Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission

• Published in: The Journal of clinical investigation Vol. 127; no. 5; pp. 1741 - 1756
• Main Authors: Du, Xiaona, Hao, Han, Yang, Yuehui, Huang, Sha, Wang, Caixue, Gigout, Sylvain, Ramli, Rosmaliza, Li, Xinmeng, Jaworska, Ewa, Edwards, Ian, Deuchars, Jim, Yanagawa, Yuchio, Qi, Jinlong, Guan, Bingcai, Jaffe, David B, Zhang, Hailin, Gamper, Nikita
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2017
• Subjects: Animals; Cellular signal transduction; GABA; GABA Uptake Inhibitors - adverse effects; GABA Uptake Inhibitors - pharmacology; GABAergic Neurons - metabolism; Ganglia; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Ganglia, Spinal - physiopathology; Health aspects; Neuralgia - chemically induced; Neuralgia - metabolism; Neuralgia - pathology; Neuralgia - physiopathology; Nociception; Nociception - drug effects; Rats; Rats, Sprague-Dawley; Rats, Wistar; Synaptic Transmission - drug effects
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci86812

The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.