Anandamide and vanilloid TRPV1 receptors

Abstract

A large body of evidence now exists to substantiate that the endocannabinoid, anandamide, activates TRPV1 receptors. It is a low intrinsic efficacy TRPV1 agonist that behaves as a partial agonist in tissues with a low receptor reserve, while in tissues with high receptor reserve and in circumstances associated with certain disease states, it behaves as a full agonist. The efficacy of anandamide as a TRPV1 agonist is influenced by a succession of factors including receptor reserve, phosphorylation, metabolism and uptake, CB1 receptor activation, voltage, temperature, pH and bovine serum albumin. There are indications that the endocannabinoid system may play a role in the modulation of TRPV1 receptor activation. The activation of TRPV1 receptors by anandamide has potential implications in the treatment of inflammatory, respiratory and cardiovascular disorders. The relative importance of anandamide as a physiological and/or pathophysiological TRPV1 receptor agonist in comparison to other potential candidates has yet to be revealed.

Figure 1

Metabolic pathways of anandamide and arachidonic acid related to the TRPV1 receptor. Anandamide (AEA) is rapidly hydrolysed by FAAH to yield arachidonic acid and ethanolamide. Arachidonic acid (AA) is oxygenated by lipoxygenase enzymes: the products include 12-(S)- and 15-(S)-HPETE, 5-(S)HETE and LTB₄ that are TRPV1 agonists (Hwang et al., 2001). Anandamide is also a substrate for lipoxygenase (see Kozak & Marnett, 2002), yielding equivalent HPETE ethanolamides (HPETEE) and HETE ethanolamides (HETEE) that may also be TRPV1 agonists (Craib et al., 2001). The lipoxygenase products of anandamide are potent inhibitors of FAAH (Maccarrone et al., 2000d). PKC can activate the TRPV1 receptor directly (Premkumar & Ahern, 2000; Olah et al., 2002), and it will also sensitise the receptor to other agonists (Vellani et al., 2001). Anandamide can activate PKC directly (De Petrocellis et al., 1995; Premkumar & Ahern, 2000). CB₁ receptor activation is coupled to the stimulation of PLC, hydrolysis of PIP2 and release of the TRPV1 receptor from the tonic inhibitory effect of this compound (see Hermann et al., 2003). Anandamide formation occurs through phosphodiesterase-mediated cleavage of a phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine (NAPE), and its production in and release from neurones is calcium dependent (Di Marzo et al., 1994). In cultured neurones, anandamide is synthesised in response to TRPV1 receptor activation (Ahluwalia et al., 2003).