Nervous System Cannabinoid Receptors

Around the turn of the century, the medical use of cannabis declined because reproducible clinical effects could not be obtained. At that time, the active constituent in cannabis had not been isolated in pure form. Instead, plant extracts were generally used and these were known to deteriorate rapidly, thus accounting for the nonreproducible effects. 

A long list of potential therapeutic effects was recorded for THC, including analgesic, bron-chodilatory, antiemetic, anticonvulsant, and anti-inflammatory action, reduction of intraocular pressure, and alleviation of some neurological conditions (such as seizure disorders, spasticity associated with spinal cord injuries, and multiple sclerosis) (Mechoulam et al., 1994). 

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Endocannabinoids are endogenous mediators acting via the binding to, and activation of, cannabinoid receptors, CBX and CB2 [1]. iV-arachidonoy 1-ethanol-amine (AEA, anandamide) and 2-arachidonoyl-glycerol (2-AG) (Fig. 1) are the two most studied endocannabinoids. In the nervous system, endocannabinoids act as... 

Gifford AN, Bruneus M, Gatley SJ, Lan R, Makriyannis A, Volkow ND. Large receptor reserve for cannabinoid actions in the central nervous system. J Pharmacol Exp Ther 1999 2 478-483. 

Cannabis sativa plants contain at least 400 different compounds, of which as many as 60 are structurally related to 5 -tetrahydrocannabinol (5 -THC), the primary psychoactive constituent of cannabis. When cannabis is smoked, hundreds of additional compounds are produced by pyrolysis, which may contribute to both acute and chronic effects (Abood and Martin, 1992). The central nervous system actions of canna-binoids are mediated primarily through the CBj receptor. A second type of cannabinoid receptor, termed the CB2 receptor, is distributed primarily in the periphery (Gifford et ah, 1999). Activation of central cannabinoid receptors modulates neurotransmitter release at... 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

Cannabinoid and endocannabinoid-induced synaptic depression is observed in both the peripheral nervous system and the CNS. Indeed, A9-THC inhibition of transmitter release was first demonstrated in mouse vas deferens (Graham et al. 1974), and further evidence for presynaptic inhibition has been obtained using this preparation (Ishac et al. 1996 Pertwee and Fernando 1996) and in the myenteric plexus (Coutts and Pertwee 1997 Kulkami-Narla and Brown 2000). In addition, anandamide was first characterized as an EC based on its actions in the mouse vas deferens (Devane et al. 1992). Subsequently, CB1 receptor-mediated inhibition of release of several neurotransmitters has been documented in various regions of the PNS (see Szabo and Schlicker 2005 for review). Cannabinoids also inhibit neural effects on contraction in the ileum (Croci et al. 1998 Lopez-Redondo et al. 1997), although it is not clear that this is effect involves direct inhibition of neurotransmitter release (Croci et al. 1998). The CB1 receptor has been localized to enteric neurons, and thus the effect on ileum certainly involves actions on these presynaptic neurons. In addition, anandamide produces ileal relaxation via a non-CBl, non-CB2-mediated mechanism (Mang et al. 2001). 

Kulkami-Narla A, Brown DR (2000) Localization of CBl-cannabinoid receptor immunoreactivity in the porcine enteric nervous system. Cell Tissue Res 302(l) 73-80 Kushmerick C, Price GD, Taschenberger H, Puente N, Renden R, Wadiche JI, Duvoisin RM, Grandes P, von Gersdorff H (2004) Retroinhibition of presynaptic Ca2+ currents by en-docannabinoids released via postsynaptic mGluR activation at a calyx synapse. J Neurosci 24(26) 5955-65... 

Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. Handbook Exper Pharmacol 168 299-325... 

Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1997) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neurosci 83(2) 393 411 Van Beugen BJ, Nagaraja RY, Hansel C (2006) Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J Neurosci 26(32) 8289-94... 

Doherty, J., and Dingledine, R. (2003). Functional interactions between cannabinoid and metabotropic glutamate receptors in the central nervous system. Cun. Opin. Pharmacol. 3, 46-53. 

Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. 2001. Studies on [3H] CP-55940 binding in the human central nervous system Regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103 9-15. 

Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. 1998. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83 393-411. 

The primary active component of cannabis is A9-tetrahy-drocannabinol (THC), which is responsible for the greater part of the pharmacological effects of the cannabis complex. A8-THC is also active. However, the cannabis plant contains more than 400 chemicals, of which some 60 are chemically related to A9-THC, and it is evident that the exact proportions in which these are present can vary considerably, depending on the way in which the material has been harvested and prepared. In man, A9-THC is rapidly converted to 11-hydroxy-A9-THC (5), a metabolite that is active in the central nervous system. A specific receptor for the cannabinols has been identified it is a member of the G-protein-linked family of receptors (6). The cannabinoid receptor is linked to the inhibitory G-protein, which is linked to adenyl cyclase in an inhibitory fashion (7). The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex. 

There have been no previous reports of propriospinal myoclonus precipitated by marijuana. The etiology was not clear but may have involved cannabinoid receptors located in the brain and spinal cord as well as the peripheral nervous system. 

Rimonabant is an inverse agonist for CBl cannabinoid receptors, which is approved in Europe for weight-loss therapy, but has significant side effects on the central nervous system. 

The mechanisms involved in THC s central nervous system (CNS) and cardiovascular effects have not been well delineated. Specific cannabinoid receptors in the cerebral cortex may be responsible for the pharmacologic effects of THC. THC also has immunosuppressive effects and results in depression... 

The effects of cannabinoids are due to an interaction with high affinity specific receptors present in the central nervous system (Devane et al.. Molecular Pharmacology (1988) 34, 605-613) and peripheral nervous system (Nye et al.. The Journal of Pharmacology and Experimental Therapeutics (1985) 234, 784-791 30 Kaminski et al.. Molecular Pharmacology (1992) 42, 736-742 Munro et at.. Nature (1993) 365, 61-65). 

The central effects are dependent on a first type of cannabinoid receptor (CBl), which is present in the brain. Furthermore, Munro et al. [Nature (1993) 365, 61-65] have cloned a second cannabinoid receptor coupled to protein G, called CB2, which is present only in the peripheral nervous system and more particularly on the cells of immune origin. The presence of CB2 cannabinoid receptors on the lymphoid cells may... 

Anandamide (N-arachidonoylethanolamine) is thought to act as an endogenous cannabinoid neurotransmitter in vertebrate nervous systems. It binds to and activates cannabinoid receptors and simulates many distinctive effects typical of plant-derived or synthetic cannabinoid drugs. 

Anandamide amidohydrolase is likely to play an important role in the physiological degradation of anandamide. Three lines of evidence support this possibility. First, anandamide amidohydrolase is highly selective. Second, anandamide amidohydrolase is discretely distributed in the central nervous system, where its localization parallels that of cannabinoid receptors. 

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