Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission
Xiaona Du, … , Hailin Zhang, Nikita Gamper
Xiaona Du, … , Hailin Zhang, Nikita Gamper
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1741-1756. https://doi.org/10.1172/JCI86812.
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Research Article Neuroscience

Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission

Abstract

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.

Authors

Xiaona Du, Han Hao, Yuehui Yang, Sha Huang, Caixue Wang, Sylvain Gigout, Rosmaliza Ramli, Xinmeng Li, Ewa Jaworska, Ian Edwards, Jim Deuchars, Yuchio Yanagawa, Jinlong Qi, Bingcai Guan, David B. Jaffe, Hailin Zhang, Nikita Gamper

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Figure 7

Effects of GABA on the somatic excitability of DRG neurons.

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Effects of GABA on the somatic excitability of DRG neurons. GABAA agonis...
GABAA agonists induce depolarization of DRG neurons in culture (A and B) and in acute slice preparation (C and D). Top traces depict exemplary current-clamp recordings during application of 200 μM GABA or 10 μM muscimol (as indicated by horizontal bars). (B) Summary of effects of GABA and muscimol during peak and plateau (steady-state) phases of response recorded from cultured small-diameter DRG neurons. (D) Summary of a steady-state depolarization produced by GABA and muscimol in DRG slices and also the inhibition of GABA response by bicuculline; number of recordings is indicated within the bars. Asterisks indicate significant difference from the baseline: *P < 0.05, ***P < 0.001 (paired, 2-tailed t test). (E–G) GABA inhibits AP firing in most DRG neurons. Shown are exemplary voltage traces before GABA application (black) and also during the peak (red) and steady-state (blue) response. Examples represent neurons in which AP firing is reduced (E), abolished (F), or increased (G). Stimulus protocol (current ramp) is depicted beneath the traces in E. (H) Proportion of neurons in which AP firing was abolished, reduced, or increased or in which there was no response. (I) GABA reduces AP amplitude; further quantification of the effects of GABA on DRG excitability is provided in Supplemental Tables 3 and 4.