Acta Anuesthesiol Scnnd 1997; 41: 94-111 Copyright Q Actn Anaesthesiol Scnnd 1997

Printed in Denmark. All rights reserved ACTA ANAESTHESIOLOGICA SCANDINAVICA

ISSN 0001-5172

Pharmacology and mechanisms of opioid analgesic activity

T. L. YAKSH
Anesthesiology Research Laboratory, University of California, San Diego, U S A

Opiates by an action at specific receptors can induce a highly
selective alteration in the response of humans and animals to
strong and otherwise aversive chemical, mechanical or thermal
stimuli. Specific investigations in a variety of species from ro-
dent to primate using microinjection techniques to examine the
pharmacology of local drug action have shown potent antino-
ciceptive actions to be mediated by a receptor specific action at
a number of sites within the brain, including the periaqueductal
gray (FAG: p receptor), the rostral ventral medulla (p/d recep-
tor) and the substantia nigra (p receptor) and within the spinal
dorsal horn (p/a/K receptor). Mechanistic studies have shown
these actions in the different sites to be mediated by several
discrete mechanisms. For example, in the PAG, the local opiate
effect is likely mediated by the indirect activation of bulbospinal
pathways, rostral projections to forebrain sites and by a local
alteration in afferent input into the brainstem core. In the spinal
cord, this effect is mediated by an action presynaptic to the pri-
mary afferent and by a post-synaptic effect to hyperpolarize pro-
jection neurons. In addition, it is now appreciated that p and K
receptors in the periphery can modulate the sensitized state of
the small afferent terminal innnervating inflamed tissue and ex-
ert an anti-hyperalgesic action. After systemic delivery of an
opiate, it is thus clear that a wide array of central and peripheral
systems serve to explain the powerful analgesic effect exerted
by this class of agents.
Key words: periaqueductal gray; substantia nigra; bulbospinal
pathway; rostral ventral medulla; spinal cord; opiate receptors;
mu receptors; delta receptors; kappa receptors; analgesia.
0 Acta Anaesthesiologica Scandinavica 41 (1997)

mong the remedies which it has pleased almighty God

A to give to man to relieve his sufierings, none is so
universal and eficacious as opium (Sydenham 1680).
The potent effects of opiates in altering the animal’s
or human’s response to strong and potentially tissue
damaging stimulus has been long appreciated, as sug-
gested by the quote attributed to Sydenham. The po-
tency of the effect and the specificity of the action is,
moreover, indicative of a highly organized substrate
which regulates the processing of and response to no-
ciceptive information. The following sections will re-
view some of the mechanisms by which this family
of agents exert their actions as defined by preclinical
investigations.
definition of the three principal receptor types. Thus,
work by Martin and colleagues (1) in spinally tran-
sected dogs led to the classification of agents as acting
at p and K sites. The subsequent work by Kostelitz
and colleagues (2) using in vitro smooth muscle bioas-
says with the then newly discovered enkephalin pep-
tides led to the designation of the d receptor subclass.
The profile of this activity is summarized in Table 1.
Receptor isolation and cloning have been accom-
plished for the p (3, 4), a (5) and K (6, 7, 8) receptor
Table 2
Opioid-receptor summary.

Receptor Bioassay Agonists Antagonists

Opioid receptors Mu Guinea pig Morphine Naloxone
ileum Sufentanil Naltrexone
Subtypes Meperidine beta-
At present, agents classified as opioids are believed to DAMGO funaltrexamine
exert their effects by a specific interaction with one or Delta Mouse vas DPDPE, DADLEl Naloxone
deferens Deltorphin, BNTX
more subclasses of three opiate receptors, designated DSLET Naltrindole
as: mu (p), delta (a) and kappa (K). Early in vivo phar-
Kappa Rabbit vas Butorphanol
macological work provided the initial definition of the deferens Bremazocine Naloxone
profile of actions that became associated with the Spiradoline Nor BNI

94
classes. Sequencing has revealed structures of 398
amino acids, 371 amino acids and 380 amino acids for
the p, a and K sites, respectively. Cells made to express
the cloned sequences typically display the appropri-
ate ligand structure activity/affinity relationships an-
ticipated for the respective sites. In general, they all
show considerable structural homology with each
other and to other G protein-coupled receptors (93.
All, for example, display a characteristic 7 transmem-
brane spanning domain in their structure. The cloned
receptors thus are in accord with the several general
classes of sites that have been identified in the phar-
macological literature.
A number of subclasses of the principal categories
of receptors have been postulated based upon their
differential pharmacology: p1 and p2 (10); dl and d2
(11)and K~~ (lo), the characteristics of these subtype
receptors continue to evolve as new agents are de-
veloped. It is important to note that in many cases
the clones have not yet demonstrated multiple types.
However, the possibility of systematic changes in re-
ceptor protein structure by post-translational pro-
cessing cannot be discounted. Moreover, separation of
subclasses within the subtypes has frequently de-
pended upon a limited and structure activity relation-
ship. Thus, for example, the p1 and p2 receptor separ-
ation has been almost exclusively based on the ability
of noncompetitive antagonists (such as naloxonazine)
to antagonize one or another effect of an opioid
agonist (analgesia is reversed, respiratory depression
is not, (10). In the case of the p subclasses no selective
agonists have been described thus far. In contrast, in
the case of the a subclasses, selective competitive
agonists (al: DPDPE; d2: deltorphin) have been iden-
tified and a distinctive antagonist activity profile has
been obtained for both sites (al: 7-brenzylidenenal-
trexone; a2: naltriben) (11, 12, 13).
For the purposes of the present review, emphasis
will largely remain with the primary classifications.
Membrane action
Agonist occupancy of opioid receptors typically leads
to several events which serve to inhibit the activation
of the neuron. Mu and a agonists have been shown to
depress cyclic AMP formation. Mu and 8 (14) and on
occasion K (15) receptors can induce a membrane
hyperpolarization through the activation of an in-
wardly rectifying K+channel. This effect of the p re-
ceptor is mediated by the activation of membrane Go
proteins, while the a effects are mediated by Gi/o pro-
teins of a different nature (16). In addition to the
hyperpolarization induced by p and a agonist recep-
tor occupancy, there is a concurrent inhibition of the
opening of voltage sensitive Ca++ channels (17, 18)
which will subsequently depress the terminal release
of neurotransmitters from the cell. These joint actions
lead to a powerful, receptor-mediated inhibition that
is typically observed with these opiates. K receptors
appear to be distinctly coupled and have been shown
to depress Ca++ conductance in neurons. While the
principal effect of the p receptor appears mediated
through an inhibitory effect, several lines of work
have suggested that under certain conditions, the p
receptors may couple through Gs protein and exert a
stimulatory effect (19). The significance of this action
is less certain, however, than for the inhibitory effect,
which appears to be broadly noted.
Sites of opiate antinociceptive action
As noted, the systemic delivery of an opioid will pro-
duce a selective alteration in the animal’s response to
a strong and otherwise aversive mechanical or ther-
mal stimulus. This antinociceptive effect is character-
ized by a structure activity relationship and antagon-
ist profile indicative of an action mediated by an
opioid receptor. The essential question is where are
such receptors located? The methodological approach
to such an issue is to deliver the agent to specific sites
in the organism and to define the effect and the phar-
macology of the action if there is an effect after local
exposure.
For central delivery, such work has involved the
placement of microinjection guide cannulae stereotax-
ically into specific brain sites and affixing them to the
skull. Through the chronic guide, a yet smaller injec-
tion cannulae is inserted to deliver small volumes of
injectate (0.2-0.5 pl). For the spinal cord, this local de-
livery has entailed the placement of a spinal catheter
into the intrathecal or epidural space (20). In each
case, the important issue has been to assess the effects
of a local drug on the nociceptive behavior of the in-
tact and unanesthetized animal.
Brain (supraspinal) sites
Mapping of brain sites in animals prepared with
mickoinjection cannulae has shown that opioid re-
ceptors associated with systems which modulate the
animal’s pain behavior are found in several surpris-
ingly restricted brain regions. Table 2 summarizes
several of the sites of actions which have been iden-
tified in the rat. The schematic localization of these
sites is presented in Fig. 1 for the rat and Fig. 2 in
the primate. The best characterization of these sites
so identified is the mesencephalic periaqueductal
95
T. L. Yaksh

Table 2
Summary of characteristicsof actions of opiates given into various sites in the unanesthetized rat.
Antinociceptive action
Microinjectionsites Reflex Escape Pharmacology References

Forebrairddiencephalon
amygdala (corticomedial) 0 ++ P? 1
N. accurnbens + P? 2
Mesencephalon
Periaqueductal grey +++ +++ p>>6=K=o 3
Mesencephalic reticular formation ++ ++ P 4
Substantia nigra ++ ++ P>>6=K=o 5
Lower brainstem
medial medulla ++ ++ p=6>K=0 6
Spinal cord +++ +++ p=&>K=O 7
Peripheral site' +++ p=K>6-0 8
~~

Reflex: tail flick/jaw jerk. Escape: Hot plate/paw pressure. Relative activity: ++ +>+ +>+>O.
*: Inflamed knee joint or foot pad.
References: 1. Rodgers RJ 1977 (42), Yaksh TL et al. 1976 (22); 2. Tseng LF, Wang Q 1992 (39). 3. Jensen TS, Yaksh TL 1986 (34), Smith
DJ et al. 1988 (155), Sanchez-Blazquez P, Garzon J 1989 (156); 4. Haigler HJ, Spring DD 1978 (33); 5. Baumeister AA et al. 1987 (36),
Baumeister AA et al. 1990 (37); 6. Jensen TS, Yaksh TL 1986 (34), Bodnar RJ et al. 1988 (182); 7. Drower EJ et al. 1991 (157), Malmberg
AB, Yaksh TL 1992 (791, Yaksh TL et al. 1986 (1581, Schmauss C, Yaksh TL 1984 (77); 8. Stein C et al. 1989 (104), NagasakaH, Yaksh TL
1995 (105).

gray (PAC). Microinjections of morphine into this re- injected agent emphasizes the possible activation of
gion will block nociceptive responses in the unanes- bulbospinal projections, as will be discussed below.
thetized rat, rabbit, cat, dog and primate (see below). Importantly, these effects are reversed by low doses
This local effect serves to block not only spinally-
mediated reflexes such as the tail flick, but supra-
spinally organized responses such as in the formalin
test (21), hot plate (see Fig. 1) or the shock titration
(22). This effect on a spinal reflex of a supraspinally

Fig. 1. Schematic representation of general regions in which the
intracerebral microinjection of morphine will induce a signifi-
cant increase in the response latency on thermal nociceptive
measures or increase the pressure applied to the hind paw
which is necessary to evoke withdrawal. A. Amygdala; B. Sub-
stantial nigra; C. Mesecephalic reticular formation; Periaque-
ductal gray; D. Raphe magnus; nucleus gigantocellularis (rostra1
ventral medulla); E. Spinal cord (dorsal horn). See text for details
and comments.
Fig. 2. Schematic drawings taken from sagittal histology (1-6
mm from midline) of the rhesus monkey. Each dot presents the
effects of a single microinjection of morphine sulfate given
through chronically implanted guide cannulae. 0: <50% increase
in baseline shock titration threshold with 40 pg of morphine: 0:
>50% increase in the baseline shock titration threshold with 40
18 of morphine; V >50% increase in threshold with 10-20 pg of
morphine. The stereotaxic axes are given for the most medial
(:LO) section (30).

96
of naloxone given either systemically or into the
microinjection site.
Mesencephalic periaqueductal gray
Tsou and Jiang discovered in 1963 that the local action
of morphine in the periventricular gray would block
thermally-evoked hind limb reflexes and this has been
subsequently verified in a variety of species, includ-
ing the rat (22,23), mouse (24), cat (25), dog (26), and
primate (27,28) (Fig. 2). Within the PAG, a somatotop-
ic organization has been reported for opiate action (22,
29). As indicated in Table 2, based on the relative ac-
tivity of several receptor agonists and antagonists, the
effects appear to be mediated by p but not a or K (30).
Binding studies focusing on the PAG have identified
a single high affinity p site for which a and K agonists
have low affinity and which is coupled to a G protein
(31, 32).
Mesencephalic reticular formation.
Bilateral injection of opiates into the mesencephalic re-
ticular formation significantly increases escape la-
tency with only modest effects upon spinal reflexes
(33). The pharmacology of these systems through the
action of morphine implicates a p site.
Medulla
Two distributions of opiate-sensitive sites have been
identified within the caudal medulla: i) medial sites
overlapping the nucleus raphe (34), and ii) lateral sites
coincident with the nucleus gigantocellularis (34, 35).
The pharmacology of these systems suggest both p
and a sites exist within the caudal medulla (34).
Substantia nigra
Bilateral microinjection of opioids into the substantia
nigra will evoke an increase in the tail flick and hot
plate response latencies in rats without evidence of
significant motor impairment ,or change in the re-
sponse to non-noxious stimuli (36, 37). Examination
of the agonist’s and antagonist’s pharmacology of this
nigra action reveals the role of p, but not a or K recep-
tors (38).
Nucleus accumbens/ventral forebrain
Microinjections of opiates into the ventral forebrain,
notably the nucleus accumbens, preoptic and arcuate
nuclei, will block spinal nociceptive reflexes (39, 40).
Tseng and colleagues observed that in the preoptic
and arcuate region, B-endorphin and morphine
yielded a dose-dependent, naloxone-reversible in-
crease in tail flick latencies. In the nucleus accumbens,
B-endorphin but not morphine displays significant ac-
tivity, suggesting two receptors (39).
In the ventral forebrain microinjections of p, a and
K agonists into the region referred to as the area tem-
pestas have been shown to attenuate thermal nocicep-
tion (41).
A mygdala
Morphine given into the basolateral amygdala in-
creased escape but not spinal reflex latencies (22,42).
The pharmacology of the amygdala has not been
characterized but p opioid agonists are active (22, 30,
42).
Thalamus and cortex
Several microinjection mapping studies of opiate ac-
tion have failed to observe activity following thalamic
or cortical injections (22, 27) but others (43) reported
that microinjection of morphine into the anterior pre-
tectal region of the rat, but not adjacent nuclei, re-
sulted in an inhibition of the tail flick.
Supraspinal mechanisms of opiate
antinociception
The multiplicity of opiate sites virtually guarantees
that the systems with which the opiate receptors are
coupled vary in the role each plays in altering no-
ciceptive processing. Accordingly, it is unlikely that
all of the mechanisms whereby opiates act within the
brain to alter nociceptive transmission are identical. A
brief overview of several classes of mechanisms will
be provided below.
50-
0-
I -
0 10 30 60
Time after MlcroinJeclion(mln)
Fig. 3. Figure presents the time course of the change in the tail
flick response latency after the microinjection of 5 p/0,5 p1 given
into the sites indicated. In this case, a single rat was prepared
with a single microinjection guide and injections were made at
progressively deeper sites (separated by 1 mm). Each injection
was separated by a 5 day interval (22).
97
T.L. Yaksh
Descending control
Mu and a opiates acting in the brainstem will inhibit
spinal nociceptive reflexes, reduce the spinal neuronal
activity evoked by noxious stimuli and alter supra-
spinally organized pain behavior. As discussed in de-
tail elsewhere (44, 45), bulbospinal pathways exert a
powerful regulatory influence over spinal cord affe-
rent processing. These effects are in accord with
studies in which:
i) activation of bulbospinal pathways which con-
tain noradrenaline or 5-HT will inhibit spinal no-
ciceptive activity (46,47);
ii) enhancement of spinal monoamine receptor ac-
tivity by local delivery of a2/5-HT agonists will
inhibit pain behavior (48, 49, 50, 51), while the
spinal action of these agonists will inhibit the fir-
ing of dorsal horn neurons evoked by high inten-
sity stimuli (52, 53, 54);
iii) opiate microinjection into brainstem sites in-
creases the spinal release or turnover of 5-HT
and/or noradrenaline (55,56);
iv) intrathecal injection of a2 or serotonergic anta-
gonists has minimal effect upon resting baseline
response latencies, but reverses the effects of
brainstem opiates on spinal reflexes and anal-
gesia (57, 58).
It is important to note that spinal inhibition and the
increase in monoamine release both occur after the de-
livery of the PAG opiates. This, in conjunction with
the absence of prominent effects on baseline responses
when the spinal monoamine antagonists are given
alone, argues that the effects of PAG opiates are as-
sociated with an increase in spinofugal outflow and
this influence can regulate spinal nociceptive pro-
cessing. The mechanisms whereby this increase in ac-
tivity in bulbospinal pathways occur after the local
PAG action of 1.1 opioid agonists is of particular organ-
izational interest, given the membrane inhibitory ef-
fects of the p opioids. Current thinking emphasizes
that the outflow of the periaqueductal gray is under
modulatory control by GABAergic neurons. Thus, to
the extent that local opiates inhibit activity in this
population of tonically active neurons, there would
be an inhibition that would permit the drive of an
excitation (Fig. 4). Indeed, opiates have been shown
to diminish a tonic GABA release from the PAG (59),
while GABA A antagonists enhance the activity of lo-
cal neurons (60).
Brainstem-brainstem inhibition of afferent trafic
Spinomedullary and spinal mesencephalic projections
are thought to play a role in the generation of the
message evoked by high threshold stimuli. Stimulat-
98
MeduI lopet aI neu ron
4
(GABA-
Medulla
Fig. 4.Schematic of organization of opiate action within the peri-
aqueductal gray. In this schema, 1 opiate actions block the re-
lease of GABA from tonically active systems that otherwise
regulate the projections to the medulla leading to an activation
of bulbospinal projections. See text for other considerations.
ion within the periaqueductal gray can inhibit nucleus
reticulo-gigantocellularis neurons (61). Fields et al.
have shown powerful mesencephalic influences upon
medullary cell populations (62). Given the role played
by the medullary system in the ascending pain traffic,
it seems probable that some of these cells may repre-
sent projection neurons which contribute to the rostral
movement of nociceptive information.
Direct inhibition of brainstem afferent trufic
Many regions in which opioids exert their effects,
such as within the mesencephalon and medulla, re-
ceive significant input from direct spinobulbar projec-
tions or collaterals of spinodiencephalic projections.
Cervical hemisection results in a reduction in opiate
in medulla PAG and the mesencephalic reticular for-
mation ipsilateral to the hemisection (63). This sug-
gests that opiate binding may be presynaptic on spi-
nofugal terminals and that locally administered opi-
ates might alter nociceptive processing through a
reduction of the excitation otherwise evoked by the
spinofugal projections.
Forebrain mechanism modulating the response
Ample evidence suggests that opiates may interact
with brainstem mechanisms to alter input by a variety
of direct and indirect systems. The behavioral seque-
lae of opioids possess a significant component that re-
flects a change in the affective component of the re-
sponse to the pain state. Numerous rostral projections
arise from the dorsal raphe nucleus (5-HT) and the
locus caeruleus (noradrenaline) that connect the peri-
aqueductal gray with forebrain systems that are
known to influence motivational and affective com-
ponents of behavior, including the n. accumbens,
amygdala and lateral thalamus (40, 64).The locus ca-
eruleus has ample projections into the limbic fore-
brain and thalamus (65). Both monoaminergic sys-
tems are strongly implicated in emotionality and
maintenance of consciousness. Lesions of raphe dor-
salis diminish the effects of morphine (66, 67) and de-
pletion of serotonin has been classically known to pro-
duce rats that are exceedingly irritable (68).
Spinal Action
Behavioral Effects
Intrathecal administration of opioids reliably attenu-
ates the response of the animal to a variety of uncon-
ditioned somatic and visceral stimuli which otherwise
evokes an organized escape behavior in a variety of
species including the mouse (69), rat (70), rabbit (70),
guinea pig (L. Crone, unpublished observations), cat
(71, 72), dog (73), and primate (macaque) (30, 74, 75).
The antinociceptive endpoints in which spinal opiates
have been shown to be effective are presented in Table
3.
Pharmacology
The pharmacology of spinal opioids has been exten-
sively examined from the perspective of agonist struc-
ture activity relationships, antagonist structure activ-
ity relationships and antagonist potency. In general,
on the tests outlined above, spinal opioids produce
a monotonic dose-dependent increase in the latency
response (tail flick, hot plate, skin twitch), the magni-
tude of the response (writhing, number of paw licks,
change in blood pressure) or the threshold for escape
(paw pressure, shock titration) (see above for refer-
ences). Based on the consideration of the available
data, several points regarding the pharmacology of
spinal opiates may be summarized.
i) The structure activity relationship for these
opioids over a range of 2-3 orders of magnitude
are similar on the several endpoints and across
species;
ii) The rank order of potency in producing a block of
spinal reflexes after intrathecal delivery correlated
with the potency of agents on the guinea pig

Table 3
Models of nociception in which spinal opiates have been examined.
General stimulus Animal Specific model References

Acute thermal Rat Hot plate (523) Yaksh TL, Rudy TA 1977 (20)
Tail flick
Rat Tail dip evoked hypertension and tachycar- Nagasaka H, Yaksh TL 1995 (105)
dia
Doglcat Skin twitch Tung AS, Yaksh TL 1982 (72)
Yaksh TI 1978 (85)
Sabbe MB et al. 1994 (73)
Primate Thermal escape Oliveras J-L et al. 1986 (97)
Yaksh TI ibid.
Acute mechanical Rat Paw pressure Taiwo YO et al. 1989 (160)
Rat Tail clamp/pinch Kuraishi Y et al 1985 (183)
Acute visceral Rat Colonic distension Ness TJ, Gebhart GF 1989 (161)
Harada Y et al. 1995 (162)
Acute electrical shock Rat Tail shocklvocalization Tang AH, Schoenfeld MJ 1978 (163)
Yaksh TL, Rudy TA 1977 (67)
Primate Shock titration Yaksh TL 1983 (75)
Acute chemical stimuli Rat Writhing Schmauss C, Yaksh TL 1984 (77)
Rat lntradermal formalin Yamamoto T, Yaksh TL 1992 (164)
Chronic neurogenic Rat Autonomy-neurectomy Weisenfeldt-HallinZ 1984 (165)
Rat Chronic nerve compression Yamamoto T, Yaksh TL 1991 (145)
(Bennett model)
Rat Root ligation (Chung model) Yaksh TI et al 1995 (76)
Lee Y-W et al. 1995 (146)
Fictive pain stimuli generated by intra- Rat lntrathecal strychnine Yaksh TL 1989 (166)
thecal drug treatment

99
T. L. Yaksh
Primate: 51C Tail Dip
ileum and on the mouse vas deferens (76), sug-
gesting a role for the p and d receptors in virtually INTRATHECAL DRUG
all endpoints (except certain neuropathic pain
models (Table 3). Kappa-preferring agonists thus
far studied typically have lower apparent efficacy
(77).
iii) Intrathecal opioids are subject to a competitive an-
tagonism by naloxone. For agents classified as p
preferring agonists (morphine, sufentanil, -20 40 loo 160
Time (min)
DAME), the pA2 (dose required to double the
EDs0 of the agonist) is similar across all tests /f T ITDRUG
examined (writhing, hot plate, tail flick in the rat)
and across species (rat and primate) and is about
0.1X that dose required to antagonize agonists
classified as d and K (78), while receptor preferring
antagonists block the agonists for the respective
receptors (e.g. 6 preferring opioids (DPDPE,
DADL) but not p preferring (morphine, DAG)
have been shown to be reversed bynaltrindole 1 10 100 1WO 1woo
Intrathecal Dose (pg)
(79). The pharmacology of these effects appear to
be similar across a number of species, including - 100

rat (12, 13, 79,80) and primate (74, 75,81) (Fig. 5). -z
w
00

6o NALOXONE (100 pg)

Based on the above overview, a case can be made that & 40
NALTRENDOLE (300 pg)
in the spinal cord of infrahuman species, there are at ae 20

least three distinguishable subpopulations of opioid 0

receptors which, according to the homology of their
agonist and antagonist structure activity profiles, re-
semble the subclassifications designated as p, d and K.
Mechanisms of spinal opiate action
Initial studies demonstrated that opiates applied by
iontophoresis (82,83) or systemically in spinally tran-
sected animals (84, 85) would inhibit selectively the
discharge of spinal dorsal horn neurons activated by
small (high threshold) but not large (low threshold)
afferents. Fleetwood-Walker and colleagues (83)
examined the pharmacology of the inhibition of dor-
sal horn neurons by iontophoretically applying recep-
tor preferring agonists for the p (DAG), d (DPDPE)
and K (U50488).In Lamina I, with nociceptive specific
neurons or with multireceptive (WDR)neurons, p and
d agonists exerted a suppressive effect upon the no-
ciceptive component. Kappa agonists had no effect. In
laminae 11-V, p and d agonists were with minimal ef-
fect, while K agonists caused a selective inhibition of
the nociceptive component. Recording evoked activity
in lamina I1 neurons in spinal cord slices revealed that
p (DAMGO) and d l (DPDPE) agonists produced a
dose-dependent reduction in the excitatory post-syn-
aptic potentials. In contrast, the d2 agonists (D-ala2-
glu 4-deltorphin) had less than a 50% effect at the
highest dose examined (86).
Receptor autoradiography with opiate ligands have
Mor (1000) DAMGO (30)DPDPE (3000)DADL (1000)
INTRATHECAL AGONISTS (pg)
Fig. 5. Top: Time effect curve for the effects of intrathecal p (mor-
phine, sufentanil) and a (DPDPE) agonists on the response la-
tency to withdraw the tail of the cynomologous primate from
a 51°C waterbath. Each line presents the mean and SEM of 4
experiments. Middle: Intrathecal dose effect curve for intrathecal
p (DAMGO, SUF: Sufentanil, MOR: morphine), 'pk (DADL: D-
ala2 d-leu 5 enkephalin: DPDPE: d-pen2-dpen5-enkephalin)or
K (U50488) agonists. Bottom: Reversal of the effects of intrathecal
Morphine (1000 pg); DAMGO (30 pg), DPDPE (3000 pg) and
DADL (1000 pg) after pretreatment with intrathecal saline (con-
trol), naloxone (100 pg) or Naltrindole (300 pg). * R 0 . 0 5 as com-
pared to control.
revealed a number of important characteristics of
spinal opiate binding. These revealed that binding
was limited for the most part to the upper laminae of
Rexed, particularly in the substantia gelatinosa (87,
88, 89, 90), the region in which small afferents show
their principal termination. The proportions of the p,
d and K opioid binding sites, assessed by autoradi-
ography in laminae I and 11, were found to be ap-
proximately 70%, 20% and lo%, respectively. Dorsal
rhizotomies resulted in a significant reduction in dor-
sal horn binding, suggesting that the binding corre-
sponding to p, a and K sites were all reduced by 50-
75% in the dorsal horn ipsilateral to the lesions, sug-
gesting that a significant proportion of all three bind-

100
 ing sites were associated with the degenerating pri-
mary afferents (91,92). This association was consistent
with the observation that opiate bindkg was found
in the dorsal root ganglia (93). This organization sug-
gested that opiates might thus exert a portion of their
activity by a presynaptic effect upon primary afferents
and a postsynaptic effect upon dorsal horn projection
neurons. Confirmation of the presynaptic action was
provided by the observation that opiates in vitro and
in vivo would reduce the release of primary afferent
peptide transmitters such as substance P, which were
contained in small primary afferents. Thus, it has been
reported that morphine, DAMGO, DPDPE and
DADL, but not U50488 (94,95,96,97) would block sP
and/or CGRP release in viva These interactions are,
however, complex as such interactions can influence
multiple spinal terminal systems and there may be
predictable differences on the effects assessed under
resting and stimulated conditions (98).
A post-synapticaction was demonstrated by the abil-
ity of opiates to block the excitation of dorsal horn neu-
rons evoked by glutamate, presumably reflecting a di-
rect activation of the dorsal horn neuron (99). The pre-
synaptic action corresponded to the ability of opiates to
prevent the opening of voltage-sensitive Ca+ chan-
+
nels, thereby preventing release. The activation of pot-
assium channels leading to a hyperpolarization was
consistent with the direct postsynaptic inhibition. The
joint ability of p and d opiates to reduce the release of
excitatory neurotransmitters from C fibers as well as
decrease the excitability of dorsal horn neurons is be-
lieved to account for the powerful and selective effects
upon spinal nociceptive processing (Fig. 6).
There is evolving data that suggests that spinal opi-
ates may exert a portion of their action by a local re-
lease of adenosine (100). However, it should be noted
that spinally delivered adenosine agonists are, unlike
spinal p and a opiates, relatively poorly effective
against acute high threshold stimuli (101) and do not
block spinal afferent peptide release (102).
Peripheral
Behavioral efects
It has been a principal tenet of opiate action that these
agents are “centrally” acting. Direct application of
opiates to the peripheral nerve can in fact produce a
local anesthetic-like action at high concentrations, but
this is not naloxone reversible and is believed to re-
flect a “non-specific’’ action (103). Moreover, in pain
models examining normal animals, it can be readily
demonstrated that if the agent does not readily pen-
etrate the brain, its opiate actions are limited.
\ C Fiber terminal
Receptors
a
C I K
K + I
2nd Order neuron
Fig. 6. Schematic presents a summary of the anticipated organ-
ization of opiate receptors in the dorsal horn regulating nocicep-
tive processing. As indicated, p/a and K binding is high in the
dorsal, particularly in the region associated with the termination
of small unmyelinated afferents (C fibers). A significant pro-
portion of these sites are located on the terminals of the small
afferent as suggested by the loss of such binding after rhi-
zotomy. In addition, there is a post-afferent terminal localization
of these sites that are apparently coupled through Gi protein to
K channels leading to a hyperpolarization of the neuron. Occu-
pancy of the presynaptic p and a sites reduce the release of sP
and/or CGRP in part by an inhibition of the opening of voltage-
sensitive Calcium channels.
Alternately, studies employing the direct injection
of these agents into peripheral sites have demon-
strated that under conditions of inflammation where
there is a “hyperalgesia”, the local action of opiates
can be demonstrated to exert a normalizing effect
upon the exaggerated thresholds. This has been dem-
onstrated for the response to mechanical stimulation
applied to the inflamed paw (104) or inflamed knee
joints (105). As indicated in Fig. 7, examination of the
pharmacology of this articular action has emphasized
the likely role of p and K, but perhaps less importantly
a sites (105, 106).
Mechanisms of peripheral action
While there are opiate ‘%inding” sites being trans-
ported in the peripheral sensory axon (107), there is
no evidence that these sites are coupled to mechan-
isms governing the excitability of the membrane, thus
the effects are not naloxone reversible (103). High
doses of agents such as sufentanil can block the com-
pound action potential, but this is not naloxone re-
versible and is thought to reflect upon a “local anes-
thetic” action of the lipid soluble agent. It is certain
that opiate receptors exist on the distant peripheral
terminals. It has been shown that opiate receptors are
101
T. L. Yaksh
. Intra-articular T stem will produce a powerful alteration in nociceptive
2 agonist. Given the ability of opiate agonists to pro-
DRUG DOSE (mg)
Fig. 7. Figure presents the dose response of the suppressive ef-
fects of maximum suppression of the evoked change in blood
pressure (expressed as the mean?SEM of the compression
evoked change in blood pressure) after injection, intra-articu-
lady or intramuscularly of SUF (sufentanil), PD: (PD117302),
MOR: (morphine),SPIR (spiradoline),DADL (dala2 dleu5 enke-
phalin), DPDPE (d-pen2-d-pen5 enkephalin) and U-50,488H.
Each point presents the mean2SEM of 4-8 rats. Because the IA
injection alone of the vehicle produced an augmentation re-
sponse, all IM drug injections were given concurrently with an
IA injection of saline. The horizontal lines indicate the mean
(so1id)eSEM (dotted lines) for rats receiving IA saline and no
other drug at time zero.
on the distal terminals of C fibers and that agonist
occupancy of these sites can block antidromic release
of C fiber transmitters e.g., sP; "axon reflex" (108).Im-
portantly, the models in which peripheral opiates ap-
pear to work are those that possess a significant de-
gree of inflammation and are characterized by a
hyperalgesic component. This raises the possibility
that these peripheral actions normalize a process lead-
ing to an increased sensitivity to the local stimulus
environment, but does not alter normal transduction.
Previous work has indeed demonstrated that local
opiates in the knee joint (109) and in the skin (110)
can reduce the firing of spontaneously active afferents
observed when these tissues are inflamed. The mech-
anism of the antihyperalgesic effects of opiates ap-
plied to the inflamed regions (as in the knee joint) is at
present unexplained. It is possible, for example, that it
may act upon inflammatory cells that are present and
are releasing cytokines and products that activate or
sensitize the nerve terminal (106).
Interactions between opiate modulated
systems
As outlined above, opioids with an action limited to
several sites, notably the spinal cord, and to the brain-
102
processing. After systemic delivery, the net result will
likely reflect upon the effects of concurrent interaction
at the sites. Ample evidence indicates that the effects
of concurrent opiate receptor occupancy result in a
powerful functional facilitation. Several specific in-
stances are outlined.
Brainstem-spinal cord
Early studies revealed that delivery of an opioid an-
tagonist into the cerebral ventricles (111, 112) or into
the lumbar intrathecal space (67) can produce a com-
plete antagonism of the effects of a systemic opioid
duce a maximum effect with an action limited to
either site alone, this significant reversal of the sys-
temic agonist after local antagonist delivery was
hypothesized to indicate that the spinal and supraspi-
nal opiate systems were interacting in a synergistic
fashion. In other words, levels of local receptor occu-
pancy which were sufficient to produce a behavioral
analgesia when both spinal and supraspinal sites
were occupied were inadequate when either contri-
bution was removed (113). The specific test of this
hypothesis was provided by Yeung and Rudy (114),
who demonstrated that the concurrent administration
of morphine spinally and supraspinally would lead to
a prominent synergy, as indicated by hyperbolic iso-
bolograms. Similar results have been observed in mice
(115,116).
Consistent with the powerful nonlinear interaction
between spinal and supraspinal opiates, and given the
considered role of bulbospinal systems in mediating
some of the supraspinal actions of opiates, it has been
shown that the concurrent spinal delivery of a2and p
and 3 opioid agonists as well as concurrent p and d
agonists can interact synergistically (44).
Supraspinal-supraspinal
In the brain, multiple sites exist that mediate an opiate
antinociceptive effect. Co-injection of opiates into the
periaqueductal gray and locus caeruleus (117) re-
sulted in a synergic interaction, while co-injection into
the periaqueductal gray and nucleus reticularis gigan-
to-cellularis (118) appeared to have only a simple ad-
ditive interaction.
Spinal-spinal cord
It is apparent that within the spinal cord there are
multiple points of interaction for opiates, including
presynaptic on C fibers and a concurrent postsynaptic
interaction that leads to a hyperpolarization of dorsal
horn projection neurons. It is likely that the net effect
Table 4
Summary of activity of several opiates delivered epidurally on human clinical pain.
Drug Receptor Approximate dose
Lofentanil
Buprenorphine
Fentanyl
Sufentanil
Hydromorphone
Alfentanil
Butorphanol
DADL
P-endorphin
Morphine
Methadone
Meperidine P Torda TA, Pvbus DA 1982 (176)
of spinally delivered agents is mediated by this con-
current action which reduces the excitatory input and
the excitability of the dorsal horn neuron. While the
importance of this concurrent interaction on the net
analgesic action of spinal opiates has not been system-
atically examined, a comparison can be made between
spinal receptor systems that have and do not have this
property. Thus, p, d and a2 agonists and neuropeptide
Y have pre-synaptic effects upon C fiber transmitter
release and appear to hyperpolarize neurons through
a G protein coupling (119, 120). These agents are
known to have a significant therapeutic ratio in ani-
mals and, where examined, in humans. In contrast,
agents such as adenosine A1 agonists and GABA B
(baclofen) agonists have binding in the dorsal horn,
can increase K conductance through G protein link-
ages, but do not significantly decrease spinal sub-
stance P release (44,45). These agents after spinal de-
livery have a comparatively poor therapeutic ratio,
e.g., they produce significant motor dysfunction at
doses that alter nociceptive endpoints (121,122). It has
been hypothesized that this concurrent pre-terminal
effect on small afferents and the post-synaptic effects
enhance the therapeutic ratio (123). Thus, these two
classes of agents argue for a potent functional contri-
bution of the two concurrent sites of action leading to
antinociception.
Similarity of mechanisms in human and
animal models
Supraspinal
In humans it is not feasible to routinely assess the site
of action within the brain where opiates may act to alter
nociceptive transmission. However, intracerebroven-
tricular opioids have been employed in humans for
Reference
Van den Abele G, Camu F 1983 (167)
Simpson KH et al. 1988 (168)
Welchew EA 1983 (169)
Geller E et al. 1993 (170)
Brose WG et al. 1991 (171)
Chauvin M et al. 1985 (172)
Camann WR et al. 1992 (173)
Onofrio BM, Yaksh TL 1983 (137)
Oyama T et al. 1982 (175)
Yaksh TL 1987 (132)
Torda TA, Pybus DA 1982 (176)
Evron S et al. 1985 (177)
pain relief in cancer patients (124,125,126,127,128). An
important characteristicof this action is that the time of
onset is relatively rapid for even the water-soluble
agent morphine. Gamma scans of human brain after
1123-morphine have shown that the agent, even at one
hour after injection, remains close to the ventricular lu-
men (129). This distribution is consistent with the slow
permeation of the water soluble agent from the ven-
tricular lumen (130).Given that the rate of diffusion for
such a drug and the size of the human brain, it seems
probable to hypothesize that the site of opiate action in
humans must lie close to the ventricular lumen. In this
regard, the preclinical studies in species such as the pri-
mate have emphasized the importance of the periaque-
ductal sites. Such a site of action would in fact lie in
close proximity to the ventricles and permit a relatively
rapid access of a slowly moving drug from the ven-
tricular lumen. While an extensive activity relationship
has not been achieved with human intracerebroventri-
cular delivery, morphine and &endorphin have been
delivered and analgesia produced with B-endorphin
appears to show a greater activity (131).
Spinal
There is an extensive literature indicating that opiates
delivered spinally can induce a powerful analgesia in
humans. The pharmacology of this action has been
relatively widely studied and it appears certain that
p, 8 and to a lesser degree K agonists are effective after
intrathecal or epidural delivery (132). The effects of
spinal opiates are reversed by low doses of systemic
naloxone (133, 134, 135, 136, 137). Importantly, in the
activity of spinally-delivered agents in modulating
acute nociception in animal models, such as for the
rodent, hot plate reveals an ordering of activity that
closely resembles that observed in humans for con-
103
T. L. Yaksh
1 OOOOl 1 tized by a local change in the chemical milieu that is
5
A
L
1oooj
100-
r-0.872 7 generated by local injury and inflammation. Given
3. Hydromorphone
L acute nociceptive models (Fig. 8). In each case, it is
in
0
L 6. Morphine
w 7. Alfentanil
8. Methadone
9. Butorphanol
10. Buprenorphine
11. Meperidine
.1 1 10 100 1000
RAT (HOT PLATE 52.5.C)
Fig. 8. The relative ordering of activity for clinically effective
doses of spinal opiates in the postoperative pain state expressed
relative to the activity of morphine (e.g. morphine=l) in
humans is plotted versus the ordering of activity relative to mor-
phine after spinal delivery in the rat model on the 52°C hot plate
test. * indicates that buprenorphine on the hot plate is a partial
agonist.
trolling clinical pain states. This similarity is indicated
by the close regression observed when the approxi-
mate relative ordering of activity observed in rats and
after spinal delivery in humans is plotted (Fig. 8).
Peripheral actions
The observation that opiates injected in the periphery
led to the clinical studies showing that observation of
injection of morphine into the knee joint of humans
after knee surgery (138, 139, 140) showed that intra-
articular morphine injections have a powerful sparing
effect upon subsequent analgesics. The appropriate
controls emphasize that the effects are indeed med-
iated by a local action and not by a CNS redistri-
bution. These results are in close accord with the ob-
servation reported in the animal models of hyperalge-
sia induced by peripheral inflammation.
Preclinical versus clinical pain states
and opiate action
Mechanistic variables
A variety of nociceptive models employed in animals
have been shown to be sensitive to the supraspinal
and spinal actions of opiates (see above and Table 3).
A common property of these states are that they in-
volve: i) activity in small primary afferents, as acti-
vated by high threshold thermal, mechanical and
chemical stimuli; or ii) in the case of the peripheral
action, a high threshold afferent that has been sensi-
2 04
these properties, it is not surprising that the clinically
employed opiates (largely p and to a lesser extent K
agonists) are noted to be particularly effective in the
postinjury/-operative pain state, as they are in the
believed that the principal input generated by mech-
anical distortion of the tissue or by the elaboration of
active factors (141, 142) from the injury similarly re-
flects input that arises from activity in small afferents.
In neuropathic pain models, the normal processing
of sensory input is altered to yield a hyperalgesic com-
ponent, as indicated in the thermal escape latency in
the model of Bennett and Xie (143), or in the tactile allo-
dynia in the nerve ligation model of Kim and Chung
(144) or the intrathecal strychnine model of Yaksh (108).
As summarized in Table 5, in these models, opiates
have been shown to have distinguishable effects. Thus,
in the Bennett and Xie model (143), systemic and intra-
thecal morphine has been shown to be effective and the
dose response curves have been shown to be shifted
modestly to the right (145).In contrast, on the tactile al-
lodynia models, intrathecal morphine has been shown
to have no effect in altering the allodynia, while sys-
temic and intraventricular opiates have been shown to
be effective in reversing the tactile threshold (76, 108,
146). These observations, suggesting that at least some
preclinical neuropathic states may not be sensitive to
spinal opiates are consistent with previous retrospec-
tive analyses in human causalgic pain states (147). As
the tactile allodynia is believed to be mediated by large,
low threshold mechanoreceptors, the modest, if any, ef-
fect upon the tactile allodynia by spinal opiates is con-
sistent with the current thinking regarding their pre-
sumed mechanisms of action at the spinal level (see
above). In this regard, the apparent efficacy of systemic
or supraspinal opiates in these models may point to an
alteration in the supraspinal systems activated by the
anomalous ascending message generated by the tactile
stimulus in the post nerve injury pain state. On the
other hand, the efficacy of spinal and systemic opiates
in some pain models such as the Bennett model and in
other models by a systemic or supraspinal action as in
the Chung model (Table 5) would suggest that in
humans at least some components of the post nerve in-
jury pain state should be affected by spinal opiates (148,
149).
Stimulus intensity
Opiate agonists generate their effect by an interaction
with a specific opiate site for which it has affinity and
the magnitude of effect produced by a given degree
Table 5
Comparable sensitivity of preclinical and clinical pain states to morphine'.

Rat Human
Spinal ICVT Systemic Spinal Systemic
Somatic (small afferent)
Acute thermaVmechanical (rat') Yes Yes Yes
Post injury (human') Yes Yes
Neuropathic
Bennett (thermal hyperalgesia: rat) Yes2 - Yes3
Chung (tactile allydynia: rat) NO^ Yes5 Yes5
IT strychnine (tactile allodynia: rat) Nos - -
Spinal ischaemia (tactile allodynia: rat) - - No7
Nerve section (autotomy) Yese - NO'
Causalgia (human) Nolo YedNoll
Visceral
Colonic distension (rat) Yes12 - -
Uteral colic (human) Yes13 --
' See text and Table 3 for references; Yamamoto T, Yaksh TL 1991 (145); Yaksh TL, unpublishedobservations; Yaksh TL et al. 1995 (76);
Lee Y-W et al. 1995 (146); Yaksh TI 1989 (166); Xu XJ et al. 1992 (178); Wiesenfeld-Hallin2 1984 (165), Puke MJ, Wiesenfeld-Hallin
'
Z 1993 (179) (Pretreatmenffextended treatment); Yamamoto T, Mizuguchi T 1992 (180) (Prolonged oral); lo Arner S,Meyerson BA 1988
(147); 'l Cherny NI et al. 1994 (149); l2Ness TJ, Gebhart GF 1989 (161); l3Olshwang D et al. 1984 (181).

of receptor occupancy is defined by the intrinsic effi-

IT SUF, LOW
cacy of the agonist. Thus, if two p agonists produce a IT SUF, Mod
given effect with different degrees of occupancy, the IT SUF, High
agent requiring the lowest occupancy is said to have
higher intrinsic efficacy. Agents with low efficacy may
be unable to achieve a maximum effect even when
the fraction of receptor occupancy approaches 1. In
contrast, other agents may produce maximum effects
when only a small fraction of the available receptors
are occupied. The relative efficacy of two agonists
may be compared by measuring the shifts in their $ 1 -20, . .......I . '..'...I . ..'.... .
I . ' ' ~ ' ' '' ~.- ..-
dose response curves in the face of receptor inacti- - 0 ITMOR,LOW
100
vation with noncompetitive antagonists. Thus, for
opiates, in models of nociception using non B-funal-
5 8 0 -- ' ITMOR,Mld
ITMOR,Hlgh
trexamine, it has been possible to demonstrate after 0
2

/&
60
spinal and/or systemic delivery that sufentanil= 8
DAMGO>morphine (150, 151). An important conse- 2 40

-1
quence of differences in efficacy arise in the face of
20
changing stimulus intensities. It is known that an in- X
crease in stimulus intensity will result in a right shift $ 0
in the dose response curve for an analgesic and if the E
intensity is sufficient, the agonists may be unable to -20, . . ....-. . .
I *'."'I ' . ...'.. . .
I .."..1 ' ' '.--I

.001 .01 .1 1 10 100

produce a full effect, e.g., it will appear as a partial
agonist. It has been hypothesized that the degree of
right shift is defined by the intrinsic efficacy of the
agonist. This speculation has been supported for p
opiate agonists (152) and generalized to a2 adrenergic
agonists (153). An example of this is presented in Fig.
9. Here, the spinal delivery of sufentanil and mor-
phine results in a dose-dependent increase in the ther-
mal escape latency. By increasing the intensity of the
lntrathecal Dose (pg)
Fig. 9. Dose response curves for sufentanil (SUF, top panel) and
morphine (MOR, bottom panel) at progressively increasing ther-
mal stimdus intensities (Low, open circles; Medium, closed
circles; and High, closed squares). All results expressed as per-
cent maximum possible effect (%WE) versus Logarithm of opi-
ate dose (pg) with the mean of 4-6 animals2SEM represented
at each data point. As indicated, for a given increase in stimulus
intensity, sufentanil shows a lesser right shift than morphine and
no decreasing maximum (154).

105
T. L. Yaksh
stimulus, the doses of sufentanil and morphine are
shifted to the right, with the greatest shift and the de-
pression of maximum being greatest for morphine. In
humans, some evidence for this has been obtained
from the ratio of potencies for sufentanil and mor-
phine defined in mild to moderate pain states (low
stimulus) versus that required for intraoperative anal-
gesia (strong stimulus) (152,154). In this regard, the p
opioid agonist buprenorphine is appreciated to be a
clinically useful analgesic, whereas in animal models
it is frequently seen as having a plateau effect. This
plateau effect reflects upon the fact that at the maxi-
mum achievable receptor occupancy, the agent has in-
sufficient efficacy to achieve a maximum effect. This
is manifested in Fig. 8, where intrathecally in the rat,
on the 52°C hotplate, buprenorphine displays a pla-
teau effect and its estimated relative potency (as com-
pared to morphine) is less than that observed in the
clinical setting. Thus, the efficacy of the opiate ap-
pears to have an impact upon the relative potency in
the preclinical model and in its clinical use.
Conclusions
This overview of opioid receptor activity raises a
number of important issues that are relevant to the
understanding of pain and pain processing.
i) The ability of opiates to produce a powerful effect
upon the organized response of the animal to a
strong and potentially tissue damaging stimulus
reflects first upon the action mediated by a speci-
fic family of receptors.
ii) The antinociceptive effects associated with such
receptor occupancy reflects the coupling of these
receptors to specific neuronal systems that are
part of a circuitry that either regulates the excitab-
ility of a neuronal pathway (as in the bulbospinal
projections that control spinal activity) or serves
to directly impede the release of a transmitter link
(as in the prevention of the release of a neuro-
transmitter from the primary afferent or by hyper-
polarizing the projection neuron).
iii) The complexity of each of these systems alone is
amplified by the appreciation that the organized
processing is impacted at many levels by even a
locally acting agent (as in the PAG or in the spinal
cord where a single site reflects multiple effect).
Importantly, in many cases, it appears certain that
the concurrent involvement of the several separ-
ate components yields a physiological or biochem-
ical consequence that is greater than an additive
(e.g. synergistic). The synergy permits significant
2 06
effects on function at levels of receptor occupancy
at which other systems (e.g. respiratory or auto-
nomic) are not sufficiently affected to produce a
physiologically relevant action. This multitude of
mechanisms and their synergistic interaction
likely accounts for the most part for how opiates
can exert a relatively potent, yet selective, effect
upon nociceptive processing.
iv) Finally, our appreciation of the actions of the opi-
ate systems provide important insights into the
mechanisms by which nociceptive information is
processed. Thus, the characteristics of the antino-
ciception will be defined by the systems with
which the opiates interact. In the case of neuro-
pathic pain, for example, it might be speculated
that in pain states in which the afferent drive is
mediated by low threshold myelinated afferents
(as in allodynia), the agent may be relatively less
effective than in a pain state in which the pain
state is mediated by a small afferent input (with
which opiate receptors are believed to be associ-
ated in the spinal cord).
v) Finally, while the data for human action of these
agents is relatively less exhaustive than the pre-
clinical work, there is a prominent comparability
across specifies when site of action and pharma-
cology are considered. Thus, there is little doubt
that in humans, as in the animal model, it is pos-
sible to demonstrate comparable supraspinal,
spinal and peripheral actions. This similarity in
pharmacology and function provides validating
support for the conclusion that animal models re-
veal mechanisms of processing that are present in
the human.
Acknowledgement
Work reported herein was supported in part by NIDA 02110. I
would like to dedicate this paper to Dr.Florella Magora who
contributed to the early clinical literature on spinal opiates, in
honor of her retirement.
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Address:
Tony L. Yaksh, PhD
Department of Anesthesiology
University of California, San Diego
9500 Gilman Drive
La Jolla, California 92093-0818
USA
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