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The present study was designed to determine whether amitriptyline, a prototypical tricyclic antidepressant, could produce pain relieving properties in a rat model of neuropathic pain. Nerve injury was produced by tight ligation of the lumbar 5th and 6th dorsal roots and this resulted in persistent stimulus evoked neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Thermal hyperalgesia was measured using a focused light beam directed at the ventral surface of the paw while tactile allodynia was determined using Semmes-Weinstein monofilaments applied to the ventral surface of the paw. Amitriptyline was administered systemically (intraperitoneal), spinally (intrathecal cannula), and locally (subcutaneously) via direct injection into the dorsal surface of the paw. Following systemic administration, amitriptyline completely reversed thermal hyperalgesia (10 mg/kg) in the injured paw. Spinal administration of amitriptyline (60 microg) also produced an antihyperalgesic effect. Interestingly, local administration of amitriptyline (100 nmol) had an immediate antihyperalgesic effect that persisted for 120 min following administration. Amitriptyline had no alleviating effect against mechanical allodynia regardless of the route of administration, but curiously, produced hyperaesthesia in the contralateral paw. These results indicate that in the rat model of spinal nerve ligation, amitriptyline is effective in alleviating thermal hyperalgesia (systemically, spinally and locally) but is ineffective against mechanical allodynia. The peripheral efficacy of amitriptyline suggests the possibility of the development of cream formulations that may be able to increase the local concentration of amitriptyline without increasing the systemic dose and the subsequent occurrence of side effects.