Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission
Xiaona Du ... Hailin Zhang, Nikita Gamper
Xiaona Du ... Hailin Zhang, Nikita Gamper
Published May 1, 2017
Citation Information: J Clin Invest. 2017;127(5):1741-1756. doi:10.1172/JCI86812.
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Categories: 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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Stimulus-induced release of GABA from DRG neurons. (A–E) “Sniffing patch...

Figure 1

Stimulus-induced release of GABA from DRG neurons.

(A–E) “Sniffing patch” experiments. (A) Coculture of DRG neurons with HEK293 cells transiently cotransfected with α1, β2, and γ2 GABAA subunits and GFP (HEKGABAA cells). (B) An example of recording from the GFP-positive HEKGABAA cell juxtaposed to a small-diameter rat DRG neuron (as shown in A). Timing of GABA (200 μM) and capsaicin (CAP, 1 μM) applications is indicated by the arrows. (C) A similar experiment but with HEKGABAA monoculture (no DRG neurons present). (D) A recording from a nontransfected HEK293 (HEKcontrol) cell in close apposition to a small DRG neuron. (E) Mechanical stimulation of DRG neuron in HEKGABAA-DRG coculture did not activate inward current in HEKGABAA cell. (F) Summary of the experiments shown in B–E; number of responsive cells from the total number of recordings is indicated within/above each bar. (G) Summary of experiments shown in E; “Mechano” indicates mechanical stimulation of DRG neuron adjacent to the “sniffing” HEKGABAA cell. *Significant difference from baseline at P < 0.05 (1-way ANOVA with Bonferroni correction). (H–L) HPLC analyses. (H) Release of GABA from the dissociated DRG cultures in response to various stimuli (as indicated). (I) Similar to H but acutely extracted, non-dissociated DRGs were used. Asterisks indicate significant difference from basal release: *P < 0.05, **P < 0.01, ***P < 0.001 (1-way ANOVA with Bonferroni correction). Number of experiments is indicated within each bar. (J–L) Effects of the synaptic transmission inhibitors concanamycin A (0.5 μM; J) and tetanus toxin (10 μg/ml; K), as well as the GAT1 blocker NO711 (200 μM; L), on the basal and high-extracellular-K+-induced GABA release from acutely extracted whole DRGs. Asterisks indicate significant difference from basal release: *P < 0.05, **P < 0.01, ***P < 0.001; number symbols indicate significant difference from high-K+-induced release: #P < 0.05, ##P < 0.01, ###P < 0.001 (1-way ANOVA with Bonferroni correction). Number of experiments is indicated within each bar.