Intrathecal carbenoxolone inhibits neuropathic pain and spinal wide-dynamic range neuronal activity in rats after an L5 spinal nerve injury

Abstract

Spinal glial gap junctions may play an important role in dorsal horn neuronal sensitization and neuropathic pain. In rats after an L5 spinal nerve ligation (SNL), we examined the effects of intrathecal injection of carbenoxolone (CBX), a gap junction decoupler, on neuropathic pain manifestations and on wide-dynamic range (WDR) neuronal activity in vivo. Intrathecal injection of CBX dose-dependently (0.1–50μg, 10μl) inhibited mechanical hypersensitivity in rats at 2–3 weeks post-SNL. However, the same doses of glycyrrhizic acid (an analogue of CBX that does not affect gap junctions) and mefloquine hydrochloride (a selective neuronal gap junction decoupler) were ineffective. Intrathecal CBX (5μg) also attenuated heat hypersensitivity in SNL rats. Further, rats did not develop tachyphylaxis to CBX-induced inhibition of mechanical hypersensitivity after repetitive drug treatments (25μg/day) during days 14–16 post-SNL. Electrophysiological study in SNL rats showed that spinal topical application of CBX (100μg, 50μl), which mimics intrathecal drug administration, attenuated WDR neuronal responses to mechanical stimuli and to repetitive intracutaneous electrical stimuli (0.5Hz) that induce windup, a short-form of activity-dependent neuronal sensitization. The current findings suggest that the inhibition of neuropathic pain manifestations by intrathecal injection of CBX in SNL rats may involve an inhibition of glial gap junctions and an attenuation of WDR neuronal activity in the dorsal horn.