Inverse agonist action of Leu-enkephalin at delta(2)-opioid receptors mediates spinal antianalgesia.
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 delta(2)-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 (delta(2)- and delta(1)-opioid receptor antagonist, respectively). This LE step was followed by N-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-Ser(2)]-Leu-enkephalin-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 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, delta(2)-opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.
Rady
J J
JJ
Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin 52395, USA. jrady@mcw.edu
Holmes
B B
BB
Tseng
L F
LF
Fujimoto
J M
JM
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004361:Drug Tolerance; D004743:Enkephalin, Leucine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*
D000701:Analgesics, Opioid; D001597:Benzylidene Compounds; D018690:Excitatory Amino Acid Agonists; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C068868:naltrindole benzofuran; C077358:7-benzylidenenaltrexone; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016202:N-Methylaspartate; D009020:Morphine; D002766:Cholecystokinin