Treating neuropathic pain with systemic opioids is associated with significant dose-limiting central nervous system (CNS) side effects, tolerance, and potential for addiction and drug abuse. Recent observation suggests a role for peripheral mu-opioid receptors (MORs) in neuropathic pain. To examine whether selective activation of peripheral MORs may attenuate neuropathic pain behavior in rats, a blinded, vehicle-controlled study was designed to test whether loperamide, a peripherally restricted MOR agonist, would attenuate the mechanical allodynia induced by ligation and transection of the L5 spinal nerve (SNL) in adult male rat. Paw withdrawal thresholds (PWT) to von Frey filaments were measured using the up-down method before and after drug administration at different time points after nerve injury. The L5 SNL resulted in a significant decrease in PWTs on the injured side in animals examined at day 4 through day 42 post-SNL. Loperamide (s.c.) dose-dependently attenuated the mechanical allodynia in animals after SNL. The anti-allodynic effect of loperamide (1.5 mg/kg, s.c) was blocked by pre-treatment with naloxone hydrocholoride (10 mg/kg, i.p.), and also attenuated by peripherally acting MOR antagonist naltrexone methylbromide (5mg/kg, i.p.). Loperamide (1.5 mg/kg, s.c) was effective in attenuating mechanical allodynia even at 6 weeks post-SNL. Our observations indicate that a peripherally selective MOR agonist, loperamide, can attenuate mechanical allodynia induced by nerve injury. These findings suggest that peripheral MORs may be an attractive therapeutic target in the treatment of neuropathic pain, and peripherally acting selective MOR agonists may be a novel therapeutic approach for alleviating neuropathic pain.