Mechanism of prostaglandin E2-induced substance P release from cultured sensory neurons.
Hyperalgesia (tenderness) is a prominent feature of the inflammatory response. It is thought to be mediated, in part, by humoral factors such as prostaglandin E2, which act directly to sensitize primary afferent nociceptors. Prostaglandin E2 also interacts with nociceptors to induce a release of substance P, which can feed back to enhance the inflammatory response and also induce a long-lasting hyperalgesia. This study examined the mechanism of prostaglandin E2-induced substance P release from cultured adult rat dorsal root ganglion cells. Release studies were performed by bathing cultures with Tyrode solution +/- test agents and substance P was measured by radioimmunoassay. Substance P release induced by 100 nM prostaglandin E2 was inhibited by the prostaglandin antagonist, SC19220, and modulated by the guanine nucleotide analogs, guanosine-5'-[gamma-thio]triphosphate and guanosine-5'-[beta-thio]diphosphate, which stimulate and inhibit, respectively, stimulatory G-proteins. Substance P release was found to be Ca(2+)-dependent, requiring an influx of Ca2+ via N-type voltage-sensitive Ca2+ channels, since it was blocked by omega-conotoxin, but not nifedipine. The results suggest that prostaglandin E2 acts via a G-protein-coupled binding site on dissociated dorsal root ganglion cells to induce a Ca(2+)-dependent release of substance P, and provide further insight into the possible mechanisms underlying hyperalgesia associated with inflammation.
White
D M
DM
Department of Anaesthesia and Pain Management, University of Sydney, Australia.
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D017950:Ganglia, Sensory / Q000187:drug effects*; D005727:Ganglia, Spinal / Q000187:drug effects*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000378:metabolism*
D013373:Substance P; D009543:Nifedipine; D015232:Dinoprostone