Evidence for the participation of peripheral α₅ subunit-containing GABA_A receptors in GABA_A agonists-induced nociception in rats

The activation of GABA_A receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have suggested that in inflammatory pain, GABA shifts its signaling from inhibition to excitation by an increased GABA-induced depolarization. The contribution of peripheral α₅ subunit-containing GABA _A receptors to the inflammatory pain is unknown. The purpose of this study was to investigate the possible pronociceptive role of peripheral α₅ subunit-containing GABA_A receptors in the formalin test. Formalin (0.5%) injection into the dorsum of the right hind paw produced flinching behavior in rats. Ipsilateral local peripheral pre-treatment (-10 min) with exogenous GABA (0.003-0.03 μg/paw) or common GABA_A receptor agonists muscimol (0.003-0.03 μg/paw), diazepam (0.017-0.056 μg/paw) or phenobarbital (1-100 μg/paw) significantly increased 0.5% formalin-induced nociceptive behavior. The pronociceptive effects of GABA (0.03 μg/paw), muscimol (0.03 μg/paw), diazepam (0.056 μg/paw) and phenobarbital (100 μg/paw) were prevented by either the GABA_A receptor antagonist bicuculline (0.01-0.1 μg/paw) or selective α₅ subunit-containing GABA_A receptor inverse agonist L-655,708 (0.017-0.17 μg/paw). The α₅ subunit-containing GABA_A receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naïve rats. The formalin injection did not modify α₅ subunit-containing GABA_A receptor expression. Overall, these results suggest that peripheral α₅ subunit-containing GABA_A receptors play a pronociceptive role in the rat formalin test.