Abstract<\/b><\/p>\n
Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a G\u03b25-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes G\u03b25 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+\/- Gnb5fl\/fl mice but not in Rgs9-Cre+\/- Gnb5fl\/fl mice, suggesting that G\u03b25 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, G\u03b25-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of G\u03b25 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist \u03b2-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+\/- Gnb5fl\/fl mice. Taken together, these results suggest that the targeted inhibition of G\u03b25 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.<\/p>\n
Mritunjay Pandey\u00a01,\u00a0Jian-Hua Zhang\u00a01,\u00a0Poorni R Adikaram\u00a01,\u00a0Claire Kittock\u00a01,\u00a0Nicole Lue\u00a01,\u00a0Adam Awe\u00a01,\u00a0Katherine Degner\u00a01,\u00a0Nirmal Jacob\u00a01,\u00a0Jenna Staples\u00a01,\u00a0Rachel Thomas\u00a01,\u00a0Allison B Kohnen\u00a01,\u00a0Sundar Ganesan\u00a02,\u00a0Juraj Kabat\u00a02,\u00a0Ching-Kang Chen\u00a03,\u00a0William F Simonds\u00a01<\/p>\n","protected":false},"excerpt":{"rendered":"
Abstract Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a G\u03b25-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice […]<\/p>\n","protected":false},"author":315,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"class_list":["post-1778","post","type-post","status-publish","format-standard","hentry","category-highimpactpublication"],"yoast_head":"\n