. all symptoms. Hence, of nervous origin, and nerves. afferent The pathways. both

sympathetic dog that a decrease

anorexia, distention of cardia

is mediated

(156) found in the unanesthetized jejunal segment may produce of nausea and Ivy bladder in the or other signs (164) demonstrated and biliary passages inspiratory position,

moderate in tonus

of distress. in unanesthetized dogs that distention produces, in addition to inhibition symptoms such as nausea, vomiting of distention. The effects on blood Distention of the biliary ducts caused of the nerve by nerves gall bladder. inhibition They were observed abolished respiratory of

Schrager of the gall respiration and distress pressure and more that striking nausea,

in proportion to the degree heart rate were not uniform. symptoms vomiting and than some distention of the

by section respiratory nic nerve. the 30 distending Goldberg to 35

of the vagi and inhibition were Section of both vagi pressure (86) showed mm. Hg

left splanchnic likewise abolished and splanchnic

and that distress and some section of the right splanchabolished all reflexes with dilute pressures pressure acids, alkalis unless of level

was greater than that distention induced regardless constant

300 mm. Hg. of pyloric pouches vomiting. of whether The effective water,


remained or mustard that such used by distention the worker the vagus of pouches

remarkably solution pouches this

was used for distention. were denervated when

It had been the previous prepared according to

contention the method

author. However, Goldberg by transthoracic vagotomy. chains that the had no effect afferent

was able to abolish the Since removal of appropriate by itself of this on the emetic arc reflex

vomiting from sections of response, that distention Burget pathway et al. defecafor are vein, this through

sympathetic concludes nerves. of the the that vomiting.


is entirely

He also reported the interesting observation gastric fundus never resulted in emesis. absorption These of glucose of a chronic authors did from closed not the loop investigate colon of the may nervous the distention of colon

In studying (34) tion found and



the response. Whether the mediated through identical Franklin and McLachlin

vomiting and defecation reflexes thus initiated pathways remains to be demonstrated. (75) showed that ligation of the mesenteric

204 but not of the even








splanchnic though the

vein, venous

produced drainage

emesis of the

in the stomach

anesthetized and first Nervous (190,

cat. few

This centiwere that


meters of the not investigated, irritation and

small intestine was entirely unaffected. but the results are in line with reports of the small intestine is more of the caused

pathways 193, 4, 132) in causing

or distention



vomiting than is similar stimulation In an intensive study of the vomiting

stomach. by staphylococcus


in the cat, Bayliss (13) made the following observations. Celiac ganglionectomy, gastrectomy, spinal cord transection at T-2, or unilateral vagotomy did not influence the emetic response. After double vagotomy, abdominal evisceration, rarely or spinal emesis cord resulted transection in response at C-7, to only enterotoxin mild retching administration. movements Vomiting of the fourth ventricle or pons. He conin vomitexplanadecerebrate Great vagal difimby is sensory and

could not be induced ventricle or by local after cluded structures the ing initiation center. This transection that the of the action

with enterotoxin injection of this brain of than be true, stem at by the staphylococcus

after trauma to the floor substance into the fourth the the action fact that anterior enterotoxin vagus) of the emesis border on enterotoxin of the

peripheral importance on the requires in

(presumably of emesis may

innervated but not

is of greater

is a direct




by pontile decerebration and tion if a satisfactory hypothesis Derbysbire and Ferguson cats and dogs by electrical ficulties in interpretation pulses motor generated stimulation by generally observed

by peripheral denervation is to be evolved. (50) produced vomiting regularly of the ventral since, not only

stimulation arise here

vagus trunk. are centripetal

but, secondary of thoracic and the

effects may be produced abdominal viscera. This

centrifugally latter possibility

strengthened onds was Ferguson no that when tion, longer

fact that a period of summation required to produce the vomiting that whenever apneustic breathing Borison and Fairbanks (24)

of approximately response. Derbyshire appeared vomiting found in the decerebrate

15 secand could cat

be elicited.

electrical stimulation stimulation of the these workers have

of the nodose ganglion may elicit vomiting at a time central end of the vagus is ineffective. In this connecdemonstrated that the nodose ganglion is the site of alkaloids (see with bilateral vagotomy, the below). vagotomy more frequent and and it may persistent be generis the

emetic action of the Vomiting is often alized vomiting. that the higher Hwang passage of barium They found that directly with the This is complicated agus, causes by food as a response a regurgitation that the regurgitated

veratrum associated the

et al. (114) made roentgenographic sulfate after section of the vagi esophageal stasis and retrograde extent by of paralysis an over-all of from the the of the esophagus tonic contraction which esophageal occurs paralyzed in the as a result esophagus.

studies of the esophageal at various levels in the dog. flow of its contents varied produced by vagotomy. of the denervated esophof a hypertonic the pharynx. of the they cardia Hwang pharynx maininto

to distention, vomiting



et al. suggest

of “irritation” Furthermore,






205 enhanced In contrast, to bilateral and intravenous cervical However, section of that Wang

tam the and

that sensitivity Borison


response (181) found


pharyngeal no reduction

stimulation after in early the death emetic

becomes vagotomy. threshold follows

to apomorphine

is increased

apomorphine It has long vagotomy Samaan

as a result of vagotomy. been thought that the to laryngeal shown that


is due (162) has

paralysis with consequent asphyxia. dogs survive in perfect condition after

the recurrent laryngeal nerves at their vagal origin. This investigator maintalus that death is the result of aspiration of food into the denervated trachea, which occurs during the vomiting resulting from vagotomy. Samaan kept vagotomized tracheotomy. omized cats the arytenoid indefinitely izing the dogs alive by the hand, slow combined Schafer asphyxia inspiration. vagotomy, procedure of glottal obstruction and On the other is due only to after cartilages double (163) believes resulting from He prepared by the simple that death in vagota falling together of cats w’hich survived procedure of cauter-

during cervical ligaments.





Alvarez of physiologists about the to report today. spite


considers that

it an he was

interesting unable to find

commentary a word vomiting. on this and effect and into activity

on in the


mental up reviewers in the by

processes to 1925, are able literature Alvarez. In the


behavior of the small bowel during that there is considerable material a great no clear part evidence bowel activity be conveniently type the and of it has been of cause and

The subject discussed is available

Indeed, of this,


concerning considerations. qua non

relationship of small This subject can (1) Is a particular or is nausea simply character of nausea different from emetic antiperistalsis normally cance in this regard? The reviewers have perimental reduced be added investigations to a minimum, that

to nausea divided

vomiting. three major the sine

of gastrointestinal response to stimuli of vomiting evoked effects precede attempted produced vomiting to limit by

of nausea (2) small Is the bowel signifiex-

which induce by stimulation other and the what following means? is its

vomiting? of the (3) Does physiologic



to those

in which participation if this is at all possible associated with

of psychic factors in the study of nausea. and frequent

has been It should rhythmic



forward licking nausea which, mild to severe.

in cats and dogs have long been considered according to some investigators, can be graded An additional but less frequent sign which the cat is a peculiar call. Of interest is the can be observed 87, of the 93, medulla

manifestations of in intensity from almost invariably which of “nausea”, in response of inis

heralds vomiting in not unlike its mating except Several parenterally for the cry to electrical stimulation

deep-throated vocalization fact that all these signs in the decerebrate cat administration.

of distress,

or to drug

workers (92, administered

167, 150, apomorphine

88, 144) have reported on the movements of

the effect the small

206 testine findings, panied changes in dogs. it is the While









is no consensus

close that

agreement the first

in the signs

various of nausea

experimental are accom-


by an inhibition of intestinal tone. in tone and motility (93). Gregory following parenteral in his experiments pedicle to constitute intestinal not contain (88). This and (97),

This may be (87) concluded

followed by variable that the response of dog is of nervous abolished by de-

the small intestine reflex origin since

apomorphine such responses an intestinal the efferent secretion in

in the were

nervation of the mesenteric more that the vagus nerves as well as for the increased the splanchnic testinal responses morphine even specific structure ing. caused morphine, scending duodenal odenal been intestinal still abdominal nerves do described induces evisceration

loop. He showed furtherpathway for this reflex response to apomorphine;

fibers finding, “vomiting”

which are concerned in the incoupled with the fact that apoafter gut denervation that presence signs nausea, neither of that of vomitwhether the of deand a unequivocally



form of activity in the small intestine nor even the is necessary for the manifestation of the premonitory in man, Ingelfinger of and Moss (116) showed by that by excitation is frequently duodenum. contraction, lumen reiterated reflex does is the semicircular accompanied by canals or a generalized

In a study

the administration contraction of

They stated that though possible, not always accompany et al. (1). of

the hypothesis is unlikely nausea. (130) cerebral

of nausea resulting from since narrowing of the duThis stated cortex, opinion that since the it has persists recently after labyrinthine-

by Abbot

Lebensohn the


transection of the mid-brain; nerves. Barclay (10) described curs and with the atropine, onset was

it is also not affected by section of the splanchnic in humans a reduction in gastric tone which ocof neostigmine and the nausea gastric Howthe and in-

of nausea. Wolf (190), using a combination able to prevent both the gastric inhibition in man. essential

evoked relaxation ever, the atropine, hibition in his of the nausea.

by vestibular stimulation and hypomotility are disturbing particularly of nausea. experiments sensation possibility on the Wolf stated

From this fact he claimed that to the occurrence of nausea. other effects of neostigmine system, might result in in gastric motility which since they of insufficient nausea antedated intensity the

remains that central nervous that changes nausea stimuli if

occurred the onset to cause conscious

did not and occurred is a moot

result from following





awareness of certain subcortical autonomic processes prodromal to emesis, then it can be argued that such processes, which also occur in the decerebrate animal (11, 18, 26), may be active in advance of cortical excitation particularly in situations of slow induction of nausea. This view is strengthened by the fact that in motion sickness the symptoms of drowsiness, pallor, cold sweating, and salivation with swallowing regularly precede the sensation of nausea (173). Indeed, Doig, Wolf and Wolff (52) reported characteristic symptoms of motion sickness, including in facial a pallor, tachycardia, weak pulse and finally retching and vomiting, of a rough plane journey. “decorticate” man In this man, irrigation subjected to of the external the stimulation auditory canals






207 although and with nystagHorstmann inhibition of than the of motility between concluded of the effect

with mus, (76) gastric nausea.



produced several the view which hand,

no minutes,

inhibition resulted. that inhibition they did stated on nausea

of gastric nausea

contractions is associated and the

lasting confirmed

Fuglsang-Frederikson starts before not believe that

of Wolf

contraction, On the other cause the of nausea. of various motor function

ends later inhibition exists They

is the
the that



no apparent and on cannot on has by been lateral these gastric

correlation motility. as a test



of the

stomach investigation cortex

be used the

of drugs on nausea. The history of intestinal Early sphere. activity workers There was

experimental of the cerebral their good on

representation by of the on

of gastroKaada cerebral the (117). hemieffects of

summarized surface investigators

confined no

studies agreement

to the

cortical stimulation areas of the cerebrum intestinal pyloric responses postcentral

gastric motility. More recently, the have been stimulated for the purpose 9, 6-8, 71). The general and tonus. Penfield and nausea vicinity resulting of the from sylvian finding Rasmussen stimulation fissure in

medial and basal of evoking gastrowas inhibition (155) described prehuman the porinof and

responses (1 17, antral contractions of salivation cortex in and the

of the conscious

beings. Abdominal tion of the island sular of cortex cases in had which

sensations of Reil and been stimulated. vomiting they or

were especially elicited from the one patient vomited a few minutes Penfield always and Erickson after were not stimulation of intussusception (154) occurred stimulation of

anterior after cited the

a number cerebral associated separated no producPenwhich

cortex. Furthermore, with nausea and points. tion field The of diarrhea and Erickson

these emetic responses resulted from cortical found no examples

necessarily at widely and


defecation (154) also

in response to stimulation described salivation, nausea

of the cortex. and vomiting

resulted from stimulation of the large the dural sinuses or from the sinuses responses are mediated via a vascular cerebral course It has been emetic tention the impulses, or irritation duodenum to reach the well established and is much that (4). brain stem. that the vomiting Indeed, more it has sensitive

veins that cross the subdural themselves. They suggested reflex pathway which follows intestine been than is a very follows demonstrated the stomach important (193, to 119, emetic

space to that these an extrasource of disthat stimuli.



intestinal 132)

Although vomiting may be readily initiated by stimulation of the duodenum and the small intestine generally, there is no reason to believe that the character of the vomiting is different from that produced by effective emetic stimuli acting elsewhere in the body. Alvarez (3, 4) has devoted much in the small intestine. in 1917, is given such discussion symptoms The syndrome comprehensive attention to the question of reverse peristalsis by him detailed

of reverse treatment

peristalsis, introduced in his textbook that Alvarez presence

of it is unwarranted that make one think

in this review. of the possible

(4) states: “Among the of mild reverse peristalsis

208 are vomiting, gurgles running coated tongue,








regurgitation, up the some

rumination, some types esophagus, nausea, perhaps of bad breath, a feeling

of heart some type of fullness

burn, belching, of biliousness, immediately strangling sensaof Alvarez conthe status of selected quotain is a the


after beginning to eat, some forms of hiccup and some of the tions felt about the cardia.” Despite the apparent certainty cerning the existence of reverse peristalsis and its consequences,



is far



as exemplified




tions from the literature. normal movement of the duodenum, conditions “Despite peristalsis coupled suggest that have an to ensure favourable the production

Bolton and duodenum.

Salmond (16) state : “Antiperistalsis Its effects are to delay the food with the digestive into the stomach.”

its admixture to regurgitation of emesis

juices, and to produce Mecray (145) states: contents no anti“These findings in any series we realize we



intestinal (150) state: of vomiting

was observed.” Oppenheimer with the appearance of bile that the activiy that we Mathur a previous

and Mann in late bouts


is antiperistalsis



is not proved.” observed that after of apomorphine

et al. (144) state: “In period of inactivity rapidly increasing

our experiments a few minutes contractions




pear, first in the jejunum and then in the distal and proximal odenum. As these contractions end in vomiting, and seem (sic), they are suggestive of antiperistalsis.” Ingeffinger and “Our are records pushed indicate backwards that into during the nausea stomach in nausea balloons even and though vomiting in the the

parts of the duto travel aborally Moss (116) state: duodenum waves conas

descending peristaltic can

tinue to travel aborally.” The role of the small follows. it may tion, found though testinal innervation production by in The intestine initiate nausea way


be summarized

is sensitive to emetic stimuli, and and vomiting, depending on the reflex pathways. Intestinal

impulses intensity contents are

arising from of stimulafrequently

of established

the vomitus, particularly following repeated bouts of retching. Alreverse peristalsis has been reported, the mechanism by which the incontents are regurgitated into the stomach is not settled. Neither the to nor even the presence of nausea and vomiting


of the small intestine is necessary a wide variety of means.



Introduction The mechanism of action problems attempts of emetic drugs has The to draw been one of the most been from perplexing utterly conanti-emetic coupled with incompletely conhas movements

and unrewarding founded by the

in pharmacology. of investigators

subject has conclusions

effects of substances the fact that the understood. clusions, after e.g., surgical that

which are pharmacologic the emetic of the an

emetic agents in their own right, actions of these drugs are only field acts has centrally been permeated if it tract. causes This with vomiting type

Furthermore, removal

unjustified of reasoning







after action. parenteral





workers is taken zone action there



extent of its

that central

vomiting emetic

administration With the chemoreceptor the longer which the concept tenable. causes

of a drug demonstration trigger of a direct Indeed, emesis, center. Hatcher

as proof

by Wang and Borison (180, 183, 28) of a specialized in the medulla, distinct from the vomiting center, of “central is, at present, chief or side (101) the drugs emetics” no good effect, published receptor on the does their on the evidence so by vomiting that direct any center stimulation studies on is no of the substance

as its and

vomiting In 1923,



location and the

of the vomiting center, interaction of various

sites for certain vomiting reflex.

emetic agents, This article has many years. On actions of drugs, pathways to acagents into was placed and sympaon

been the source of authoritative the basis of their experiments Hatcher and Weiss constructed count thetic anatomic lished markable sympathetic poisons, paralyzes impulses. a number by the for and the For pathways sympathetic was the afferents postulated example, with and suggestion only, antagonists. visceral

information on emesis for on the emetic and anti-emetic a system of autonomic afferent effects afferent However, of a variety fibers have no been restriction

peripheral types.

of emetic divided


the result that parasympathetic that whereas normal

both types autonomic afferent abnormal emetic

could traverse nerves. Even emetic impulses impulses,

the estabmore repass induced up the by

may traverse either path. Ergotoxine according to Hatcher and Weiss, the sympathetic type of afferent fiber; hence it blocks normal emetic In spite of the glaring lack of physiological evidence for such a system, of later investigators Weiss. of the analyzed their results after the scheme proposed arisen that from autoAs a consequence, endless confusion has unfounded and totally erroneous conception afferent as According are indistinguishable often to the However, well to

Hatcher and perpetuation blocking in the and

nomic mission somatic and and light

drugs selectively interrupt autonomic nervous system. afferent found investigations nerve fibers

as efferent transmodern concepts, morphologically work such of Hatcher in the an and underWeiss of perti-


pharmacologically. The reviewers have Weiss of more and recent

it necessary point-by-point is highly

to refer analysis desirable.

a thorough

of their


taking is inappropriate here. will be considered in separate nent drugs.

Instead, the experiments parts in connection with

of Hatcher the discussions

Apomorphine Thumas center had apomorphine (172) and later Hatcher and

and Weiss

Morphine (101) believed that the vomiting of the

been localized by the elicitation to the medulla oblongata. and after Hatcher removal

of emesis with This observation

topical application combined with

finding of Eggleston with apomorphine

(68) that vomiting of the gastrointestinal

movements tract,

are elicitable appeared to

210 constitute irrefutable center. However, two exclude remained nervous the








evidence problems

that apomorphine were unresolved.

acts First,

directly on the the experiments

vomiting did not

possibility of additional sites of action of apomorphine ; second, it possible that apomorphine acts on receptors located in the central system and not on the vomiting center itself. Proof that apomorphine act trigger directly zone on the has vomiting been center presented zone but on the (page closely 195). That situated chemoalready apomorphine demonstrated in response by chronic to



acts solely by Wang apomorphine, ablation copper Hatcher

on the medullary emetic trigger and Borison (183) by experiments given orally as well

was only recently in which vomiting was prevented

as intravenously,

of the chemoreceptor sulfate, on the other and Weiss They (101) believed

trigger zone. The hand, was not altered found that endings. center that ergotoxine ergotoxine

emetic responsiveness to oral by destruction of this zone. abolishes acts peripherally of This the emetic only action and on of

of apomorphine. sympathetic-type apomorphine

afferent on the vomiting

Hence the concept had to be modified.

a direct action they accomplished action afferent which impulses. that with

by making the assumption results in hyperexcitability The the inhibitory action drug reduces the inactivation view with is not

that apomorphine of the vomiting of ergotoxine normal influx the

has a strychnine-like center to normal

is then easily of impulses

explained by to the vomiting

assuming center

consequent lenged this emetic agent

of the emetic reflex. argument that the with the claim

Koppanyi and Evans (123) central action of ergotoxine of peripheral inhibition

chalas an of af-


ferent impulses in preventing the emesis induced by apomorphine. stration of a specialized receptor apparatus for certain central ing apomorphine, makes the claim for a strychnine-like action obsolete, but the mechanism of antagonistic action of ergotoxine

The demonemetics, includof apomorphine remains to be have action and since

elucidated. Effects of the ergot alkaloids on the central nervous system been reviewed by Nickerson (149). It is probable that the anti-emetic of these drugs is effected through direct brainstem depression. It is well known (see Hatcher (97)) that large doses of apomorphine, morphine, This effect are capable the of result inhibiting of fatigue the vomiting induced by trigger for five (Eggleston is not of the chemoreceptor zone

apomorphine. or six and vomiting times in Hatcher with to the sulfate abolishes

small doses of apomorphine succession without diminution (68)). morphine medulla persisted Koppanyi (121) was administered oblongata; the concomitantly. only the either emetic De

continue to elicit vomiting in emetic responsivity able to prevent intravenously response to oral Busscher (48) or by mercuric


local application chloride or zinc that morphine


the emetic effect not sulfate. This suggests emetic effects parenteral morphine copper sulfate. Leake induces vomiting

of apomorphine but also possibility of two separate Indeed, Dordoni (54)

of arsenious mechanisms differentially

oxide or copper for the antiinhibited with and oral morphine of vomiting to

of morphine.

the emetic actions (129) demonstrated approximately

of subcutaneous that although ten minutes,

apomorphine subcutaneous prevention







211 lasts for a number

emetine of hours. induced that appears phine

or apomorphine Leake emesis that is the




for about

an hour


has shown, furthermore, without causing vomiting prevents the vomiting the anti-emetic result of a direct

that morphine can inhibit apomorphineby itself. Gold et al. (83) demonstrated in response doses reticular 175) view reticular experiments to oral digitoxin in the cat. It of apomorphine formation. and of morThe facts that the yet depresses localizaand perof been action for


effect of certain action on the (174,

apomorphine respiration tion Wang of the (26,

reduces postural tone support such a suggestion. vomiting 180, 183). center However, in the


and that is consistent formation have

morphine with by not



formed which conclusively demonstrate the locus or loci of anti-emetic morphine and apomorphine upon drug-induced vomiting. Dose-effect data for both apomorphine and morphine are given variety (125). ject of animals in the monumental More detailed consideration of apomorphine-induced (64). subject The which vomiting present require action these in potency. apomorphine, to applied. effective dogs action (15) for and emetic Bernheim activities the dog Wang doses with of of review of Krueger, Eddy the historical development may be found in the review this light been their

a wide

and Sumwalt of the subby du Toit to indiscussion of recent as thoroughly general emetic opinion action

and Christensen phases of the vestigations. The mechanism investigated among except (101) ing effect strated evoke on

reviewers have reconsideration of morphine Nevertheless agents On are identical

in has the not in

of the that

emetic that

as has pharmacologists

of apomorphine.

it is the

for their difference showed that, whereas direct when that emesis application similarly normally in of and chronic

the other hand, Hatcher and Weiss morphine and heroine produce vomitcodeine exerts no perceptible demonfail to The (186) have intravenous trigger alkaloids (126) morphine. recently morphine ablation. is incompletely high suggested

medulla, and Glaviano of oral and

chemoreceptor other opium and Surles and


mechanism(s) elucidated. Bernheim anti-cholinesterase


demonstrated They


that a cholinergic mechanism might provide the basis However, Eggleston (67) showed that intravenous preventing vomiting due to subcutaneous apomorphine Furthermore, Cheymol and Quinquaud response to intravenous apomorphine floor of the fourth ventricle. Similarly, prevent the emetic action of apomorphine Hatcher is synergistic and Weiss with that (101) demonstrated but that of ouabain,

of action of central emetics. atropine was ineffective in or morphine in the dog.

(39) were unable to prevent the emetic in the dog by applying atropine to the Hatcher and Weiss (102, 103) failed to with nicotine. that the more emetic than action 50 per of apomorphine cent of the emetic Gold et al. (85) and demonstrated Gold emetic (79) showed of small action


of each is required to produce vomiting in combination. produced tolerance to the emetic action of cardiac glycosides a simultaneous that morphine cross-tolerance habituation to results apomorphine. in tolerance Previously, to the

212 doses of intramuscular large








apomorphine. doses




found daily

it in

necessary dogs in

to order




of apomorphine

produce tolerance to the emetic subcutaneous doses of morphine period sult of apomorphine apomorphine in contrast to the stands habituation. of intravenous

action of minimal intravenous doses. Minimal also became ineffective for vomiting during the Conversely, of Downs and tolerance Eddy to the (55) that emetic dogs. dogs action in morphine-habituated in response dogs given and of intravenous Glycosides were more their tract, action effective intravenous Hatcher digitalis and of the by vein Eggleston bodies than by (98) repreexperithat

developed finding



ated to large doses of morphine vomited which were ineffective in non-habituated Co were Tui not showed tolerant further to the that emetic both morphineaction Cardiac From mouth, the and surgical the the facts that removal “irresistibly” that emesis digitalis promptly of the that the bodies followed emetic gastrointestinal

to doses of apomorphine small doses of morphine. dogs pilocarpine.



in dogs is exerted

upon sents mental those


vomiting center. A statement from the same article actually only reasonable conclusion which could be derived from these facts: “Our experiments on eviscerated dogs proved conclusively bodies which we employed movements, tract.” (Italics in this way are capable


of inducing

emesis, or nausea and vomiting the action on the gastrointestinal

in dogs without the participation of are those of the reviewers.) Nevermentioned and Egexerted
. .

theless, in 1927, Hatcher and Weiss (102) in referring to the above work enlarged on the significance of the results, as follows: “Hatcher gleston. on the
. .



the tract

emetic regardless


of the of the mode



is not


of administration.

Obviously, the only gastrointestinal tract nervating some structure diminishing expression. To return was emetic and that further with agents Weiss (100) the digitalis obtained the

way to exclude is to eliminate or structures of the

the possibility of an emetic action the emetic response to digitalis other than the gastrointestinal tract, center or interfering action concluded the vomiting of digitalis, (69). Indeed, that with this from practically center.

on the by dewithout its motor concept results all Hatcher



This has not yet to the question entrenched evisceration in common reversed bodies in by

been accomplished. of a central emetic Eggleston experiments, use act directly and Hatcher they upon


position, for reflex nausea Their bodies when

digitalis at least, and and vomiting through

they claimed stimulation

of afferent fibers (1) The application apomorphine interruption prevented bodies. Failure

the heart. of digitalis vomiting

conclusion was based on to the medulla was without administered in this way.

two main facts. effect whereas (2) The acute

induced of nervous nausea and to elicit

connections between the vomiting after the injection by topical application

heart and the medulla always of moderate doses of digitalis to the medulla, although







213 constitute proof alteraor the site site among appeared cardiac accepted acthe of


is an


of negative



does undergo it active


for a number of reasons. For example, tion after systemic administration chemical after emetic many to be tivity local action which the and properties application. is weakened are denervated receptor of these toxicity of digitalis The second may

digitalis may which renders prevent argument the and its cited heart cord bodies and

a metabolic centrally the receptor for a cardiac

access above is but section.


by the fact that by vagotomy site for drugs. the Eggleston

one structure The heart to (70) the



owing Wyckoff

conclusions of Hatcher action of digitalis was believed invariably that this preceded (67) of

and Weiss, and discarded in favor

Eggleston’s original of the cardiac reflex by the in their fact that patients.

view of a central mechanism. They cardiac to toxicity the and fact Acfollowed that its

action was demonstrated the production of emesis and Hatcher the cardiac the idea the that almost and glycoside Weiss

Eggleston emetic action Weiss that cording logically anti-emetic type afferent Dresbach emetic reflex. (101) ergotoxine

(101) were atropine. site of emetic

unable However, action

inhibit Hatcher with the


of a cardiac prevented




to these workers, from their claim action endings. and Waddell They showed

concept of a cardiac ergotoxine acts only through very soon a selective challenged

reflex mechanism peripherally, and paralysis the theory vomiting

is accomplished (61-63) that

of sympatheticof the in cats cardiac after



thorough denervation for recovery from the is the critical difference (97). Hatcher denervations Hatcher ganglionectomy Dresbach thetic response cardiac chains to and as and

of the heart, provided that sufficient time was allowed immediate effects of the operation. This last qualification between Dresbach’s experiments and those of Hatcher (102, 103) questioned by Dresbach and originally more for obtained clearly fact accurately cardiac by Dresbach that attributed of sympathetic denoted innervation and the as a means the completeness Waddell. This is great cardiac the (37). Waddell cardiac importance denervation upper The thoracic consistent (62) after 99) innervation of the surprising to cardiac since stellate whereas sympaemetic chronic is not placed route of

and Weiss performed Weiss alone Waddell pathways digitalis (101)



essential to digitalis-induced great importance on the

vomiting. Hatcher that Dresbach used

et al. (102, 103, the intraperitoneal

administration for strophanthidin, and that nicotine prevented elicited by intravenous and intramuscular strophanthidin but not followed intraperitoneal administration (66). The inhibitory effect was attributed to a selective paralysis of afferent endings in the sumably of the supposed to act intraperitoneafly, blocked strated sympathetic to induce induces type, vomiting. vomiting support

the emesis that which of nicotine heart, pre-

upon which the cardiac glycosides were They claimed that strophanthidin, given by local irritation and hence cannot be idea

by nicotine. In that strophanthidin

of this combined

Hatcher procaine

and or

French cocaine,


demongiven in-

214 traperitoneally, phanthidin anesthetic action, at








given the

was less alone.

effective in The rationale irritation absorbed

eliciting emesis after for this procedure and the nicotine strophanthidin.

nicotine was that prevented these

than the the

strolocal emetic

prevented heart,

peritoneal of the



did not report control studies with strophanthidin caine or cocaine, but without the prior administration Dresbach has shown that emesis may be elicited with various (49), cord They routes in pursuing the pathway concluded of administration the cardiac of afferent that impulses after reflex cardiac from chronic cardiac

in combination with proof nicotine. In any event, digitalis glycosides through denervation. Davis et al.

theory, attempted to localize in the spinal impulses initiated by digitalis glycosides. the heart are transmitted via the anterior after vagotomy, (60) who showed prevent for the prevented emesis. that chronic cord

columns since acute section of these columns, This claim has been countered by Dresbach section That emesis 183). the combined cardiac


vagotomy does adequately by Fukuda is the

does not not suffice

digitalis-induced vomiting. abolition of digitalis-induced a number of workers (96, 94, (77) once more claims that

has been quite A recent report cardiac innervation

confirmed by and Kushizaki essential emetic





this above after re-

work was performed in the acute animal preparation, to which all the mentioned criticisms apply. The inhibition of digitalis-induced vomiting acute denervation of the heart may be explained on the basis of temporary duction in the central excitatory a consequence of interruption citatory impulses. For example, tion, but in time the respiratory it is probable animal, result center to its out that not enumerated action. Dock in the that compensatory

state of the medullary reticular formation as of pathways from sources generating tonic exsection of the vagus causes a slowing of respirarhythm returns to its original rate. Similarly, phenomena, in the chronic denervated-heart

in a restoration of the central excitatory state of the emetic preoperative level. Nonetheless, Wang and Borison (183) point until all the receptor sites for the emetic action of digitalis are can the heart be excluded more

as one
digitalis and Wood

of the

possible in

sites the this

of emetic liver work than and


remains et al. (51) of the

to be done. showed that pigeon. action arises

accumulates (96) extended


claimed that the of a vagus reflex trated in the liver, vomiting was still on cats hepatic tine, but confirmed denervation neither

emetic which

of digitalis in the pigeon consists predominantly from a local irritant action of digitalis concensecondarily from after hepatectomy. digitalis Hanzlik was how other abdominal viscera, because Dresbach (56), in experiments continues to induce emesis and Wood (96) found that effective extensive in preventing the denervation after nico-

but also elicitable

the finding that or hepatectomy. atropine found nor that

ergotoxine, no matter

digitalis of

emesis in the pigeon. Dresbach (56-60) thoracic and reflex provided this basis, he

abdominal organs, cardiac glycosides good recovery had occurred from assumed that digitalis elicits vomiting

could excite the vomiting the surgical procedures. On through a central action,






215 fact remained application showed cinerea, that the that prein-

although digitalis

he realized substances

this was not proved. The disturbing did not induce vomiting after direct 101). However, directly applied to subsequent Hatcher to the and region


medulla oblongata (60, large doses of digitalis vented jection digitalis Borison glycoside following demonstrated Nevertheless, could still be (21) substantiated more but that with the vomiting in

Weiss (101) of the ala or




of digitalis. Koppanyi (121) reported, as an incidental observation, that did not elicit vomiting following chronic damage to the ala cinerea. and Wang (28) found that the prompt vomiting response to intravenous was invariably abolished in dogs of the which were refractory trigger to apomorphine zone. This finding of digitalis. (1-8 hours) Borison furtherbe elicited that chronic destruction chemoreceptor

the existence these workers elicited the emetic

of the long-debated observed that

central emetic action a late emetic response

infrequently after near-lethal intravenous central action of digitalis, in the cat, and response sensitivity following after trigger oral digitalis zone ablation. could He

doses. showed still suggested


the late response to intravenous same peripheral receptors which Pinschmidt (157) found that

glycoside is probably mediated through the are stimulated by the oral glycoside. vomiting initiated by digitoxin is not abolished of the comthat impulses

by removal of the carotid bodies and sinuses and by denervation parable aortic structures in the dog. He suggested the possibility may arise from any one denervated in the same Borison and Brizzee (19), section vomiting. receptor possibility with Eggleston massive of the carotid of several structures animals to abolish in one cat, confirmed and aortic nerves

all of which would have to be the emetic response to digitalis. the finding of Pinschmidt that not prevent digitalis-induced


In addition, they showed trigger zone was effective of a local gastrointestinal

that a subsequent lesion in the chemoin preventing the emetic response. The irritant action in the elicitation of emesis, glycosides, had already been discounted by it is generally accepted that of inducing emesis by such an with moderate investigations (80), time by that intravenous oral doses of of Gold, et al. methods, had been resulted route vomiting

moderate and doses

Hatcher of these

of oral


(68) in 1912. Nonetheless, substances are capable by action the

action (68). the cardiac

The question of a local emetic glycosides has been reopened workers glycoside the demonstrated to induce tract in emesis


These from

the by at

cat the the






from the oral administration of the substances. irritant effect of certain glycosides (scilliroside, A) was the chief if not the sole mode of emetic by occur the oral as long route, and that hours

They claimed that the local lanatoside C, ouabain, scillaren action of these drugs when given for This vomiting group which of investigators local emetic in the cat that unaffected by to oral may



is responsible

as eight


(89, 81) more recently reported observations action of digitalis glycosides in man. Borison the emetic responsiveness to oral which lanatoside resulted chronic

on the postulated (21) demonstrated C and scilaren emetic A was



in marked


216 copper While sulfate. these Wang findings








and do not

Borison exclude

(183) an et al. causes

substantiated irritant action

these on the

results gut,

in the they

dog. essen-

tially contradict the mechanism by which

claim of Gold oral glycoside

(80) that local irritation emesis. If the postulated

is the chief local enteric

action actually occurs, gut denervation should result in a marked reduction in sensitivity or even abolition of the emetic response. This was not the case, since no diminution in emetic sensitivity could be detected. White and Gisvold (188) administered larger doses of lanatoside C than were (80) yet they did not obtain vomiting in cats after the This was used as an argument, but without justification, in the acquainted mals are gastrointestinal with restrained the tract. in the It supine the is apparent fact position normal that (97). cat that White vomiting Borison which were long-established latency in et al. (80). reported expected against and (21) in by Gold et al. latency period. a local action were when data agreement not anion

Gisvold reported close

is inhibited

dosage and emetic with those of Gold Ostling of man.

(151) reported He found that

the effects of large digitalis only 2 out of 50 patients


on the congestive

empty stomach heart failure that has the argued hence A study a

local It poorly action that the

after irritation appears developed

taking 1.0 gram of digitalis at 6:00 A.M. He concluded rarely follows oral administration of digitalis. from the work of Hanzlik, and Wood (96) that the pigeon central with that receptor of other apparatus emetic for agents emesis. in the to direct must be with By pigeon, comparing they

of digitalis the seat

central emetic mechanism of emetic action of digitalis

is insusceptible in the pigeon

stimulation; peripheral.

of medullary morphology in the pigeon in comparison susceptible animals is greatly to be desired. Gold et al. (84, 85) reported the very interesting repeated simultaneously doses of the increasing digitalis the glycosides intensity may of the depress cardiac


of apomorphinethat after to produce significance frequently reflex an while initial emesis is the had for from

observation the vomiting poisoning; may fail Of great was found

period of vomiting, and may even cause fact that, during to seat developed the exact

the continued death without experiments with

administration further vomiting. digitalis, it



apomorphine. Gold et al. (84, 85) claimed no direct evidence of this inhibition of the vomiting reflex; but they suggested,

the then prevalent idea of the cardiac reflex emetic action of digitalis, that the suppression of vomiting was probably also due to a peripheral action. However, in view of the demonstration of a central action of digitalis, it appears more likely receptor In that the trigger inhibitory effect occurs zone or at the vomiting the digitalis central A local under the emetic of emetic most glycosides either center elicit at the proper. medullary by acting emetic at more chemothan chemotract is innervation been excluded.



one receptor site. The receptor trigger zone. probably is not The insignificant essential peripheral to site(s)

site of emetic irritant action circumstances. its reflex, action

action is the medullary on the gastrointestinal While the has cardiac not



to be discovered.







Copper Copper such doses sulfate may be considered and zinc expression the sulfate.

Sulfate prototype The of peripherally-acting action of minimal irritation effective mediated emetics oral via 202). dogs after

as mercuric is probably

chloride a pure

of gastrointestinal

visceral afferents However, Wang that large doses absorption, Dogs which tion did Koppanyi jected into He attributed not

in both the vagus and sympathetic and Borison (181) have demonstrated of oral copper sulfate are capable

nerves (see page in gut-denervated of inducing vomiting, chemoreceptor in addition of oral dose copper of copper

by a direct action on the medullary were subjected to trigger zone ablation vomit (122) in response showed that to even an lethal doses emetic effective

trigger zone. to gut denervasulfate. sulfate 3 hours action inlater. of the

a duodenal loop of a dog was ineffective if repeated the failure of the second dose to the astringent

drug. Koppanyi (122) also found that the injection of atropine fistulas prevented retching and vomiting to copper sulfate intestinal loop, whereas intravenous atropine failed to do so. can On probably the other be explained hand, to copper sulfate on the placed Quinine Eggleston center removal to induce in the tion was dog. and Hatcher (69) believed basis tartrate of the local loop. anesthetic administered ergotamine locally

into the duodenal instilled into the This phenomenon action did of atropine. not prevent


in a jejunal and that

Quinidine quinine acts agent Hatcher that showed medulla directly on the vomiting

because of the vomiting

the vomiting gastrointestinal by the and direct

response to this tract. However, application (72) demonstrated They to the

persisted after surgical and Weiss (101) failed to the chronic medulla cardiac oblongata denerva-

of quinine



not ineffective

prevent quinidine emesis. on direct application

further (73) that quinidine of the cat, that nicotine

prevented quinidine vomiting, that atropine failed to prevent the vomiting, and that ergotoxine largely prevented the vomiting; in short, the emetic action of quinidine resembles that of digitalis in its susceptibility to pharmacologic agents. Ernstene and Lowis (72) found that bilateral vagotomy but high and spinal evisceration cord section failed to prevent the emetic prevented vomiting in most response cases. Veratrum Eggleston vomiting center gastrointestinal reflex emetic and Hatcher because tract action (69) it could concluded still evoke they to quiidine,

Alkaloids that emesis veratrine after acts surgical the directly removal possibility and Weiss and sulfate Swiss on the of a (101) to the (169)

of the

in dogs; however, from the alimentary

did not deny mucosa. Hatcher

failed to evoke vomiting dog medulla. Christiansen expressed the belief that action. Borison and after chronic ablation

in dogs by local application and McLean (40) and veratrum derivatives that (25) found chemoreceptor

of veratrine Marsh (142) elicit emesis


a central

Fairbanks of the

veratrum trigger zone

alkaloids elicit emesis and after more com-

218 plete cerebrate structures Of all the deafferentation nodose emesis. ganglion emesis, prevented (25) associated In destruction cats to nonessential








of the a series

area of to the

postrema. neurological vomiting

These reflex

workers procedures

(74, by the

25) veratrum

subjected to eliminate alkaloids. to above


designed were tantamount of the vagus


procedures of the

utilized, which compositely lower brain stem, interruption the essential of maneuver for on cats, neither vagal the ganglion interfered

total the


abolishing section with

veratrum-induced below the nodose the elicitation of invariably Fairbanks nervous and to cat, oral

chronic experiments nor decapsulation the interruption emetic that the


of the vagus above the nodose ganglion response to veratrum alkaloids. Borison and the nodose site of emetic ganglion and and action is not of these located alkaloids in the central

concluded with

is intimately

system. Swiss respectively, veratrum. after intravenous administration Pilocar’pine, These drugs

(169) and Borison that gut denervation and veratrum injection, of veratrine, Pituitrin, are

Fairbanks (25) does not prevent album do not emesis as a result

showed for the dog the emetic response produce vomiting


in pigeon,

but violent presumably Posterior as Pituitary, a class

occurs after intraperitoneal of local irritation (51, 96). and fail to Physostigniine produce vomiting

Acetylcholine because all

considered to the elicits

by topical application but, surprisingly, each

medulla vomiting

oblongata and/or

(vomiting center of Thumas); nausea when injected into the to any these agents is completely of the parenteral routes in they vomiting dogs by in the direct cat, or

lateral ventricle. Moreover, prevented or inhibited by by direct Hatcher administration and Weiss of pilocarpine They found that

the emetic response atropine injected by lateral unable medulla

into the (101) were to the ergotoxine

cerebral ventricle. to evoke vomiting oblongata, but pilocarpine

application instead.




but mercuric chloride remained effective showed that atropine and ergotoxine piocarpine but vagotomy did not. These basis drugs limited Hatcher in that The time lack of their scheme for autonomic thereon, to the that the emetic action sympathetic system.

in causing emesis. Furthermore, they both inhibited the emetic action of investigators (101) concluded, on the transmission and the effects of is exerted on afferent endings was subsequently reiterated by an apparent efferent (121) paradox nerves.” at failed that to

afferent of piocarpine This claim

and Weiss pilocarpine of knowledge the with mercuric multiplied

(103) at which time is a typical stimulant of the pitfalls pilocarpine chloride physiology of such in dogs remained

they pointed out of “parasympathetic of neurohumoral

transmission Koppanyi lesions emetic.

interpretations. with chronic an effective

cause vomiting although oral

in the medulla, Local application

of morphine to the Thumas area likewise prevented pilocarpine vomiting. These facts stand in contrast to the earlier findings of Hatcher and Weiss (101) that local application of pilocarpine to this region failed to evoke vomiting. Cushing (44-47) lateral obtained ventricle prompt of the vomiting in man by brain. Prior injection injection of pilocarpine of atropine by the into same the route






219 Henderson and








Wilson (104) but not with in the monkey prevented the

elicited vomiting in an unanesthetized subcutaneous piocarpine. Light and

infant with intraventricular Bysshe (131) induced vomiting Quinquaud (39) dog by applying of three possible

emetic floor

intraventricular pilocarpine. Cheymol and action of intravenous pilocarpine in the of the fourth ventricle. vomiting may be explained on the basis

atropine to the Pilocarpine-induced

mechanisms. According (127) pilocarpine acts Koppanyi intravenously T-2. either trigger applied nicotine Koppanyi surgically zone locally administered (28). to and Evans after (121)

to Hatcher and Weiss (100, 101) and on the heart to produce vomiting (123) obtained vagotomy the and medulla by local vomiting with emetic the Quinquaud oblongata. application in cats. On intraventricular vomiting and region response later (39) Koppanyi to the the medulla with transection shown did piocarpine of

Kwit and Hatcher reflexly. However, administered spinal cord at by inactivating chemoreceptor with found the atropine the

bilateral abolished morphine Cheymol the

to pilocarpine to be the likewise (122) reduced

or with




of pilocarpine-induced have induced vomiting produced this pine inhibited the intravenous It seems unlikely vomiting medulla effect by the emetic injection

other hand, numerous workers pilocarpine which, presumably, hypothalmic intraventricular for nuclei. Atroas well as piocarpine. It is

stimulation response of pilocarpine. the heart

of subependymal elicited by the as the site


to discount

of action

that injection by diffusion since direct might

of pilocarpine into the lateral ventricle should result in of this substance to the chemoreceptor trigger zone in the application to the latter region fails to elicit vomiting. On predict that decerebration retching in man, prior would abolish the emetic response

this basis one to pilocarpine. Cushing injection elicited cerebral to posterior intraventricular elicited no

(47) obtained of posterior such response. ventricle

prompt pituitary The

and vomiting with the whereas intravenous of atropine prevented either the to obtain monkeys pilocarpine is not surprising Hatcher

intraventricular administration into emetic vomiting although administered in view and Weiss (101) the lateral response with they in of the

injection completely

or subcutaneously

pituitary. Light and posterior pituitary in one out with The failure

Bysshe (131) failed in unanesthetized animals pituitary with in general.

vomiting manner. insensitivity

of four posterior


of monkeys

to emetics

failed to evoke vomiting by medulla. The same arguments vomiting Cushing posterior

local application presented above well for prevents is not

of posterior pituitary for the mechanism posterior the emetic pituitary. response as by cat. vomiting to evidence injecting Henderson acetylcholine

to the dog of pilocarpine The finding to intracerebral for a direct of

may be applied equally (47) that tribromoethanol pituitary and pilocarpine

convincing of nausea

action of these agents Silver and Morton into (104), the on lateral the other

on the hypothalamus. (166) obtained signs of the hand, regularly elicited

acetyicholine and Wilson injected



220 into seconds vomiting for the lateral after with








ventricle administration. or subcutaneous intraventricular of approximately


unanesthetized This response, atropine. physostigmine 10 These

man, while

sometimes in progress,

as was likewise

early abolished

as obtained

30 by

intraventricular a period

investigators the demonstrated

although They





a synergistic

action of substimulant doses of physostigmine choline. Hatcher and Weiss (101) had previously has no perceptible effect on the vomiting center. deglutition vomiting. physostigmine by The obtain the applying acetyicholine in response or prevented with the intraventricular species insensitivity to the deglutition and abolished vomiting However, importance injection,

and intraventricular acetylclaimed that physostigmine Miller (147) obtained repeated obex Light the but was and monkey caused did not report by (131) emetics by augmented Bysshe to


to acetyleholine by atropine. of



acetylcholine Methacholine administration

in the



minimizes intraventricular dose

of this finding. whereas subcutaneous

vomiting of an equivalent


failed to evoke of neostigmine

emesis (104). administered

Kremer (124) intrathecally

elicited vomiting with large by lumbar puncture in unof

anesthetized spinal block, level. small similar He

human beings. Since this response the author placed the emetic action found that intrathecal acetylcholine

could not be elicited in cases of neostigmine at a supraspinal alone had no effect. However, in combination ubiquitous action mentioned

amounts of acetylcholine and neostigmine to large doses of neostigmine. The the emetic effects of the above

produced effects of atropine in cholinergic agents a


suggests that this substance acts to block transmission from the hypothalamus to the vomiting center, perhaps at a number of interneural synapses. Such view is compatible with recent hypotheses of the role of atropine in modifying central nervous function. Tartar Thumas dog by (172) direct and application that then Hatcher tartar and of tartar Weiss emetic induces mainly to Emetic (101) to failed the vomiting by way induced these to induce medulla vomiting in the Hatcher impulses They were


and Weiss claimed in the heart which

finding nerves.

emetic upward,

by initiating of the vagus.

unable to explain their by way of sympathetic induces tartar emetic atropine of large significantly showed lesions that in the vomiting emetic are

that impulses According

by digitalis travel mainly workers tartar emetic also of

by a local action no longer effective, is apparently

in the gut. regardless effective

After vagotomy small doses of the route of administration. in preventing vomiting to tartar



given by any route of administration. in any dose is capable of preventing doses of tartar emetic into a loop affect the emetic tartar although action of intravenous medulla

However, neither vagotomy vomiting following the introduction of the duodenum. Ergotoxine does oral tartar emetic. Koppanyi ineffective following copper sulfate orally

nor not (122)

emetic became zinc sulfate and

chronic elicited






221 when apomorphine such application in as digitalis to the in animals the case of abolishes the to elicit resembles digitalisthe








emetic a medullary the type vomiting



failed to elicit vomiting in a dog with Tartar emetic apparently represents and pilocarpine, but which which fails

lesion. of emetic by

agent, direct



produce vomiting


to cause

by systemic trigger whether

administration zone. As decerebration

with chronic pilocarpine, response vomiting pilocarpine induced vomiting parenteral

lesions in the chemoreceptor it has not yet been established

to tartar emetic. in the decerebrate in that both are vomiting is unaffected to both digitalis administration

Digitalis, on the other hand, continues but otherwise intact cat. Tartar emetic antagonized by atropine; on the other hand, by atropine. In contrast, ergotoxine and pilocarpine; of tartar emetic the effect of ergotoxine has not been reported. and Cephaline) alkaloids may of ipecac elicited

prevents on subsequent

Ipecac According have a dual central action Presumably, demonstrated Leake (129) emetine in the tion of emetine both cause duodenal although and ministered prior direct they emetine. action similarly vomiting; inhibits concluded Although of emetine in the on the emesis. loop this to Eggleston action, such and that

(Emetine Hatcher an emetic

(69) the response


probably through


as well as through these two mechanisms that atropine showed that

a reflex action are capable prevent prevents (101) They

from the alimentary mucosa. of synergism. Eggleston (67)

did not morphine

vomiting to intravenous emetine. the vomiting to subcutaneous induced vomiting later concluded in atropine cephaeline by the emetic the by direct applicathat emetine acts to a

dog. Hatcher and Weiss to the dog medulla. vomiting Koppanyi prevented response (39) were

center and peripherally (122) found that the was able vomiting not prevented to prevent to

gastrointestinal tract introduced locally into given action by the of same emetine, route atropine. Cheymol




either intravenously application of atropine that oral atropine, but not following ipecac

or by local application to the medulla, by the to the floor of the fourth ventricle. In addition, induces vomiting applied only to the by means of the absorbed the emetic act inhibit medulla, inhibits


that of apomorphine, emetine and respects: (a) intravenous atropine by local application to the medulla;

apomorphine fails to (c)

(b) emesis vomiting.

is elicited


Nicotine From tract, vomiting reduced (101) They results Eggleston with and animals Hatcher subjected (69) to surgical concluded that removal nicotine that nicotine. of the acts gastrointestinal directly on the atropine and Weiss dog medulla. in contrast

center. In the incidence elicited were vomiting unable to

1916, Eggleston (67) showed of vomiting to intravenous by the inhibit direct application action with

intravenous Hatcher to the This stands

of nicotine atropine.


222 to the finding of

















floor of the fourth Nicotine abolishes strophanthidin nicotine is on intravenous mercuric vomiting initiated

ventricle prevented the emetic action Hatcher endings without Dresbach (60)

the emetic action of intravenous

of intravenous nicotine. but not intraperitoneal of to

(103). afferent digitalis

and Weiss in the heart affecting the

(103) concluded that the action because it blocked the vomiting emetic on the action basis that of intraperitoneal produces nicotine



and yet does not block its own action, that the impulses for emesis by nicotine and the cardiac glycosides arise at different points. Hatcher reported bodies fact for in that the that nicotine the dog. It nicotine cardiac site had but is therefore little quite influence on surprising the emetic that these

and Weiss (103) action of digitalis workers used the cat as an argument

inhibited digitalis-induced emesis in the of emetic action of digitalis, especially similarly to the activity of lobeline substances is lacking. digitalis glycosides. and nicotine, it is are identical although

since the cat and the Because of the similar often presumed that evidence the experimental

dog respond pharmacological emetic for such actions


of these

a similarity Ergot Alkaloids that

Eggleston center removal hand, directly,








on the by on vomiting

vomiting surgical the other center to other and of

because the emetic response to this agent of the gastrointestinal tract. Hatcher claimed and that that ergotoxine any to inhibitory has no perceptible effect it exerted

was not prevented and Weiss (101), effect on the on emetic


substances is due Evans (123) failed ergotamine dose is application responses oral large copper doses to the smaller

the depression of afferent nerve to produce vomiting in the dog but they found effective as that the the minimal of ergotamine ergotamine to tartrate intravenous

endings. by direct emetic dose.

Koppanyi application intracarotid Furthermore,

medulla, than


of large doses to intravenous

to the medulla suppressed well as apomorphine and Like morphine, vomiting in dogs response to evoke and ventricle but did

the vomiting digitalis, but small and but cats. bilateral demonemetic with the not In ad-

sulfate continued of ergotamine morphine ergotamine. and spinal ergotamine to intravenously

elicit emesis. produced vomiting was able Cheymol fourth drugs the

addition, ministered vagotomy strated responses that

prevented the Ergotamine cord section instilled into

to subsequently emesis after Quinquaud prevented not interfere (38) the

at T-2.


emetic action of electrolytes the chemoreceptor trigger indicated that the vomiting

given orally. It appears that zone since a positive response center was active at the

ergotamine depressed to oral copper sulfate time that apomorphine

failed to cause emesis. The depression by morphine of ergotamine-induced vomiting cannot be considered evidence for the site of emetic action of ergotamine since morphine probably depresses the medullary reticular formation which includes the vomiting cente’r. However, it has been demonstrated recently by Wang and Glaviano (186) that intravenous Hydergine, a mixture of dihy-






223 chronic ablation

drogenated of the

ergot medullary

alkaloids, emetic


to cause

vomiting trigger zone.

in dogs



Atropine Hatcher application the intact has no atropine pilocarpine, as well as that and Weiss of atropine animal. They effect on the applied to emetine, (101) failed to to the medulla claimed, induce vomiting although toxic that atropine in dogs by doses elicited in moderate (39) emetic it did to the direct emesis in amounts found that action of not prevent ad-


vomiting center. Cheymol the medulla of the dog nicotine locally to and methylene applied intravenous

and Quinquaud antagonized the blue administered but or medulla;

intravenously, electrolytes

of emetine response

to the

the vomiting in ministered orally.


Aconitine From concluded confirmed application results that with aconitine evisceration acts directly experiments, on the Eggleston vomiting center. and Hatcher This belief (69) was

by Hatcher of aconitine

and Weiss who to the medulla. on the Eggleston prior heart (67)

induced vomiting Nevertheless, these because failed with

in dogs by investigators

the direct believed reduced to intraand Weiss

that aconitine also acts its emetic effectiveness. venous (101) aconitine prevented by the

stellate ganglionectomy to antagonize vomiting of atropine. ergotoxine. Hatcher They

administration emesis




confirmatory Hatcher and with nicotine A comparison with regard antagonisms. mechanism peripheral

evidence for a peripheral Weiss (103) attributed the to a slight depression of the of aconitine to the ability It would of action;

action of aconitine. On the inhibition of aconitine-induced vomiting center caused

other hand, vomiting nicotine.

by the

with apomorphine to induce vomiting appear, therefore, this remains emesis that to

reveals a number of similarities as well as to pharmacological these be from agents proved. have a similar a demonstrated. Certainly,



in aconitine-induced Staphylococcus

is far

Enterotoxin of vomiting He showed inhibited that or in response morphine delayed to staphyprevented the emetic

The lococcus the


definitive and

work is that that

on the ergotoxine

mechanism (13). severely


of Bayliss


response. On the other hand, atropine failed to antagonize the response. The direct application of enterotoxin to the medulla failed to induce vomiting, whereas the intraperitoneal injection of enterotoxin in the same animal elicited vomiting. Spinal cord section did not prevent the response but emesis rarely occurred enterotoxin posterior in progress. invariably following vagotomy. None of seven cats vomited stem the The in response to of the it was for after decerebration. Transection of the brain hypothalamus abolished the enterotoxin-induced Extensive prevented destruction vomiting of the in response obex including to enterotoxin. at the level emesis while nucleus only support


224 the contention








of a peripheral




staphylococcus However, the same

enterotoxin these objections experiments apply

was as

the marked reduction in vomiting after were performed in acute preparations, outlined in with regard vomiting response that the the section on digitalis. to decerebration, it was reported

vagotomy. to which

Although is noteworthy following

similar that

objections may be raised not a single instance of whereas It is possible, in the forebrain. Drugs which only fragmentary their mechanisms the emetic therefore,

to enterotoxin

decerebration vagotomy. is situated

was not invariably site of emetic action Miscellaneous

prevented by of enterotoxin


Under information emetic or cats brucine, These and successful Byashe histamine,


heading are is available

considered to give

those drugs about some hints concerning (101) to the evoked medulla choline, vomiting Magnini


action. Hatcher by the local picrotoxine, workers evoked to the evoking obtained the in (131)

and Weiss application sodium “nausea” medulla. vomiting vomiting a considerable

emesis in unanesthetized dogs of the following substances: epinephrine and by the application and by with hour). Bartolomei histamine. of cocaine (139) were and period through in the caffeine,

salicylate. but not However,


with strychnine in one monkey delay (one

this technic. Light cerebral intraventricular The long latent


suggests that the cerebrospinal dog with the

histamine acted at the medullary fluid. Hatcher and Weiss (101) medullary application of

level after diffusion failed to evoke vomiting the following agents:


creatine, guanidine, and thyroxine. Sadusk et al. (161) failed to evoke vomiting in the dog with sulfapyridine administered by this technic. Hatcher and French (99) reported that atropine antagonizes, to a variable extent, the emetic actions of intramuscular magnesium chloride, intravenous but not oral potassium arsenite, interferes distinctly hypertonic mustard, structures mustard vomiting cerebral mediated not and with oral the hypertonic emetic sodium action atropine Preliminary emetic in chloride. They also magnesium found that chloride, nicotine and is of intramuscular

more active than sodium chloride. methyl are failed to bis essential cause

in antagonizing the studies by Brand amine, action chronic have revealed drug. of this decorticate

emetic action of oral et al. (30) on nitrogen that cats certain and forebrain nitrogen furthermore, Intravenous

($-chlorethyl) to the vomiting

was evoked in cats by local application of nitrogen mustard to the cortex. Unlike pilocarpine-induced emesis which probably is also by cerebral structures, the vomiting response to nitrogen mustard is by atropine.


The of the the

authors nervous

of this


have The

attempted The action emetic

to reorient proposed of a drug

the new

conceptual concept cannot be

meaning is based considered on

mechanism considerations:

of vomiting.


a “central” action unless localized within the central

the specific site of emetic nervous system. There

stimulation is at present

is unequivocally no good evidence






225 center. All

that emetic through at





by is known, regardless

a direct


on via these



responses, as far as the vomiting center or central

are mediated of whether The vomiting

reflex arcs which pass responses are initiated center is located in the




reticular formation with neuronal loci emetic regulatory influences. Certain aspects

of the medulla oblongata which regulate somatic and center excitatory have been

in close functional association visceral functions involved in the like other brain stem nervous and metabolic this review. These include

syndrome. The vomiting mechanisms by tonic of vomiting

is influenced and inhibitory omitted from

such important of vomiting. wich that approach general the

topics as vomiting All too little is known many vomiting vomiting associated clinical mechanism

in pregnancy, radiation sickness, and therapy about the processes concerned in the vomiting syndromes. cannot functions, be the of the Since most specific it has become without intelligent cause rather apparent concurrent therapeutic than the depressed

chharacterizes central to clinical effect.


of closely


is elimination

for their suggestions

authors and help

in the

pleasure in thanking preparation of this

Drs. L. S. Goodman review.


S. Loewe

I. ABBOT, 2. 3. 4. 5. 6. 7. 8. 9. 10. II.

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