Mu and delta receptors: Their role in analgesia and in the differential effects of opioid peptides on analgesia

Abstract

Utilizing the mouse tail-flick assay, the rank order of analgesic potency for various opioids (i.c.v.) is β h 2 - endorphin > D-Ala 2-D-Leu 5eenkephalin > morphine > D-Ala 2- met-enkephalinamide ⪢ met-enkephalin ⪢ leu-enkephalin. Assuming mu receptor mediation of analgesia, there is an obvious lack of correlation at times between mu receptor affinity and analgesic potency (ie: D-Ala 2-D-Leu 5-enkephalin has 1 7 the affinity of morphine for the mu receptor but is 18X more potent as an analgesic). Additionally, sub-analgesic doses of various opioid peptides have opposite effects on analgesic responses. Leu-enkephalin, D-Ala 2-D-Leu 5-enkephalin or β h-endorphin potentiate morphine or D-Ala 2-met-enkephalinamide analgesia whereas metenkephalin or D-Ala 2-met-enkephalinamide antagonize opioid- induced analgesia. Using the enkephalins as the prototypic delta ligands (100 fold selective) and based on their effects on analgesia, we suggest that leu-enkephalin- like peptides interact with the delta receptor as an “agonist” to facilitate and met-enkephalin-like peptides as an “antagonist” to attenuate analgesia. Given the biochemical evidence of a coupling between mu and delta receptors, we suggest that the mechanism of facilitation or attenuation of analgesia by the enkephalins is a direct in vivo consequence of this coupling. Further, the analgesic potencies of various opioid ligands can be better correlated to the combination of their simultaneous occupancy of mu and delta receptors.