Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception
Introduction
Cannabis has been used for thousands of years as a therapeutic agent for pain relief, as well as for recreational purposes. Delta-9-Tetrahydrocannabinol (Δ9-THC) is the most prevalent and well characterized constituent of the approximately 70 cannabinoids identified in cannabis (Elsohly and Slade, 2005), and largely accounts for the psychoactive properties of this plant. Δ9-THC produces antinociceptive effects in a wide range of preclinical assays of pain, including tail-flick, hotplate, inflammatory, cancer, neuropathic, and visceral nociceptive models (Martin et al., 1984, Formukong et al., 1988, Burstein et al., 1988, Compton et al., 1991, Varvel et al., 2005). Visceral pain (e.g., myocardial ischemia, upper gastrointestinal dyspepsia, irritable bowel syndrome, and dysmenorrhea) is one of the most common forms of pain. Importantly, both cannabinoid receptors are expressed in the viscera (Matsuda et al., 1990, Bouaboula et al., 1993, Munro et al., 1993, Galiegue et al., 1995, Wright et al., 2005). Intraperitoneal administration of acetic acid or various other chemicals causes distension of the hollow walled muscular organs and the release of prostaglandins and inflammatory cytokines that induce abdominal stretching. Δ9-THC has been well established to produce antinociceptive effects in the acetic acid (Sofia et al., 1975), and phenyl-p-quinone (PPQ) (Welch et al., 1995, Haller et al., 2006) models of visceral nociception.
Other prevalent phytocannabinoids that are structurally similar to Δ9-THC include cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and tetrahydrocannabivarin (THCV). CBD has been demonstrated to have anti-edema effects (Lodzki et al., 2003, Costa et al., 2004) and potentiate the antinociceptive effects of Δ9-THC (Varvel et al., 2006, Hayakawa et al., 2008). However, orally administered CBD was inactive in the acetic acid stretching model and CBN was only effective at high concentrations (Sofia et al., 1975, Welburn et al., 1976, Sanders et al., 1979). In addition, neither CBC nor THCV has been characterized in visceral pain models. Interestingly, THCV has been shown to act as a competitive cannabinoid receptor antagonist (Thomas et al., 2005). The primary goal of the present study was to compare the antinociceptive effects of Δ9-THC to other prevalent phytocannabinoids, including CBC, CBD, CBN, and THCV, in the acetic acid stretching model.
Δ9-THC binds to and activates both CB1 (Matsuda et al., 1990) and CB2 (Gerard et al., 1991) cannabinoid receptors, both of which are coupled to Gi/o proteins (for review see (Howlett et al., 2002). CB1 receptors are located extensively throughout the central nervous system (CNS) (Matsuda et al., 1990, Munro et al., 1993, Zimmer et al., 1999), and are believed to mediate marijuana's psychomimetic effects. CB2 receptors are expressed predominately in cells of the immune and hematopoietic systems (Munro et al., 1993) though CB2 receptor messenger RNA and protein are expressed in microglia (Carlisle et al., 2002, Nunez et al., 2004) and brainstem neurons (Van Sickle et al., 2005). Consequently, a secondary goal of this study was to determine whether phytocannabinoids produce their antinociceptive effects through a cannabinoid receptor mechanism of action. Accordingly, we examined the involvement of CB1 and CB2 receptors using rimonabant and SR144528, selective antagonists for these respective receptors. Because cannabinoids elicit antinociceptive effects as well as motor suppressive effects, in the final set of experiments, we evaluated each active drug for hypomotility.
Section snippets
Subjects
The subjects consisted of male ICR mice (Harlan Laboratories, Indianapolis, IN) weighing 20–25 g. The mice were housed in stainless steel cages in groups of five in a temperature-controlled vivarium on a 12-h light/dark cycle. Food and water were available ad libitum. All animal studies were approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.
Drugs
Δ9-THC,
Results
As shown in Fig. 1, Δ9-THC dose-dependently suppressed abdominal stretching, with an ED50 value of 1.1 mg/kg (95% confidence interval 0.8–1.6 mg/kg). This drug was considerably less potent in decreasing locomotor activity than in producing antinociception. Its ED50 value in suppressing locomotor activity was 7.7 mg/kg (95% confidence interval 4.2–14.3 mg/kg) (see Table 1). Δ9-THC was 8.5 (95% confidence interval: 3.4–20.6) fold more potent in eliciting antinociception than in decreasing locomotor
Discussion
Marijuana has been overlooked as an analgesic compound, in part, due to its psychoactive properties, which are primarily caused by the actions of Δ9-THC. However, other constituents of marijuana may have analgesic properties with minimal psychoactive effects compared to Δ9-THC. The results of the present study demonstrate that while Δ9-THC and CBN elicited antinociception in the acetic acid abdominal stretching model, other phytocannabinoids (i.e., CBD, CBC, and THCV) did not affect abdominal
Role of funding source
This work was supported by the National Institute on Drug Abuse (R01DA002396, R01DA003672, and T32DA007027). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
L. Booker conducted the bulk of the behavioral studies, data analysis, and contributed to the writing of the manuscript. S.P. Naidu contributed to the design of some of these studies. R.K. Razdan and A. Mahadevan synthesized phytocannabinoids used in these studies. A.H. Lichtman oversaw the study, contributed to the experimental design, and contributing to the writing of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
None of the authors report any conflict of interest that could have influenced, or be perceived to influence, this work.
Acknowledgements
The authors thank their dear friend and long-time collaborator, the late Dr. Billy R. Martin, for his substantial contributions and support of this research. The authors also thank Dr. Irina Beletskaya for her work in conducting the binding assays.
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