Antihyperalgesic effects of ACE2 activation in a neuropathic pain model involve spinal MAS1 receptor signaling and ATP-sensitive potassium channels.

Exogenous angiotensin (Ang) (1-7) supplementation and MAS1 receptor activation have been implicated in pain regulation; however, the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2), which promotes endogenous Ang (1-7) production, on neuropathic pain remain unclear. In this study, we investigated the antihyperalgesic effects of diminazene aceturate (DIZE), an ACE2 activator, and its underlying mechanisms in chronic constriction injury (CCI) mice. DIZE (15 mg/kg, i.p.) was administered once daily after CCI surgery, and mechanical and thermal sensitivity were assessed using the von Frey and Hargreaves tests, respectively. DIZE significantly attenuated CCI-induced mechanical and thermal hyperalgesia. CCI itself did not alter the expression levels of Ang-generating system components in the dorsal root ganglion or spinal cord, whereas DIZE increased ACE2 expression in the spinal cord. Immunofluorescence analysis showed increased ACE2 expression in the spinal dorsal horn, particularly in laminae I-II. Intrathecal administration of the MAS1 receptor antagonist A779 suppressed the antihyperalgesic effects of DIZE. Pharmacological ATP-sensitive potassium (KATP) channel opening with diazoxide attenuated CCI-induced hyperalgesia, whereas blockade of these channels with glibenclamide induced mechanical and thermal hyperalgesia in naïve mice. DIZE attenuated glibenclamide-induced hyperalgesia, and this effect was reduced by A779. Furthermore, MAS1 receptor immunoreactivity overlapped with that of KATP channel subunits, including SUR1, SUR2A, and Kir6.1, in the spinal dorsal horn. These findings suggest that DIZE attenuates neuropathic pain-related hyperalgesia through activation of the spinal ACE2/MAS1 receptor axis and the involvement of KATP channels.