We investigated the effects of acute and of chronic morphine treatment on T-lymphocyte function and natural killer (NK) cell activity in rats receiving chronic constriction injury (CCI) of the sciatic nerve. T-Lymphocyte function was evaluated based on concanavalin-A (ConA)- and phytohemagglutinin (PHA)-induced splenocyte proliferation. The effects of morphine on thermal hyperalgesia were also assessed by measuring paw withdrawal latency (PWL) in rats. All of the rats that received CCI developed thermal hyperalgesia while sham-operated rats did not. Thermal hyperalgesia was dose-dependently reversed after acute (single injection) and after chronic (daily injection for 7 days) administration of morphine but persisted in saline-treated CCI rats. There was no significant difference between sham and saline-treated CCI groups in splenocyte proliferation and NK cell activity. NK cell activity and splenocyte proliferation induced by ConA and PHA were significantly suppressed by acute morphine treatment in a dose-dependent manner. The reversal of the thermal hyperalgesia persisted throughout the period of chronic morphine treatment. No tolerance to the suppression of NK cell activity and splenocyte proliferation was observed after chronic morphine treatment. These data suggest that both acute and chronic morphine treatment can cause a dose-dependent reversal of thermal hyperalgesia and inhibition of NK cell activity and splenocyte proliferation in rats with sciatic CCI, without concomitant development of tolerance. Opioid therapy for chronic neuropathic pain should be used cautiously, especially in immune-compromised cases.