Peripheral nervous system cannabinoid receptors

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). 

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

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. 

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... 

Distribution of Cannabinoid Receptors in the Central and Peripheral Nervous System... 

Abstract The CBi cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CBi receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The consequence is inhibition of neurotransmission via a presynaptic mechanism. Inhibition of glutamatergic, GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many regions... 

Advances in the understanding of endogenous control of pain were obtained with cannabinoids. Throughout history, Cannabis sativa L. has been used as a natural therapeutic herb as well as an analgesic. The Cannabis plant contains a complex mixture of substances that include at least 60 different cannabinoids, including A9-tetrahydrocannabinol (THC) [29]. Pharmacological studies have demonstrated that THC and other active cannabinoids act at specific receptors called CB1 and CB2 [30]. The cannabinoid receptors are expressed in both the peripheral and central nervous system and are endogenously activated by... 

From the discovery of anandamide in the central nervous system and the identification of classical cannabinoid CB, and CBj receptors, both centrally and peripherally, the cardiovascular actions have received interest. To date there have been a number of studies which point to endocannabinoids having vasodilator actions, whereas the in vivo effects are less clear. One key point to emerge is that endocannabinoids may act via a range of mechanisms, of which action at vanilloid receptors is now well established. 

Although cannabinoid drugs have been used recrea-tionally and therapeutically for millennia little was known regarding their sites of activity and mechanisms of action. In recent years the pharmacological and behavioral properties of these molecules have been more thoroughly defined [1,2]. Development of ligands that preferentially bind to peripheral receptors may offer the promise of effective analgesia without the central nervous system effects of nonselective cannabinoids. 

The existence of cannabinoid receptors was confirmed when it was observed that cannabinoids decreased cAMP levels in neuroblastoma cell cultures (Howlett, 1984). This finding was followed by the determination and characterization of a cannabinoid receptor in rat brain (Devane et al., 1988). Shortly after, the stmcture of this CBj receptor and functional expression of the cloned cDNA was reported (Matsuda et al, 1990). The CBj receptor is found in the central nervous system as well as in several peripheral tissues, including testis, small intestine, vascular endothelium, utems and vas deferens (Herkenham et al., 1990). The distribution and localization of CBj receptor in the brain correlates well with the known effects of cannabinoids on memory, perception and the control of movement. CBj receptors are highly expressed in the hippocampus, association cortex, cerebellum and basal ganglia. 

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