ANTIPYRETIC, ANALGESIC AND ANTI-INFLAMMATORY EFFECTS OF
DELTA-9-TETRAHYDROCANNABINOL IN THE RAT


European Journal of Pharmacology 24 (1973) 1-7

Donald S, Kosersky, William L. Dewey, and Louis S. Harris

Department of Pharmacology, School of Medicine, University of North
Carolina, Chapel Hill, North Carolina 27514

The effects on body temperature produced by graded doses of
delta-9-tetrahydrocannabinol and phenylbutazone were compared in both
normal and pyretic rats. Dose related hypothermic responses were produced
by the oral administration of delta-9-THC in normal animals. Moreover,
delta-9-THC significantly reduced elevated temperatures in yeast-induced
pyretic rats to near normal levels at doses which exhibited little
hypothermic activity in normal rats. The oral antipyretic potency of
delta-9-THC was approximately 2 times that of phenylbutazone. The
comparative oral antinociceptive activity of delta-9-THC and selected
narcotic and non-narcotic analgesics was determined by the increase in
response latency to pressure applied to normal and yeast-inflamed paws.
Delta-9-THC administered orally was essentially inactive at dose levels
below those producing pronounced central nervous system depression. The
oral anti-inflammatory efficacy of delta-9-THC was compared to
phenylbutazone and acetylsalicylic acid. Delta-9-THC was ineffective in
inhibiting carrageenin-induced edema of the rat paw following acute or
chronic administration.

Terms....delta-9-Tetrahydrocannabinol, Antipyretic activity, Analgesic
activity, Anti-inflammatory activity.

1. Introduction

Prior to the introduction of numerous synthetic drugs into western
medicine, various preparations derived from cannabis were frequently
employed for therapeutic purposes. Among its numerous and diverse
applications, cannabis was used principally for its analgesic and sedative
properties. Although these same properties are incorporated into most
clinically employed anti-inflammatory drugs, no reports evaluating the
anti-inflammatory actions of cannabis derivatives have appeared in the
current literature. The present studies were undertaken to investigate
delta-9-trans-tetrahydrocannabinol, recognized as the major active
component of cannabis, for possible anti-inflammatory and related
pharmacologic activity. A preliminary account of the data has been
presented.

Discussion

The hypothermic response to cannabis and its derivatives has been
noted in numerous reports and extends across several species including man
(Miras, 1965; Holtzman et al., 1969; Garattini, 1965; Waskow et al.,
1970; Lomax and Campbell, 1971; Abel et al., 1972). The results
presented in this paper further demonstrate that orally administered
delta-9-THC produces dose-related hypothermic actions in the rat. However,
the most important finding in the present study is that delta-9-THC is an
effective antipyretic agent in rats with an acute oral potency exceeding
that of phenylbutazone. Of further significance is the demonstration that
delta-9-THC effectively reduces the body temperature of febrile rats at
dose levels which have little effect on normal body temperature and which
produce no apparent behavioral effects. Although the antipyretic actions
of phenylbutazone are generally considered to be mediated by central
mechanisms similar to those of the salicylates, no direct evidence for a
central site of antipyretic action for delta-9-THC is provided in the
present study. Accordingly, the antipyretic effects produced by relatively
low doses of delta-9-THC may be due in part to non-specific peripheral
effects such as vasodilatation, as suggested by Beaconsfield et al.
(1972). Cannabis has been utilized as a febrifuge in the folk medicine of
Argentina (Manfred, 1947). In this regard, further investigations
concerning the therapeutic usefulness of delta-9-THC in the treatment of
hyperpyrexia in man seem warranted.

Several reports have appeared in the literature pertaining to the
analgesic activity produced by cannabis derivatives in laboratory animals.
The results obtained in these studies, however, have been inconsistent and
often contradictory. Our findings indicate that delta-9-THC is essentially
devoid of antinociceptive activity in the rat at dose levels below those
which produce other pronounced central depressant effects.
Bicher and Mechoulam (1968) reported the analgesic effects
produced by delta-9-THC (20 mg/kg, i.p.) in mice as being comparable to
those of morphine sulfate (10 mg/kg) in the writhing, hot plate and
tail-flick tests. Buxbaum (1972) found delta-9-THC to be equipotent to
morphine when administered intraperitoneally to rats in both the hot plate
and tail-flick tests. However, utilizing the same testing procedures Sofia
and Barry (1972) determined delta-9-THC to be 1/2 -- 1/3 as potent as
morphine in mice and only 1/8 as potent as morphine in rats.

In contrast to these reports Davies et al. (1946) were unable to
produce analgesia in rats (tail-flick) by i.v. injection of hashish
distillate and Scheckel et al. (1968) failed to produce analgesic effects
in squirrel monkeys with doses of delta-9-THC that produced pronounced
behavioral aberrations. Moreover, Dewey et al. (1969) reported that
delta-9-THC administered i.v. or orally was essentially inactive in the hot
plate and tail flick procedures in both mice and rats.
The wide divergence in the reported analgesic activity of
delta-9-THC may be due, in part, to differences in rates of absorption and
metabolism in different animal species and strains. Accordingly, Ho et al.
(1971) have demonstrated that tritiated delta-9-THC injected i.p. in rats
remains in the abdominal cavity with little absorption or distribution to
other tissues. Nonspecific irritant effects may also account for the
variability in the reported analgesic activity of delta-9-THC when
different routes of administration are employed. Of particular
significance in this regard are the findings of Manning et al. (1971) and
Sodetz (1972). These investigators have clearly demonstrated that
delta-9-THC, like other phenolic compounds, produces severe irritation and
inflammation of the peritoneum in rats after i.p. injection. However,
because of the relative water insolubility of delta-9-THC this route of
administration is favored by many investigators. The toxicological
consequences of these irritant effects have important behavioral and
pharmacological implications since responses to nociceptive stimuli are
significantly modified by other stimuli simultaneously perceived (Beecher,
1957). Noteworthy in this regard are the findings of Winter and Flataker
(1965) concerning the effects produced by irritants in various analgesic
testing procedures. The results of their experiments demonstrate that
irritant or inflammatory substances injected i.p. into rats yield dose
related analgesic-like effects which are similar, in all respects, to the
centrally mediated antinociceptive effects produced by clinically proven
analgesic compounds. Accordingly, the failure of delta-9-THC to produce
antinociceptive activity after oral or i.v. administration would suggest
that the reported analgesia produced by delta-9-THC following parenteral
injection may be due to non-specific irritative actions of the compound.

Inflammatory edema induced by carrageenin provides a rapid and
sensitive means for evaluating non-steroidal anti-inflammatory agents.
Moreover, a high empirical correlation exists between the activity of drugs
in this test and their anti-inflammatory activity in man (Kampmann and
Frey, 1966). The results of the present investigation indicate a complete
lack of activity for delta-9-THC in this model of inflammation and do not
lend support to a body of folk medicine reporting the use of cannabis as an
effective anti--inflammatory agent (Mikurya, 1969; Kabelik et al., 1960).
It is important to note, however, that apart from delta-9-THC cannabis
contains numerous other active components which separately or in
combination may produce significant anti-inflammatory activity. [In fact
Formukong & Evans (1988) discovered that Cannabidiol (CBD) was in fact more
effective as an anti-inflammatory than aspirin in rats. ]


Footnotes [available soon]

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