Gα q/11 signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization

Abstract

Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled receptors) coupling to G s, G i/o, G 12/13, or G q/11 G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. The G q/G 11 signaling branch is of particular interest because it leads to the activation of phospholipase C-β, protein kinase C, the release of calcium from intracellular stores, and it modulates extracellular regulated kinases. To investigate the contribution of the entire G q/11-signaling pathway in nociceptors towards regulation of pain, we generated double-deficient mice lacking G q/11 selectively in nociceptors using a conditional gene-targeting approach. We observed that nociceptor-specific loss of G q and G 11 results in reduced pain hypersensitivity following paw inflammation or spared nerve injury. Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G q/11 mutant mice, suggesting a novel function for G q/11 in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G q/11, whereas potassium currents remained unchanged. Our results indicate that the functional role of the G q/G 11 branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain.