The functional antiopioid action of the ventrolateral periaqueductal gray nociceptin/orphanin FQ and nociceptin receptor system underlies DAMGO analgesic tolerance

Nociceptin/Orphanin FQ (N/OFQ) counteracts supraspinal opioid effects and plays arole in antinociceptive morphine tolerance. Therefore, in the present study, the selective mu-opioid agonist [D-Ala(2)-NMe-Phe(4)-Gly-ol(5)]-enkephalin (DAMGO)was used. Repeated injection of DAMGO (1 microg/ 1 microl) into the ventrolateralperiaqueductal gray (vlPAG), a key site for the development of opioid tolerance, induced analgesia that lasted up to 3 days. In DAMGO-tolerant rats, injection of the N/OFQ antagonist (+/-)-J 113397 (4 microg/1 microl), into the same site,restored the antinociceptive effect of DAMGO. If (+/-)-J 113397 treatmentpreceded each DAMGO injection, tolerance did not develop. Inhibition of N/OFQsignaling can reverse and prevent the development of DAMGO tolerance in thevlPAG. The results confirm that N/OFQ acts as a functional opioid antagonist.