Neuropeptides 5: 73-76, 1984

INTRACEREBROVENTRICULAR VS. SUBCUTANEOUS DRUG AIMINISTRATION:

APPLES AND ORANGES?

Martin w. Adler, Cheryl H. Rowan, and Ellen B. Geller, Dept. of Pharmacology,

Temple U. Sch. of Med., Philadelphia, PA. 19140 (Reprint requests to MWA).

ABSTRACT

For numerous reasons, the icv route is commonly used to administer endoge-
nous opioid peptides and other newly discovered or synthesized substances
and may often indicate whether the drug has actions on the brain. Effects are
then routinely compared to the actions of prototypic agents given by some sys-
temic route, such as se or ip. Unfortunately, there is little appreciation that
qualitative as well as quantitative differences can be seen when the same drug
is administered by central as opposed to peripheral routes. Numerous factora
undoubtedly contribute to the final effect. Whatever the explanation, failure
to recognize that such differences may occur could result in incorrect conclu-
sions as to the involvement of specific receptor types or subtypes.

INTRODUCTION

The procedure most frequently used to determine the actions of a chemical

or drug is to administer that compound to a subject by injection. In animals,
this is usually done by the intravenous (iv), intraperitoneal (ip), or sub-
cutaneous (se) route. In the case of compounds that are expected to act
centrally but are available in only small amounts, undergo rapid degradation,
and/or cannot easily pass the blood-brain barrier, it is often desirable to admi
nister the drug via the cerebral ventricles or directly into brain tissue. The
endogenous opioid peptides and their analogs, for example, are usually handled
in this manner. Indeed, this technique has provided us with most of the current
information we have as to the pharmacological effects of the drugs and their
potential physiological significance.

Unfortunately, effects seen following central administration of a peptide

are often compared to the actions of standard or prototypic agents given by some
systemic route. There is little appreciation that qualitative as well as quan-
titative differences can be seen when the same drug is administered by central
as opposed to peripheral routes. In order to illustrate this point, we can
refer to work from our own laboratory using two standard measures of opioid
effects - seizure threshold and body temperature in rats. In addition, severa!
non-opioid related studies from other laboratories will serve as examples of the
fact that such differences are also seen with drugs affecting other systems.

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 EXAMPLES OF QUALITATIVE DIFFERENCES

Using the rat flurothyl seizure threshold test (Adler et al, 1976), we
determined that opioids, when administered by the se route, can be divided into
4 groups based on their activity on threshold, stereospecificity,
tolerance/cross-tolerance, and naloxone sensitivity (Cowan et al, 1979).
When the endogenous opioid peptides (endopioids) are given icv, however, all
produce a dose-related increase in seizure threshold (Tortella et al, 1981). To
which opioids should these compounds be compared? Like many other investigators,
our first tendency was to say that the endopioids are like morphine and unlike
agents such as meperidine or pentazocine. The resulte of the icv administration
of the opioids cast sOllle doubt on this interpretation, bowever (Tortella et al,
1981; 1984). Table 1 diagrame these resulte. In order to determine wbether the
endopioids are more similar to morphine or to meperidine in terms of brain ex-
citabil ity, one would have to examine the effects of the endopioids after se ad-
ministration, a procedure not feasible for reasons cited above.

TABLE 1

INFLUENCE OF ROUTE OF ADMINISTRATION ON OPIOID-INDUCED CHANGES IN

FLUROTHYL SEIZURE THRESBOLDS IN RATS

ROUTE OF CBANGE IN EFFECT WITH

DRUG AIMINISTRATION SEIZURE THRESHOLD NALOXONE

Morphine se A Blocked
icv A Blocked
Meperidine se Potentiated

Pentazocine
icv
se
A' Blocked
Potentiated

Normeperidine
icv
se
'A Unchanged
Unchanged
icv
'' Potentiated

Like the flurothyl test, body temperature measurement in rata, at an

ambient temperat~re of 20°c, can be used to differentiate among the opioids
(Geller et al, 19"83). For example, se morphine produces the well-known dual
effect of low dose hypertbermia and high dose bypothermia while ethylketazocine
(EK) produces only hypothermia. If these same opioids are given icv, both pro-
duce only hyperthermia. Table 2 diagrame these resulta. Since both
D-ala2-metenkephalinamide and a-endorpbin produce a dual effect when given icv
(Adler et al, 1983), do we say that they are like morphine even though se
morphine differs from icv morphine? Do we say that the dose-related hypothermia
produced by icv dynorphin¡7 is like or unlike EK, which decreases body tem-
perature se but increases it icv?

That this phenomenon is not restricted to the peptides is shown by a report

(Tapia et al, 1976) tbat ruthenium red, a dye that is a calcium blocker, produ-
ces convulsiona in rats and cats when administered intracisternally or icv, but
causes a flaccid paralysis when given se. The authors postulate that both

74
effects are the result of calcium blockade, but that the flaccid paralysis is
due to prevention of ACh release at the neuromuscular junction, while the
seizures are due to preventing the release of GABA and glycine when the dye is
administered centrally. Also of interest is a report (Millhorn et al, 1983)
that 5-HTP, when administered to cats, increases respiratory activity (as
measured by phrenic nerve activity) when given into the tbird ventricle but pro-
duces a profound inhibition when administered iv. As a final example, work with
tubocurarine can be cited. By the icv route, it produces convulsions; by the iv
route, it produces motor paralysis or neuromuscular block (Feldberg, 1963).

TABLE 2

INFLUENCE OF ROUTE OF AIMINISTRATION ON OPIOID-INDUCED CHANCES IN

.BODY TEMPERATURE OF RATS

DOSE
DRUG RANGE ROUTE EFFECT EFFECT WITH NALOXONE

Morphine Low se i. Blocked

icv i. Blocked
se Blocked

Etorph ine
High

Low
icv
se
'i.i. Blocked
Blocked
lCV i. Blocked
High se Blocked

l-Ethylketazocine Full
icv
se
'' i.
Blocked

d-Ethylketazocine Full
icv
se
'i.
o
Blocked
O or Y
icv i. Blocked

DISCUSSION

A variety of factors and mechanisms undoubtedly contribute to the final

effects produced after central administration of drugs. One factor, for
example, is the rate and pattern of diffusion from the site of injection. These
characteristics are influenced, in turn, by such things as the volume of injec-
tion, and the pH, osmolarity, electrovalence, solubility, and molecular weight
of the substance administered (Myers, 1966). Other critica! determinants of
specific drug effects are drug metabolism and the location of the receptors in
relation to the site of injection. The longer it takes for a drug to reach its
sites of action, the greater the chance that it wíll no longer be in its active
form (Herz and Teschemacher, 1971). In addition, the temporal order in which
the receptors in specific brain areas are activated may influence the ultimate
effect. The passage of the compound into the general circulation and subsequent
redistribution throughout the brain must be considered as well (Feldberg, 1963).
Whatever the explanation, one must bear in mind that the effects of a drug ad-
mini~tered centrally and peripherally may not only differ in the expected quan-
titative way but may actually be opposite qualitatively. Thus, comparisons made
among different drugs without regard to route could result in incorrect conclu-
sions such as the involvement of a specific receptor type or subtype.

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 ACKNOWLEDGEMENT

This work was supported in part by NIDA GRANT DA 00376.

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