%0 Journal Article %A Jodie J. Rady %A Blythe B. Holmes %A Leon F. Tseng %A James M. Fujimoto %T Inverse Agonist Action of Leu-Enkephalin at δ2-Opioid Receptors Mediates Spinal Antianalgesia %D 2001 %J Journal of Pharmacology and Experimental Therapeutics %P 582-589 %V 297 %N 2 %X Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to produce an antianalgesic action against spinal morphine in the tail-flick test in CD-1 mice. The present study showed that following the cholecystokinin step, a δ2-opioid inverse agonist action of Leu-enkephalin (LE), was involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally produced antianalgesia that like that from dynorphin A(1-17) and cholecystokinin was eliminated by naltriben but not 7-benzylidenenaltrexone (δ2- and δ1-opioid receptor antagonist, respectively). This LE step was followed byN-methyl-d-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), cholecystokinin-8s, and LE. Furthermore, none of the three were effective against morphine analgesia in 129S6/SvEv mice possibly because of their deficiency in NMDA receptor response. In 129S6/SvEv mice, [d-Ser2]-Leu-enkephalin-Thr analgesia was not attenuated by LE; thus, this δ2-analgesic agonist and LE inverse agonist action did not occur through competition at the same δ2-receptor in CD-1 mice. In CD-1 mice, a linear sequence of dynorphin A(1-17) → cholecystokinin → LE → NMDA receptors was indicated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltriben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A(1-17), cholecystokinin, δ2-opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine. U.S. Government %U https://jpet.aspetjournals.org/content/jpet/297/2/582.full.pdf