Abstract

Previous work supports the existence of two types of δ opioid receptor (δ₁ and δ₂) 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 δ opioid receptors. This study used isobolographic analysis to determine how δ₁ and δ₂ opioid receptors in the VMM interact with their respective receptors in the spinal cord to produce antinociception. Concurrent administration of the δ₁ 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 δ₂ 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 δ₂ opioid receptor agonists. The difference in the nature of the interaction produced by δ₁ and δ₂ opioid receptor agonists provides additional evidence for the existence of different subtypes of the δ opioid receptor. These results also suggest that δ₂ opioid receptor agonists capable of crossing the blood-brain barrier will be more potent or efficacious analgesics than δ₁ opioid receptor agonists after systemic administration.