Mechanism of prostaglandin E(2)-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 E(2), which act directly to sensitize primary afferent nociceptors. Prostaglandin E(2) 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 E(2)-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 E(2) 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 Ca2+-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 E,acts via a G-protein-coupled binding site on dissociated dorsal root ganglion cells to induce a Ca2+-dependent release of substance P, and provide further insight into the possible mechanisms underlying hyperalgesia associated with inflammation.