Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats

Abstract

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.

Figure 1

Effects of intracerebroventricular (i.c.v.) OFQ/N administration on morphine tolerance in the rat hot plate test. Rats were treated for 3 days with saline or morphine (10 mg kg⁻¹, s.c.) followed, 15 and 75 min later, by two i.c.v. injections of aCSF or OFQ/N. On day 4, rats were tested 30 min before and 30, 60 and 90 min after morphine (10 mg kg⁻¹, s.c.) in the hot plate test. Treatment with morphine for 3 days produced a significant decrease in the antinociceptive effect of the drug (P<0.05, SAL – aCSF vs MOR – aCSF) and this tolerance was attenuated by i.c.v. OFQ/N (P<0.05, MOR – OFQ vs MOR – aCSF) administration (post hoc Newman-Keuls test). Data were analysed by a two-way ANOVA with repeated measures on hot plate latencies before and after morphine administration on day 4.

Figure 2

Effects of intra-hippocampal OFQ/N treatment on morphine tolerance in rats using the hot plate test. Rats received the same treatment and were tested as described in the legend to Figure 1 except aCSF or OFQ/N was administered into the CA3 region of the hippocampus. Morphine treatment for 3 days induced tolerance (P<0.05, SAL – aCSF vs MOR – aCSF) and this phenomenon was blocked by administration of OFQ/N (P<0.05, MOR – OFQ vs MOR – aCSF) into the CA3 region of the rat hippocampus (post hoc Newman-Keuls test). Data were analysed by a two-way ANOVA with repeated measures on hot plate latencies before and after morphine administration on day 4.