The P2Y agonist UTP activates cutaneous afferent fibers.
The majority of adenosine triphosphate (ATP)-induced nociceptive transduction and pain has been attributed to ionotropic P2X3 receptors. Metabotropic P2Y receptors, some of which bind pyrimidines as well as purines, have received little attention. Here we have examined the ability of P2Y receptor signaling to evoke action potential firing in functionally identified afferent fibers using the skin nerve preparation from adult mouse. The P2Y2/P2Y4 ligand UTP activated sustained action potential firing in 54% of C fibers in a concentration-dependent manner. The effect was specific for P2Y2/P2Y4 receptors, as the P2Y6 ligand UDP never activated C fibers. In comparison to C fibers, few thinly myelinated A-mechanoreceptors (AM) (12%) were activated by UTP. The majority (70-80%) of the UTP-sensitive C and Adelta fibers responded to the algogen capsaicin with a barrage of action potentials, whereas the UTP-insensitive fibers were largely unresponsive to capsaicin. Furthermore, 86% of the UTP-sensitive C fibers and 100% of the UTP-sensitive AM fibers also responded to the P2X agonist alpha,beta-methylene ATP, indicating that P2Y and P2X receptors are widely co-expressed. Surprisingly, a significant proportion (20-40%) of low threshold slowly and rapidly adapting Abeta fibers were also activated by UTP and alpha,beta-methylene ATP. These data indicate that P2Y receptors on the terminals of capsaicin-sensitive cutaneous sensory neurons effectively evoke nociceptive transmission, and support the hypothesis that UTP may be an endogenous nociceptive messenger. Furthermore, P2Y signaling may contribute to mechanotransduction in low threshold Abeta fibers under normal or pathological conditions.
Stucky
Cheryl L
CL
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA. cstucky@mcw.edu
Medler
Karen A
KA
Molliver
Derek C
DC
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects; D058910:Purinergic P2 Receptor Agonists; D012867:Skin / Q000294:innervation; D014544:Uridine Triphosphate / Q000494:pharmacology*
D000970:Antineoplastic Agents; D058910:Purinergic P2 Receptor Agonists; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D002211:Capsaicin; D014544:Uridine Triphosphate