Interaction between vanilloid receptors and purinergic metabotropic receptors: pain perception and beyond.

Abstract

The capsaicin or vanilloid receptor (VR) plays an important role in transducing thermal and inflammatory pain. The VR is a nonselective cation channel that possesses a high permeability to Ca2+ ( P Ca/ P Na ratio ≈10, similar to that of the N- methyl-d-aspartate receptor), exhibits strong outward rectification, and desensitizes after repeated stimulation (tachyphylaxis) (1). Two types of VRs (VR1, VR-L) and a splice variant (VR.5′sv) have been cloned (2–4). Generally, VRs are thought to be distributed in peripheral sensory nerve endings and involved in the perception of noxious stimuli. The activation of VRs depolarizes the sensory nerve endings and evokes a train of action potentials that propagates to the spinal cord and brain. Mice lacking the VR1 gene have deficits in thermal- or inflammation-induced hyperalgesia but are sensitive to noxious heat, which largely confirms a role in certain modalities of nociception (5, 6). On the other hand, purinergic receptors (P2Y) also are expressed in nociceptive sensory nerve endings. They are either coupled directly to ion channels (ionotropic) or to the G protein-mediated production of second messengers (metabotropic). Seven ionotropic (P2X1–7) and six genuine metabotropic receptors (P2Y1,2,4,6,11,12) (from a total of 13 P2Y-like cDNA clones) have been cloned. The P2X3 subtype is exclusively expressed in the peripheral nerve endings (7, 8). Algesic properties of ATP are thought to occur by the activation of P2X receptors. Although the source for extracellular ATP is a debated issue, a number of possibilities have been suggested: ( i ) mechanical stimulation; ( ii ) activation of connexin hemichannels; ( iii ) synaptic vesicle exocytosis; ( iv ) tissue damage; and ( v ) from nerve endings after noxious stimulation (7, 9). Activation of P2X3 receptors by ATP is not a favorable means of nociception because …