ReviewCannabinoid receptors and the regulation of immune response
Introduction
Marijuana (Cannabis sativa) is one of the oldest drugs of abuse but its medicinal value has also been known by many cultures throughout human history. Indications for the medicinal use of cannabis can be found in ancient Chinese and Egyptian civilizations. Cannabis preparations were included in British and US pharmacopoeias and were used extensively up to the 1930s for treatment of convulsive disorders and as analgesics. In the 1930s, marijuana started to lose medical attention as new, pure pharmaceutical drugs began to appear such as opiates, aspirin and barbiturates which could be given in standard doses with reliable effects. As marijuana's medicinal use began to wane, its recreational use started to increase in Western countries. Shortly thereafter, abuse of marijuana led to withdrawal of cannabis preparations from pharmacopoeias and laws were passed prohibiting its use. The identification of Δ9-tetrahydrocannabinol (Δ9-THC) as a major psychoactive principle in marijuana and its chemical synthesis by Gaani and Mechoulam, 1964 opened a new era of synthetic cannabinoids as pharmacological agents. Δ9-THC preparations have been used, albeit occasionally, for pain relief, as an anti-emetic and appetite stimulant during cancer chemotherapy, as anti-convulsant and analgesic.
A significant increase of interest in cannabinoids developed shortly after pharmacological identification (Devane et al., 1988) and subsequent cloning (Matsuda et al., 1990) of a central CB1 cannabinoid receptor which is expressed mainly by neuronal cells. Subsequent identification of a peripheral CB2 cannabinoid receptor (Munro et al., 1993), which is expressed predominantly by immune cells, revealed a basis for the known, while modest, immunomodulatory effects of cannabis preparations. Thus, the molecular basis for cannabinoid action on the central nervous and immune systems was established.
The identification of N-arachidonoylethanolamine, referred to as anandamide (Devane et al., 1992), and more recently 2-arachidonoylglycerol (2-AG) (Lee et al., 1995, Mechoulam et al., 1995, Sugiura et al., 1995) as endogenous ligands for cannabinoid receptors raised questions about the role of ‘endocannabinoids’ and cannabinoid receptors in the maintenance of physiological homeostasis and in the development of some neuronal and immune system disorders.
Since cannabinoid research initially was primarily of sociological interest, one of its objectives has been to clarify the mechanism of action of natural cannabinoids and their synthetic derivatives. Information concerning cannabinoid-induced responses tends to characterize cannabinoid-induced signalling as an extremely complex event. This complexity is determined by the linkage of multiple signalling cascades to cannabinoid receptors as well as by the apparent non-receptor-mediated action of high doses of cannabinoids. Also, the physiological consequence of cannabinoid receptor activation may depend on the type of cell, the presence of other concomitant signalling events, and the chemical nature of the agonist. In contrast to studies on Δ9-THC and its synthetic analogs, questions regarding the intrinsic role of ‘endocannabinoids’ and their receptor-inactive congeners in cell signalling have been less explored. Nevertheless, a better understanding of the functioning of the endogenous cannabinoid system may help to clarify its possible role in the development of some pathologies like autoimmune disorders and propagation of HIV infection. It is the objective of this review to present information concerning the complexity of cannabinoid receptor-mediated signalling and the resulting modulation in the functioning of the immune system.
Section snippets
Variability and distribution of cannabinoid receptors
Presently, two main subtypes of cannabinoid receptors have been characterized. The first pharmacological evidence for cannabinoid receptors (CB1 cannabinoid receptor) was reported by the Howlett group (Devane et al., 1988) which characterized the binding of radioactive synthetic cannabinoid CP 55, 940 to rat brain homogenates. Two years later, Matsuda et al., (1990) isolated and cloned a complementary DNA that encodes rat brain cannabinoid receptor. Subsequently, human (Gérard et al., 1991) and
Signalling events following activation of cannabinoid receptors
A significant part of information concerning signalling events triggered by cannabinoid receptor activation was obtained using CHO, Cos and AtT cells transfected with CB1/CB2 receptors. While transfected cells offer a useful tool to explore functional properties of receptors, one should take into account the artificial nature of transfected cells and carefully extrapolate the obtained data when compared with cells naturally expressing these receptors. In fact, the number of receptors expressed
The effect of natural and synthetic cannabinoids on immune response
Cannabis sativa preparations were used for centuries in Asian medicine to reduce the severity of pain, inflammation and asthma (Mechoulam, 1986). However, the recent tremendous increase in recreational use of marijuana revealed a deleterious effect of marijuana smoke on defense mechanisms against bacterial and viral infections (Klein, 1999). Recent investigations prompted by the discovery of cannabinoid receptors and their endogenous ligands significantly improved our knowledge concerning
Endocannabinoids and the immune system
N-acylethanolamines became of interest to immunologists almost 50 years ago when antiinflammatory properties of some fractions from peanut oil, soybean lecithin and egg yolk, whose active principle was later identified as N-palmitoylethanolamine, were discovered (Coburn et al., 1954, Long and Martin, 1956, Kuehl et al., 1957). In the late 1960s antiviral and antibacterial properties of N-palmitoylethanolamine were also reported (Perlı́k et al., 1971a, Perlı́k et al., 1971b, Perlı́k et al., 1973
Conclusion
Cannabinoid research has experienced tremendous progress in the last decade, and credit for this fact should be given to the identification of cannabinoid receptors and their endogenous ligands. A range of potent cannabinoid receptor ligands and their selective antagonists/inverse agonists, as well as CB1/CB2 receptor binding antibodies, is now available to ensure additional breakthroughs in our understanding of the functioning of ‘endocannabinoid’ system. The complexity of signalling pathways
Acknowledgements
The author's work was supported in part by United States Public Health Service grant GM45741, INTAS grant 97-1297 and RFBR grant 98-04-48049 and The Hormel Foundation. I thank Dr Harald Schmid, Patricia Schmid and Dr Doug Bibus of the Hormel Institute, University of Minnesota, for helpful discussion during preparation of the manuscript.
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