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

Abstract 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 α 5 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 α 5 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 α 5 subunit-containing GABA A receptor inverse agonist L-655,708 (0.017-0.17 µg/paw). The α 5 subunit-containing GABA A receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naive rats. The formalin injection did not modify α 5 subunit-containing GABA A receptor expression. Overall, these results suggest that peripheral α 5 subunit-containing GABA A receptors play a pronociceptive role in the rat formalin test.