Abstract: Objective: Peripheral nerve injury downregulates connexin43 (Cx43) expression in spinal astrocytes. Therefore, restoration of spinal astrocyte Cx43 expression to normal levels could lead to the reduction of nerve injury-induced pain. It has been shown that inhibitors of phosphodiesterase-4 (PDE4), an enzyme catalyzing the hydrolysis of cyclic AMP (cAMP), reverse mechanical pain in mice with neuropathic pain. However, the antinociceptive mechanism remains unclear. In the present study, we evaluated the antinociceptive effect of PDE4 inhibitors and demonstrated a novel mechanism by which PDE4 mediates nociception via Cx43 in spinal astrocytes. Methods: The effects of PDE4 inhibitors on neuropathic pain and Cx43 expression in spinal astrocytes were evaluated in mice with partial sciatic nerve ligation (PSNL). Results: Single or repeated, intraperitoneal treatment with the selective PDE4 inhibitor rolipram or roflumilast of mice with PSNL significantly reduced mechanical hypersensitivity. This was mimicked by intrathecal administration of rolipram or roflumilast. In addition, repeated intrathecal treatment with rolipram or roflumilast of mice with PSNL completely prevented the downregulation of Cx43 expression in the spinal dorsal horn. Conclusion: The results suggest that PDE4 inhibitors ameliorate neuropathic pain, which is mediated by a spinal mechanism through the restoration of spinal Cx43 expression.

Key words: phosphodiesterase-4 （PDE4）, connexin43, rolipram, roflumilast, neuropathic pain