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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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