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 P2Y(2) is the principal UTP receptor in somatosensory neurons: P2Y(2) is highly expressed in dorsal root ganglia and P2Y(2)-/- mice showed profound deficits in UTP-evoked calcium transients and potentiation of capsaicin responses. P2Y(2)-/- 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). P2Y(2) 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 P2Y(2)-/- 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 P2Y(2)-/- 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 P2Y(2) plays a key role in thermal nociception.
Malin
Sacha A
SA
Department of Medicine, University of Pittsburgh, Pittsburgh, S841 Scaife Hall, 3550 Terrace Avenue, PA 15261, USA Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA.
Davis
Brian M
BM
Koerber
Richard H
RH
Reynolds
Ian J
IJ
Albers
Kathryn M
KM
Molliver
Derek C
DC
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods*; D012333:RNA, Messenger / Q000096:biosynthesis; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014544:Uridine Triphosphate / Q000378:metabolism
C546386:P2ry2 protein, mouse; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002211:Capsaicin; D014544:Uridine Triphosphate