Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2

Recent studies indicate that ATP and UTP act at G protein-coupled (P2Y) nucleotide receptors to excite nociceptive sensory neurons; nucleotides also potentiate signaling through the pro-nociceptive capsaicin receptor, TRPV1. We demonstrate here that P2Y2 is the principal UTP receptor in somatosensory neurons: P2Y2 is highly expressed in dorsal root ganglia and P2Y2(−/−) mice showed profound deficits in UTP-evoked calcium transients and potentiation of capsaicin responses. P2Y2(−/−) mice were also deficient in the detection of painful heat: baseline thermal response latencies were increased and mutant mice failed to develop thermal hypersensitivity in response to inflammatory injury (injection of complete Freund's adjuvant into the hindpaw). P2Y2 was the only Gq-coupled P2Y receptor examined that showed an increase in DRG mRNA levels in response to inflammation. Surprisingly, TRPV1 function was also attenuated in P2Y2(−/−) mice, as measured by the frequency and magnitude of capsaicin responses in vitro and behavioral responses to capsaicin administration in vivo. However, TRPV1 mRNA levels and immunoreactivity were not reduced, and behavioral sensitivity to capsaicin could be largely restored in P2Y2(−/−) mice by pretreatment with bradykinin, suggesting that normal function of TRPV1 requires ongoing modulation by G protein-coupled receptors. These results indicate that nucleotide signaling through P2Y2 plays a key role in thermal nociception.