Peripheral neurosteroids enhance P2X receptor-induced mechanical allodynia via a sigma-1 receptor-mediated mechanism

The role of peripheral neurosteroids and their related mechanisms on nociception have not been thoroughly investigated. Based on emerging evidence in the literature indicating that neurosteroids and their main target receptors, i.e., sigma-1, GABA(A) and NMDA, affect P2X-induced changes in neuronal activity, this study was designed to investigate the effect of peripherally injected dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulfate (PREGS) on P2X receptor-mediated mechanical allodynia in rats. Intraplantar injection of either neurosteroids alone did not produced any detectable changes in paw withdrawal frequency to the innocuous mechanical stimulation in naive rats. However, When DHEAS or PREGS were co-injected with a sub-effective dose of alpha beta meATP, mechanical allodynia was developed and this was dose dependently blocked by pre-injection of the P2X antagonist, TNP-ATP. These results demonstrates that DHEAS and PREGS potentiate the activity of P2X receptors which results in the enhancement of alpha beta meATP-induced mechanical allodynia. In order to investigate the potential role of peripheral sigma-1, GABA(A) and NMDA receptors in this facilitatory action, we pretreated animals with BD-1047 (a sigma-1 antagonist), muscimol (a GABA(A) agonist) or MK-801 (a NMDA antagonist) prior to DHEAS or PREGS + alpha beta meATP injection. Only BD-1047 effectively prevented the facilitatory effects induced by neurosteroids on alpha beta meATP-induced mechanical allodynia. Collectively, we have shown that peripheral neurosteroids potentiate P2X-induced mechanical allodynia and that this action is mediated by sigma-1, but not by GABA(A) nor NMDA, receptors. (C) 2016 Elsevier Inc. All rights reserved.