Antagonism of GABA-A receptor inhibits the effects of progesterone on nociceptive behaviors and electrophysiological alterations in a rat model of neuropathic pain.

Growing evidence highlights the neuroprotective potential of progesterone in mitigating various forms of nervous system injury. In previous research, we demonstrated that progesterone ameliorates both electrophysiological and behavioral deficits associated with chronic constriction injury (CCI) of the sciatic nerve in rats. However, the precise mechanisms underlying these effects remain poorly understood. This study aimed to elucidate the involvement of GABA-A receptors in mediating the therapeutic effects of progesterone on nociceptive behaviors, specifically thermal hyperalgesia and mechanical allodynia, as well as electrophysiological alterations in a rat model of CCI-induced neuropathic pain. Male rats received daily intraperitoneal injections of progesterone (6 mg/kg) starting on day 12 post-CCI and continuing through day 26. To evaluate the role of GABA-A receptors, the antagonist bicuculline (0.5 or 2 mg/kg, i.p.) was administered 30 min prior to progesterone in designated groups. Behavioral assessments were conducted on days 0, 12, 26, 28, and 35 post-CCI, followed by electrophysiological evaluations of the tibial and sural nerves. The results revealed that progesterone significantly attenuated both thermal hyperalgesia and mechanical allodynia and reversed CCI-induced electrophysiological impairments. Nevertheless, pretreatment with bicuculline blocked these beneficial effects at both behavioral and electrophysiological levels, suggesting that progesterone's neuroprotective and analgesic properties are, at least in part, mediated through GABA-A receptor signaling pathways.