This study investigated the involvement of nitric oxide (NO) in peripheral neuropathy produced by chronic constriction injury (CCI) of the sciatic nerve in Sprague-Dawley rats, using NO precursors, NO donors, and nitric oxide synthase (NOS) inhibitors. CCI produced marked neuropathic pain, as demonstrated by enhanced mechanical, thermal, and cold allodynia in nociceptive behavioural assays. Administration of the NO precursor L-arginine and the NO donor’s sodium nitroprusside and S-nitroso-N-acetyl penicillamine significantly intensified hyperalgesia and allodynia, indicating a pro-nociceptive role of NO in neuropathic conditions. Intracerebroventricular administration of NOS inhibitors, including L-NG-nitroarginine methyl ester, N-iminoethyl-L-lysine, and 7-nitroindazole, did not alter pain responses, whereas their intraperitoneal administration—particularly aminoguanidine, L-NG-nitroarginine methyl ester, and 7-nitroindazole—significantly reduced neuropathic pain. Elevated nitrate and nitrite levels in the ligated sciatic nerve further suggest local up-regulation of NO contributing to the development and persistence of neuropathic pain. Overall, these findings demonstrate that both endogenous and exogenous NO play a critical role in CCI-induced neuropathy, highlighting modulation of the L-arginine–NO pathway as a potential therapeutic strategy for neuropathic pain management.

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