Inverse agonist action of Leu-enkephalin at delta(2)-opioid receptors mediates spinal antianalgesia

Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to pr oduce an antianalgesic action against spinal morphine in the tail-flick tes t in CD-1 mice. The present study showed that following the cholecystokinin step, a delta (2)-opioid inverse agonist action of Leu-enkephalin (LE), wa s involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally pro duced antianalgesia that like that from dynorphin A(1-17) and cholecystokin in was eliminated by naltriben but not 7-benzylidenenaltrexone (delta (2)- and delta (1)-opioid receptor antagonist, respectively). This LE step was f ollowed by N-methyl-D-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), c holecystokinin-8s, and LE. Furthermore, none of the three were effective ag ainst morphine analgesia in 129S6/SvEv mice possibly because of their defic iency in NMDA receptor response. In 129S6/SvEv mice, [D-Ser(2)]-Leu-enkepha lin-Thr analgesia was not attenuated by LE; thus, this delta (2-)analgesic agonist and LE inverse agonist action did not occur through competition at the same delta (2)-receptor in CD-1 mice. In CD-1 mice, a linear sequence o f dynorphin A(1-17) --> cholecystokinin --> LE --> NMDA receptors was indic ated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltr iben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A (1-17), cholecystokinin, delta (2)-opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.