CB2-like receptors

It is possible that palmitoylethanolamide may produce antinociception in rat and mouse models of inflammatory or neuropathic pain by acting on a CB2-like receptor (Calignano et al. 1998, 2001 Conti et al. 2002 Farquhar-Smith et al. 2002 Farquhar-Smith and Rice 2001 Helyes et al. 2003). The existence of such a receptor is supported by the finding that even though palmitoylethanolamide lacks significant CB2 receptor affinity or efficacy (Griffin et al. 2000 Lambert et al. 1999  

Central G Protein-Coupled Receptors for Anandamide and R-(+)-WIN55212 

It has also been found that [ H] R- (-1-)-WIN55212 undergoes selective binding to CBi C57BL/6 membranes obtained from brain areas in which R-(+)-WIN55212 enhances binding (cerebral cortex, hippocampus and brain stem) 

Evidence has emerged for the presence of G protein-coupled, non-GBi receptors on glutamatergic axonal terminals in the hippocampus with which at least some cannabinoid receptor agonists can interact to inhibit glutamate release. More specifically, results from electrophysiological experiments with hippocampal slices 

In these experiments, however, glutamatergic transmission was facilitated by anandamide and/or capsaicin. 

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Farquhar-Smith WP, Jaggar SI, Rice ASC (2002) Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CBl and CB2-like receptors. Pain 97 11-21... 

Direct CB2 antisense oligonucleotide miCToinjection into the mouse brain induced anxiolysis, indicating that CB2 or CB2-like receptors may influence behavior (Fig. 2). The CB2 antisense oligonucleotide used is 5 -TGTCTCCCGGATCCTC-3, CB2 sense is 5 -GAGGGATGCCGGGAGACA-3, and CB2 mismatch is 5 -TCTATCCGGTCTTGCGTC-3. ... 

The fact that saturated and monosaturated NAEs were co-re-leased with anandamide from stimulated neurons raised the possibility that the former may also serve a physiological function related to cannabimimetic signaling.This hypothesis finds support in a recent report. A major NAE released from neurons, N-palmitoylethanolamine, was found to bind to and activate a CB2-like receptor subtype expressed by peripheral mast cells and by the mast cell-derived cell line, RBL-2H3. If confirmed, these observations would support the idea that a single biochemical event leads to the co-release from neurons of a family of cannabimimetic NAEs, acting on both CBl and CB2 receptors. Let us examine now in greater detail the possible nature of this biochemical event. 

Mouse vas deferens (MVD) seems to express CB1 and at least one CB2-like cannabinoid receptor type, as is demonstrated by the presence of CB1 and CB2-like mRNA as well as by data collected from experiments with cannabinoid receptor selective agonists and antagonists (Pertwee, 1999). Furthermore, evidence indicates that a CBl-like receptor exists in vascular endothelium, which upon activation produces significant hypotension (Wagner, 1999). This receptor differs from CB1 in its pharmacological response to some well-characterized cannabimimetics. 

Anandamide may reduce pain by a peripheral action, by acting on CB 1-like receptors located outside the CNS (Calignano et al. 1998). Palmitylethanolamide (PEA) is an endocannabinoid that is coreleased with anandamide and activates peripheral CB2 receptors. When the two are administered together, they show a 100-fold synergistic effect on analgesic measures. Measurements of anandamide and PEA levels in the skin show that there are sufficient amounts to create tonic activation of local cannabinoid receptors. Thus, endocannabinoids may tonically inhibit cutaneous pain. 

Aso E, Juves S, Maldonado R, Ferrer I (2013) CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in A(3PP/PS1 mice. J Alzheimers Dis 35 847-858... 

Griffin G, Fernando SR, Ross RA, McKay NG, Ashford MLJ, Shire D, Huffman JW, Yu S, Lainton JAH, Pertwee RG (1997) Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 339 53-61... 

Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2 69-82... 

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-... 

Malan TP, Ibrahim MM, Vanderah TW et al, (2002) Inhibition of pain responses by activation of CB2 cannabinoid receptors, Chem Phys Lipids 121 191-200 Martin WR, Eades CG, Thompson JA et al, (1976) The effects of morphine- and nalorphine-like drugs in nondependent and morphine-dependent chronic spinal dog, J Pharmacol Exp Ther 197 517-532... 

Noladin ether (3) was recently isolated from porcine brain [16] and found to bind to the CBi receptor (/fj = 21.2 nM), to bind weakly to the CB2 receptor K, > 3 /iM) and it causes typical cannabinoid-like effects such as sedation, hypothermia, intestinal immobility and mild antinociception in mice [16]. This endocannabinoid had previously been synthesised independently by both Mechoulam and co-workers [176] and Sugiura et al. [173]. SAR studies of this endocannabinoid are lacking in the literature, however, a recent publication highlighted the importance of the tetra-unsaturated C20 chain... 

More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CBi receptor (CBp Ki — 0.08 nM CB2 Ki — 1.44nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) [194]. Although these compounds bind to both CBi and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects. 

The discovery of the peripheral CB2 receptor, which localizes in cells of the immune system, is very likely linked to the well-known immunosuppression of marijuana smokers. 

Huang etal. assumed that N-arachidonoyl-dopamine (NADA) may exist as an endogenous capsaicin-like cannabinoid in mammalian nervous tissues and may possibly bind to the vanilloid receptor VRl. They found that NADA is indeed a natural endocannabinoid, in nervous tissues, with high concentrations found in the striatum, hippocampus, and cerebellum. They were also found in lower concentrations in the dorsal root ganglion. NADA binds to the cannabinoid receptors with a 40-fold selectivity for the CBi (K = 250 it 130 nM) over the CB2 receptors. 

Its hypnotic properties were characterized. Its mechanism of action is far from being understood. Although it does not bind with high affinity to CB] or CB2 receptors, it exhibits some cannabimimetic actions, which could be explained at least in part by entourage effects. It is likely that oleamide and anandamide have common as well as distinct pathways of action. The 5-HT2A receptor appears to be a target for oleamide but the possibility of the existence of specific receptors for this compound is still open. Legget et have reported that oleamide is a full cannabi-... 

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