Proglumide selectively potentiates supraspinal μ₁ opioid analgesia in mice

The cholecystokinin antagonist proglumide potentiates morphine analgesia. To understand more fully the opiate receptor subtypes involved with this effect, we investigated the effect of proglumide on spinal and supraspinal μ and spinal δ analgesia in mice. Proglumide alone had no effect on tailflick latencies, but increased, in a dose-dependent manner, tailflick latencies in morphine-tolerant mice. Proglumide also potentiated morphine analgesia in naive mice in a dose-dependent manner, with a maximal effect at 5-10 mg kg. Proglumide both shifted the dose-response curve for morphine analgesia to the left and prolonged morphine's duration of action. Proglumide increased the sensitivity of supraspinal μ₁. receptor mechanisms of analgesia without influencing spinal mechanisms. Proglumide administered subcutaneously potentiated the analgesic actions of intracerebroventricular [D-Ala²MePhe⁴,Gly(ol)⁵]enkephalin (DAGO; (μ₁), but not intrathecal DAGO (μ₂) or (D-Pen², D-Pen⁵]enkephalin (DPDPE; δ). The selective μ₁. receptor antagonist naloxonazine blocked proglumide-enhanced morphine analgesia.