Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance

The neuropeptide orphanin FQ/nociceptin (OFQ/N) has been shown to counteract several effects of endogenous and exogenous opioids, and it has been proposed as an opioid-modulating agent involved in the development of morphine tolerance and dependence. However, conflicting results have been obtained from animal models using different protocols to induce morphine tolerance. Here, we report that both genetic and pharmacological blockade of OFQ/N signaling can effectively prevent development of morphine tolerance. OFQ/N knockout mice injected daily with low doses of morphine (10 mg/kg) fail to develop tolerance even after 3 weeks of treatment, whereas their wild-type litter mates show profound tolerance starting after 10 days. Likewise, coadministration of morphine together with the synthetic N/OFQ peptide antagonist, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), is able to block tolerance development in normal mice. These data indicate that release of endogenous OFQ/N after morphine administration might produce a gradual decline of analgesic potency, i.e., tolerance. Interestingly, tolerant and nontolerant groups of mice receiving repeated daily low morphine doses did not differ in their withdrawal behavior after naloxone injection. In contrast, mice receiving escalating doses of morphine developed analgesic tolerance independent of their OFQ/N genotype, whereas withdrawal symptoms were attenuated in OFQ/N-deficient animals. These results indicate that the endogenous OFQ/N system is differentially involved in morphine tolerance development and establishment of opiate dependence, depending on the specific morphine dosage regimen. Furthermore, it suggests that OFQ/N antagonists could provide a novel therapeutic strategy to attenuate morphine tolerance development.