Received for publication March 6, 2006.
Revised March 31, 2006.
Accepted for publication March 31, 2006.

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

Abstract

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 while their wildtype littermates show profound tolerance starting after 10 days. Similarly, co-administration of morphine together with the synthetic NOP antagonist, J-113397, is able to block tolerance development in normal mice. These data indicate that release of endogenous OFQ/N following morphine administration might produce a gradual decline of analgesic potency, i.e. tolerance. Interestingly, tolerant and non-tolerant 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.

Key words: analgesia, dependence, neuropeptide, opioid, orphanin FQ, tolerance