Repeated exposure to opioid drugs can lead to the development of tolerance, which manifests as a reduction in analgesic potency, and physical dependence, a response indicated by a withdrawal syndrome. Accumulating evidence suggests that the nerve growth factor (NGF) family of neurotrophins may have an important modulatory role in the induction of opioid analgesia and opioid addiction. Because neurotrophins universally bind the p75 neurotrophin receptor (p75NTR), we investigated whether the activity of this receptor is involved in the development of opioid analgesic tolerance and physical dependence. We found that in both the wild-type and p75NTR-/- mice an acute systemic (i.p.) injection of morphine produced a maximal analgesic response as measured by the thermal tail-immersion test. Repeated injection of morphine over 5 days in wild-type mice resulted in a progressive decline of the analgesic effect and a concomitant loss of the agonist potency, reflecting development of morphine tolerance. However, the loss of morphine analgesia was not observed in p75NTR-/- mice. In the second part of this study, mice were given escalating doses of systemic (i.p.) morphine over 5 days and subsequently challenged with the opioid receptor antagonist naloxone. This challenge precipitated a robust withdrawal syndrome that was comparable in wild-type mice and p75NTR-/- mice. The findings suggest that p75NTR activity plays a critical role in the development of opioid analgesic tolerance but not in the induction or the expression of opioid physical dependence.