Peripheral GABA_A receptor-mediated signaling facilitates persistent inflammatory hypersensitivity.

Unlike in the central nervous system (CNS), in the adult peripheral nervous system (PNS), activation of GABA_A receptors (GABA_AR) is excitatory because of the relatively high concentration of intracellular chloride in these neurons. Indeed, exogenous GABA and muscimol, a GABA_AR agonist, exacerbate acute inflammatory hypersensitivity in rodents. However, it remains unclear whether peripheral GABA_AR and the endogenous GABA play an important role in persistent inflammatory hypersensitivity. In this study, we thus investigated how peripheral GABA_AR affects pain hypersensitivity by using the complete Freund's adjuvant (CFA)-induced persistent inflammatory pain mouse model. We found that intraplantar (i.pl.) administration of GABA_AR antagonists, picrotoxin, and 1(S),9(R)-(-)-bicuculline methiodide significantly inhibited both spontaneous nociceptive (paw licking and flinching) behavior and mechanical hypersensitivity in CFA-injected mice at day 3 (D3), but not in naïve mice. Interestingly, CFA-induced mechanical hypersensitivity was significantly reversed by anti-GABA antibody (anti-GABA, i.pl.). In addition, RT-qPCR revealed that glutamate decarboxylase Gad1 (GAD 67) and Gad2 (GAD 65) mRNA expression was also upregulated in the ipsilateral hind paw of CFA-injected mice at D3. Finally, 5α-pregnan-3α-ol-20-one (3α,5α-THP), a selective positive allosteric modulator of GABA_AR, produced mechanical hypersensitivity in naïve mice in a dose-dependent manner. Taken together, our results indicate that peripheral GABA_AR and endogenous GABA, possibly produced by the inflamed tissue, potentiate CFA-induced persistent inflammatory hypersensitivity, suggesting that they can be used as a therapeutic target for alleviating inflammatory pain.

Duke Scholars

Author Seog Oh Physics