Abstract
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.
Footnotes
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Send reprint requests to: Jodie J. Rady, Research Service-151, VA Medical Center, Milwaukee, WI 53295. E-mail:jrady{at}mcw.edu
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This study was supported by VA Medical Funds (VA Merit Review, Research Career Scientist Award to J.M.F).
- Abbreviations:
- i.t.
- intrathecal
- Dyn
- dynorphin A(1-17)
- CCK
- cholecystokinin
- CCK8s
- sulfated CCK8
- LE
- Leu-enkephalin
- NMDA
- N-methyl-d-aspartate
- % MPE
- percentage maximum possible effect
- BNTX
- 7-benzylidenenaltrexone
- MK801
- dizocilpine
- ME
- Met-enkephalin
- DPDPE
- [d-Pen2,5]-enkephalin
- DSLET
- [d-Ser2]-Leu-enkephalin-Thr
- DOR-1
- δ-opioid receptor-1
- LE-Arg6
- Leu-enkephalin-arginine6
- Received September 26, 2000.
- Accepted January 15, 2001.
- U.S. Government
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