MECHANISM OF PROSTAGLANDIN E(2)-INDUCED SUBSTANCE-P RELEASE FROM CULTURED SENSORY NEURONS

Hyperalgesia (tenderness) is a prominent feature of the inflammatory r esponse. It is thought to be mediated, in part, by humoral factors suc h as prostaglandin E(2), which act directly to sensitize primary affer ent nociceptors. Prostaglandin E(2) also interacts with nociceptors to induce a release of substance P, which can feed back to enhance the i nflammatory 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 +/- te st agents and substance P was measured by radioimmunoassay. Substance P release induced by 100 nM prostaglandin E(2) was inhibited by the pr ostaglandin antagonist, SC19220, and modulated by the guanine nucleoti de analogs, guanosine-5'-[gamma-thio]triphosphate and guanosine-5'-[be ta-thio]diphosphate, which stimulate and inhibit, respectively, stimul atory 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 res ults suggest that prostaglandin E,acts via a G-protein-coupled binding site on dissociated dorsal root ganglion cells to induce a Ca2+-depen dent release of substance P, and provide further insight into the poss ible mechanisms underlying hyperalgesia associated with inflammation.