Non-CB2 receptors

Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin BR (2000) Levels, metabolism, and pharmacological activity of anandamide in CBI cannabinoid receptor knockout mice evidence for non-CBl, non-CB2 receptor-mediated actions of anandamide in mouse brain. J Neurochem 75 2434-2444... 

Whether this central TRPVl-like receptor has the same properties as the better characterised peripheral TRPVl receptors (Szallasi and Di Marzo 2001), and whether it represents the same non-CBi non-CB2 receptor characterised by Breivo-... 

De Petrocellis L, Di Marzo V (2010) Nrai-CBl, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic caimabimimetics focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmun Pharmacol 5 103... 

A fourth important pharmacophoric element was established for the non-classical cannabinoid series in the form of a southern aliphatic hydroxyl group. Addition of this group to (192) resulted in the high-affinity CBi and CB2 receptor full agonist CP 55,940 (193) [129, 133], the tritiated form of which was used to first demonstrate specific cannabinoid binding sites in brain tissue [134]. Its enantiomer, CP 56,667 (194) has lower affinity for the CBi receptor (Table 6.17). 

CBt receptors are found in particularly high concentrations within the central nervous system, but also on some peripheral neurons as well as in certain non-neuronal tissues (Herkenham et al., 1990). CB2 receptors mainly occur in immune cells where they can mediate an immunosuppressant effect (Iwamura et al., 2001). Both... 

Anandamide was isolated from water-insoluble fractions of the porcine brain. It binds to CB1 with rather moderate affinity (Ki 61 nM) and a low affinity for the CB2 receptor (Ki 1930 nM). The name anandamide is based on its chemical nature (an amide) and the Sanskrit word ananda meaning bliss. The chemical structure of anandamide can be divided into two major molecular fragments a polar ethanolamido head group and a hydrophobic arachidonyl chain. The polar head group comprises a secondary amide functionality with an N-hydroxyalkyl substituent while the lipophilic fragment is a non-conjugated c/ s tetraolefinic chain and an n-pentyl chain reminiscent of the lipophilic side chain found in the classical cannabinoids. A number of anandamide analogs have been synthesized and demonstrated to have considerable selectivity for the CB1 receptor in comparison to the CB2 receptor. 

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). 

The investigations conducted to date on the pharmacological effects mediated by cannabinoid receptors show that the non-psychoac-tive effects of Cannabis derivatives are mediated by CB2 peripheral receptor. Furthermore, the CB2 receptor localization proves that said non-psychoactive effects, i.e. the effects on the immune system, the anti-inflammatory, myorelaxant and antinociceptive effects, as well as the effects on pressure systems, are mediated by said receptor. 

This chapter describes the in vitro and in vivo bioassays that have been most widely used to characterize ligands for CBi and/or CB2 receptors and reviews the ability of compounds commonly used in cannabinoid research as experimental tools to activate or block these receptors. The likelihood that the most widely used cannabinoid receptor antagonists are inverse agonists rather than neutral antagonists is also discussed, as is evidence for the presence in mammalian tissues of non-CBi, non-CB2 pharmacological targets for cannabinoids. 

CB2 receptor activation can also inhibit oedema and plasma extravasations produced by inflammation at a peripheral level (Malan et al. 2002). Cannabinoid CB2 receptors are likely located on non-neuronal cells in inflamed tissues, where they inhibit the release of inflammatory mediators that excite nociceptors (Mazzari et al. 1996). 

Whilst most of the research of the endocannabinoid system in the last decade has focussed on the CBi and CB2 receptors, we have also made substantial advances in the identification of endocannabinoid degrading and synthesizing enzymes and the effects of endocannabinoids that are not mediated by these receptors. Future animal models will therefore increasingly address the relevance of non-CBi and non-CB2 endocannabinoid binding sites and the regulation of endocannabinoid levels. 

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