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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

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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 4

Focal application of GABA to DRG reduces pain in vivo.

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Focal application of GABA to DRG reduces pain in vivo.
(A) DRG cannula i...
(A) DRG cannula implant. Top inset shows schematic of the procedure; colors indicate route of drug administration. Images on the bottom are bright-field (left) and fluorescent (right) micrographs of DRG (top) and proximal spinal cord (bottom) after the focal application of a fluorescent dye, CFSE (20 μM in 5 ml), via the DRG cannula. All images were taken at the same magnification (as indicated by the scale bars). (B) Focal DRG application of GABA (200 μM, 5 μl) via DRG cannula strongly reduced pain produced by hind-paw injection of bradykinin (BK, 200 μM, 50 μl). (C) Similar to B but the specific GABAA receptor agonist muscimol (musc, 200 μM, 5 μl) was applied. (D) Focal DRG application of GABA (200 μM, 5 μl) via DRG cannula reduced pain produced by hind-paw injection of capsaicin (CAP, 20 μM, 50 μl). (E) Comparison of effects of focal DRG application of GABA, muscimol, baclofen, and glutamate (GLUT) (all at 200 μM, 5 μl) on the BK-induced nocifensive behavior. Black bars depict effect of intrathecal injection of glutamate (200 μM, 10 μl) and a vehicle control. (F) Focal DRG application of GAT1 inhibitor NO711 (200 μM, 5 μl) significantly reduced pain produced by hind-paw injection of BK. (G) Focal DRG application of GABAA receptor inhibitors bicuculline (BIC, 200 μM, 5 μl) and gabazine (200 μM, 5 μl) and GABAB receptor inhibitor CGP35348 (CGP, 200 μM, 5 μl) exacerbated nocifensive behavior produced by hind-paw BK injection. (H) In the absence of plantar injection of BK, focal DRG application of bicuculline and gabazine resulted in distress in the paw and nocifensive behavior similar to that induced by plantar injection of BK. In B–H the number of experiments is indicated within or above each bar; asterisks indicate significant difference from the appropriate control: *P < 0.05, **P < 0.01, ***P < 0.001 (Kruskal-Wallis ANOVA with Mann-Whitney test for between-group comparison).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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