Possible Involvement of P2Y₂Metabotropic Receptors in ATP-Induced Transient Receptor Potential Vanilloid Receptor 1-Mediated Thermal Hypersensitivity

Abstract

The capsaicin receptor transient receptor potential V1 (TRPV1; also known as vanilloid receptor 1) is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that extracellular ATP potentiates the TRPV1 currents evoked by capsaicin or protons and reduces the temperature threshold for its activation through metabotropic P2Y receptors in a PKC-dependent pathway, suggesting that TRPV1 activation could trigger the sensation of pain at normal body temperature in the presence of ATP. Here, we show that ATP-induced thermal hyperalgesia was abolished in mice lacking TRPV1, suggesting the functional interaction between ATP and TRPV1 at a behavioral level. However, thermal hyperalgesia was preserved in P2Y1 receptor-deficient mice. Patch-clamp analyses using mouse dorsal root ganglion neurons indicated the involvement of P2Y2 rather than P2Y1 receptors. Coexpression of TRPV1 mRNA with P2Y2 mRNA, but not P2Y1 mRNA, was determined in the rat lumbar DRG using in situ hybridization histochemistry. These data indicate the importance of metabotropic P2Y2 receptors in nociception through TRPV1.

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…This has been mainly due to their complex pharmacology and to the longstanding lack of selective ligands for different P2Y receptor subtypes, an issue that has only recently started to be resolved (Table 1; Figures 1 and 2). Messenger RNAs for P2Y 1,2,4,6,12,13,14 subtypes have been found in DRG neurons [30,31,32], suggesting that these receptors may play an ancillary role in peripheral somatosensory transmission [33,34]. P2Y receptors are located not only in the cell body, but also in peripheral and central terminals [35,36], where their activity is presumably integrated within the complex molecular network associated with the transmission of nociceptive signals to the CNS.…”

“…Also activation of P2Y 2 receptors can excite DRG neurons [41], but again the underlying mechanism remains obscure. This receptor subtype can sensitize TRPV 1 channels in mouse DRGs [33,42], and modulate pro-algogenic neuropeptide release. In fact, the P2Y 2,4 preferential agonist, UTP, can induce the release of CGRP from rat DRG neurons [43].…”

Enhancement of purinergic signalling by excessive endogenous ATP in resiniferatoxin (RTX) neuropathy

“…However, P2Y2-mediated neuropathic pain behaviors required co-activation with TRPV1 receptor [27][28][29]. Taken together, this implies that the P2Y2 purinoceptor might have minor roles in RTXinduced neuropathic pain due to high coexpression with the TRPV1 receptor [27,29] which was depleted by RTX [17]. In the current study, apyrase removed endogenous ATP and relieved neuropathic pain behaviors.…”

“…This was verified by linear regression analyses: variations in endogenous ATP were linearly correlated with P2X3 expression and the degree of neuropathic pain. The above observations were further confirmed by apyrase treatment which degraded ATP-mediated neuropathic pain behaviors also involve G protein-coupled P2Y2 purinoceptors [25,26] which are widely expressed by DRG neurons [27]. However, P2Y2-mediated neuropathic pain behaviors required co-activation with TRPV1 receptor [27][28][29].…”

“…The above observations were further confirmed by apyrase treatment which degraded ATP-mediated neuropathic pain behaviors also involve G protein-coupled P2Y2 purinoceptors [25,26] which are widely expressed by DRG neurons [27]. However, P2Y2-mediated neuropathic pain behaviors required co-activation with TRPV1 receptor [27][28][29]. Taken together, this implies that the P2Y2 purinoceptor might have minor roles in RTXinduced neuropathic pain due to high coexpression with the TRPV1 receptor [27,29] which was depleted by RTX [17].…”