1. Recent evidence from studies in mice lacking the opioid receptor-like (ORL-1) receptor and from experiments using antibodies raised against orphanin FQ/nociceptin (OFQ/N) suggest that this peptide may be involved in morphine tolerance. In the present study we sought to investigate if administration of exogenous OFQ/N would modulate the development of tolerance to the antinociceptive effect of morphine. 2. Rats were treated for 3 days with either saline or morphine (10 mg kg(-1), s.c.) followed, 15 and 75 min later, by two intracerebroventricular injections of either artificial cerebrospinal fluid (aCSF) or OFQ/N. The dose of OFQ/N was doubled each day (7.5, 15, 30 nmol). On day 4, rats were tested on a hot plate apparatus before and 30, 60 and 90 min after morphine administration. 3. Repeated OFQ/N treatment did not affect basal nociceptive responses or morphine-induced antinociception. However, the same treatment significantly attenuated the development of morphine tolerance. 4. Since learning and memory could contribute to the development of morphine tolerance, in subsequent studies, we examined the effect of OFQ/N administered in the CA3 region of the hippocampus, where OFQ/N has been shown to block LTP and impair spatial memory. A greater attenuation of morphine tolerance with no alteration of baseline hot plate latency or morphine-induced antinociception was observed when OFQ/N was administered in this area of the rat brain. 5. Taken together, our results demonstrate that OFQ/N may act in the hippocampus to attenuate morphine tolerance.