Renin-angiotensin system blockade modulates both the peripheral and central components of neuropathic pain in rats: Role of calcitonin gene-related peptide, substance P and nitric oxide.

Nonetheless, renin-angiotensin-aldosterone system (RAAS) blockers attenuate neuropathic pain (NP), the exact molecular mechanisms of this effect are not completely understood. The study aimed to investigate the role of calcitonin gene-related peptide (CGRP), substance P (SP) and nitric oxide (NO), which are all involved in pain modulation, in the analgesic effect of different RAAS blockers in NP both on the peripheral and on the central levels. NP was induced by sciatic nerve chronic constriction injury (CCI, 14 days) in rats, that were given either centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) acting angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs). Behavioural assessment was performed, and CGRP, SP and NO levels were detected in the injured sciatic nerve and the brainstem at the end of experiment. CCI rats showed increased spontaneous pain response and foot deformity along with elevated CGRP, SP and NO levels. ARBs and ACE-Is treatment improved pain behaviour and reduced SP and NO levels. However, sciatic CGRP was increased with different interventions and brainstem CGRP was only elevated in the losartan group. These findings suggest an intermediary role of CGRP, SP and NO in RAAS blockers analgesic effect in NP.