Vol. 289, Issue 2, 993-999, May 1999

Interaction Between Medullary and Spinal ₁ and ₂ Opioid Receptors in the Production of Antinociception in the Rat¹

Robert W. Hurley , Theodore S. Grabow, Ronald J. Tallarida and Donna L. Hammond

Committee on Neurobiology (R.W.H., D.L.H.) and Department of Anesthesia and Critical Care (R.W.H., D.L.H., T.S.G.), University of Chicago, Chicago, Illinois; and Department of Pharmacology (R.J.T.), Temple University, Philadelphia, Pennsylvania

Previous work supports the existence of two types of  opioid receptor (₁ and ₂) and a role of both subtypes in the spinal cord and the ventromedial medulla (VMM) in the production of antinociception. Although it is well established that spinal and supraspinal µ opioid receptors interact in a synergistic manner to produce antinociception, little is known about the interaction of  opioid receptors. This study used isobolographic analysis to determine how ₁ and ₂ opioid receptors in the VMM interact with their respective receptors in the spinal cord to produce antinociception. Concurrent administration of the ₁ opioid receptor agonist [D-Pen²,D-Pen⁵]enkephalin at spinal and supraspinal sites in a fixed-dose ratio produced antinociception in an additive manner in the tail-flick test. In contrast, concurrent administration of very low doses of the ₂ opioid receptor agonist [D-Ala²,Glu⁴]deltorphin at spinal and medullary sites produced antinociception in a synergistic manner. However, as the total dose of [D-Ala²,Glu⁴]deltorphin increased, this interaction converted to additivity. These observations suggest that different mechanisms mediate the antinociceptive effects of different doses of ₂ opioid receptor agonists. The difference in the nature of the interaction produced by ₁ and ₂ opioid receptor agonists provides additional evidence for the existence of different subtypes of the  opioid receptor. These results also suggest that ₂ opioid receptor agonists capable of crossing the blood-brain barrier will be more potent or efficacious analgesics than ₁ opioid receptor agonists after systemic administration.