Role of μ1-opiate receptors in supraspinal opiate analgesia: a microinjection study

Microinjection of opiates into either the periaqueductual gray, locus coeruleus, nucleus raphe magnus, or nucleus reticularis gigantocellularis elicits a profound naloxone-sensitive analgesia. μ-Opioid receptors have been implicated in supraspinal analgesia and studies from our laboratory have demonstrated the importance of the μ₁-receptor subtype. In an effort to examine the receptor subtypes responsible for opioid analgesia in specific brain regions, we examined dose-response relationships and naloxonazine sensitivity of morphine and two enkephalin derivatives in the above 4 brain regions. Both morphine and [-Ser², Leu⁵]enkephalin-Thr⁶ (DSLET) were effective analgesics in all regions examined. The poor affinity of DSLET for μ₂-receptors and of morphine for δ-receptors, combined with their similar, high affinity for μ₁-receptors, implied a μ₁-mechanism of action. The μ₁-selective antagonist naloxonazine effectively blocked the analgesic responses of both compounds in all regions. [-Pen²,-Pen⁵]enkephalin (DPDPE), a potent δ-ligand which does not interact with μ₁-receptors, did not elicit analgesia in either the periaqueductal gray or locus coeruleus at any dose tested. These results suggest that opiates and opioid peptides produce analgesia in these 4 brain regions through μ₁-receptors. The inactivity of DPDPE argues against a role for δ-receptors and the similar analgesic potencies of morphine and DSLET makes a significant role for μ₂-receptors unlikely.