Abstract
Previous work supports the existence of two types of δ opioid receptor (δ1 and δ2) and a role of both subtypes in the spinal cord and the ventromedial medulla (VMM) in the production of antinociception. Although it is well established that spinal and supraspinal μ opioid receptors interact in a synergistic manner to produce antinociception, little is known about the interaction of δ opioid receptors. This study used isobolographic analysis to determine how δ1 and δ2 opioid receptors in the VMM interact with their respective receptors in the spinal cord to produce antinociception. Concurrent administration of the δ1 opioid receptor agonist [d-Pen2,d-Pen5]enkephalin at spinal and supraspinal sites in a fixed-dose ratio produced antinociception in an additive manner in the tail-flick test. In contrast, concurrent administration of very low doses of the δ2 opioid receptor agonist [d-Ala2,Glu4]deltorphin at spinal and medullary sites produced antinociception in a synergistic manner. However, as the total dose of [d-Ala2,Glu4]deltorphin increased, this interaction converted to additivity. These observations suggest that different mechanisms mediate the antinociceptive effects of different doses of δ2 opioid receptor agonists. The difference in the nature of the interaction produced by δ1 and δ2 opioid receptor agonists provides additional evidence for the existence of different subtypes of the δ opioid receptor. These results also suggest that δ2 opioid receptor agonists capable of crossing the blood-brain barrier will be more potent or efficacious analgesics than δ1 opioid receptor agonists after systemic administration.
Footnotes
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Send reprint requests to: Donna L. Hammond, Ph.D., Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, M/C 4028, Chicago, IL 60637. E-maildh15{at}midway.uchicago.edu
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↵1 This work was supported by U.S. Public Health Service Grants R01-DA06736 (to D.L.H.), T32-HD07009 and F30-DA05784 (to R.W.H.), and R01-DA09793 (to R.J.T.).
- Abbreviations:
- DELT
- [d-Ala2,Glu4]deltorphin
- DPDPE
- [d-Pen2,d-Pen5]enkephalin
- NRM
- nucleus raphe magnus
- NGCpα
- nucleus reticularis gigantocellularis pars α
- VMM
- ventromedial medulla
- i.t.
- intrathecal
- SNC80
- (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
- TAN67
- 2-methyl-4-aα(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3-g]isoquinoline
- Received August 11, 1998.
- Accepted December 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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