Mechanisms Involved in Angiotensin Receptor Blockade Superiority over ACE‐inhibition in Attenuating Neuropathic Pain Induced in Rats

Abstract

Although, the beneficial role of angiotensin‐converting enzyme inhibitors (ACEi) or AT1 receptor blockers (ARBs) in attenuating Neuropathic pain (NP) was previously reported, the exact underlying mechanisms as well as superiority of using central versus peripheral acting Renin angiotensin aldosterone system (RAAS) drugs in NP is not yet explored. We investigated the effect of 14 days treatment of centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) ARBs and ACEi, respectively in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats compared to pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (nuclear factor‐kappa B (NFкβ), tumor necrosis factor (TNF)‐α release, Cyclooxygenase‐2 (COX‐2), prostaglandin E2 (PGE2) and bradykinin), oxidative stress markers (NADPH oxidase and catalase), signal transducer and activator of transcription 3 (STAT‐3) activation, levels of phosphorylated P38 mitogen activated protein kinase (P38 MAPK), angiotensin converting enzyme (ACE), AT1 receptor (AT1R) and AT2 receptor (AT2R) as well as histopathological picture were assessed in brain stem and sciatic nerve. CCI resulted in an obvious painful behavior along with increased levels of inflammatory and oxidative stress markers, STAT3 activity as well as the levels of phosphorylated P38 MAPK, ACE, AT1R and AT2R and worsened histopathological picture in both the brainstem and sciatic nerve. Treatment of CCI rats with ARBs resulted in improving in animal behavior and all measured parameters and were more effective compared to ACE inhibitors. Centrally acting ARBs or ACEi were not superior compared to their peripherally acting drugs of the same category. These findings suggest ARBs (central or peripheral) as an effective treatment modality for NP.