Involvement of Local Orphanin FQ in the Tolerance Induced by Repeated Microinjections of Morphine into Ventrolateral Periaqueductal Gray in Rats

The present study evaluated the role of ventrolateral periaqueductal gray ( vlPAG)-located orphanin-FQ ( OFQ) in the opioid tolerance induced by repeated microinjections of morphine ( MOR) into vlPAG. Microinjection of MOR ( 5 mu g/0.5 mu l) into vlPAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days ( tolerance). However, if MOR microinjection was preceded by the OFQ receptor antagonist nocistatin ( NST; 1 ng/0.5 mu l), the microinjections of MOR did not induce tolerance. If NST microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single NST microinjection into vlPAG was enough to restore the antinociceptive effect of MOR. Furthermore, if OFQ ( 1 ng/0.5 mu l) was microinjected into vlPAG, then a MOR microinjection administered 15 min later into vlPAG did not elicit antinociception. Finally, opioid tolerance induced by repeated systemic MOR injections ( 5 mg/kg, i.p.) was reversed by a single microinjection of NST into vlPAG. This emphasizes the central importance of vlPAG-located OFQ in the MOR tolerance. Copyright (c) 2007 S. Karger AG, Basel.