Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats.

Although previous reports described the beneficial role of angiotensin-converting enzyme inhibitors (ACE-Is) or AT1 receptor blockers (ARBs) in attenuating neuropathic pain (NP), no study has yet explored the exact underlying mechanisms, as well as the superiority of using centrally versus peripherally acting renin-angiotensin-aldosterone system (RAAS) drugs in NP. We investigated the effects of 14 days of treatment with centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) acting ARBs and ACE-Is, respectively, in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats. We also compared these with the effects of pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (NFкB, TNF-α, COX-2, PGE2, and bradykinin), oxidative stress markers (NADPH oxidase and catalase), STAT3 activation, levels of phosphorylated P38-MAPK, ACE, AT1 receptor (AT1R), and AT2 receptor (AT2R), as well as histopathological features, were assessed in the brainstem and sciatic nerve. CCI resulted in clear pain-related behavior along with increased levels of inflammatory and oxidative stress markers, and STAT3 activity, as well as increased levels of phosphorylated P38-MAPK, ACE, AT1R, and AT2R, along with worsened histopathological findings in both the brainstem and sciatic nerve. ARBs improved both animal behavior and all measured parameters in CCI rats and were more effective than ACE-Is. At the tested doses, centrally acting ARBs or ACE-Is were not superior to the peripherally acting drugs of the same category. These findings suggest that ARBs (centrally or peripherally acting) are an effective treatment modality for NP.

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.