Selective inhibition of the NOP receptor in the ventrolateral periaqueductal gray attenuates the development and the expression of tolerance to morphine-induced antinociception in rats

The ventrolateral periaqueductal gray (vlPAG) is a major site of opioid analgesic action and a key locus for the development of morphine tolerance. Previous experimental evidence supports the hypothesis that the brain synthesizes and secretes neuropeptides, which act as a part of the homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. Among the known antiopioid peptides, nociceptin/orphanin FQ (N/OFQ) has been shown to inhibit various opioid effects, especially analgesia. The present study investigated the effect of NOP receptor blockade on the tolerance to morphine antinociception in the vlPAG. Systemic morphine (10 mg/kg s.c. twice per day) induced an antinociceptive effect that diminished significantly on the third day when tolerance developed, as quantified by the tail flick and the hot plate tests. Intra vlPAG (i.vlPAG) administration of the NOP receptor antagonist (±)–J 113397 restored the opioid's analgesic effect. When (±)–J 113397 was administered beginning the first day preceding each morphine administration, tolerance did not develop, but it appeared if the NOP antagonist had been suspended. These data suggest that the N/OFQ in the vlPAG may play a key role in opioid-induced antinociceptive tolerance.