Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors

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JCI Insight. 2023 Jul 10;8(13):e134685. doi: 10.1172/jci.insight.134685.

Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors

Mritunjay Pandey, Jian-Hua Zhang, Poorni R Adikaram, Claire Kittock, Nicole Lue, Adam Awe, Katherine Degner, Nirmal Jacob, Jenna Staples, Rachel Thomas, Allison B Kohnen, Sundar Ganesan, Juraj Kabat, Ching-Kang Chen, William F Simonds

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA. Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA. Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

Service type: Knock-in mice


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 Gβ5-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 Gβ5 (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 Gβ5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gβ5-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 Gβ5 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 β-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 Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.

Keywords: G protein–coupled receptors; G proteins; Neuroscience; Pain.

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