Abstract
This study investigated three possible mechanisms by which the antinociceptive effects of the μ-opioid receptor (MOR) agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and the δ-opioid receptor (DOR) agonist [d-Ala2,Glu4]-deltorphin (deltorphin II) (DELT), microinjected into the rostral ventromedial medulla (RVM), are enhanced in rats with persistent inflammatory injury. Radioligand binding determined that neither the Bmax nor the Kd values of [3H]DAMGO differed in RVM membranes from rats that received an intraplantar injection of saline or complete Freund's adjuvant (CFA) in one hindpaw 4 h, 4 days, or 2 weeks earlier. Likewise, neither the EC50 nor the Emax value for DAMGO-induced stimulation of guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding differed in the RVM of saline- or CFA-treated rats at any time point. Microinjection of fixed dose combinations of DAMGO and DELT in the RVM of naive rats indicated that these agonists interact synergistically to produce antinociception when DAMGO is present in equal or greater amounts than DELT and, additively, when DELT is the predominant component. Thus, unlike the periphery or spinal cord, potentiation of MOR-mediated antinociception does not entail an increase in MOR number, affinity, or coupling. Rather, the data are concordant with our proposal that potentiation results from a synergistic interaction of exogenous MOR agonist with DOR-preferring enkephalins whose levels are increased in CFA-treated rats (J Neurosci 21:2536–2545, 2001). Virtually no specific [3H]DELT binding nor stimulation of [35S]GTPγS binding by DELT was obtained in RVM membranes from CFA- or saline-treated rats at any time point. The mechanisms responsible for the potentiation of DELT-mediated antinociception remain to be elucidated.
Footnotes
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This work was supported by the National Institutes of Health Grant R01DA06736 (to D.L.H.) and F30DA017447 (to K.T.S.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.121954.
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ABBREVIATIONS: MOR, μ-opioid receptor; DOR, δ-opioid receptor; CFA, Complete Freund's adjuvant; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; DELT, [d-Ala2,Glu4]-deltorphin (deltorphin II); RVM, rostral ventromedial medulla; GTPγS, guanosine 5′-O-(3-thio)triphosphate; PWL, paw withdrawal latency; NGCpα, nucleus reticularis gigantocellularis pars α; CL, confidence limits.
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↵1 Current affiliation: Tohoku Pharmaceutical University, Department of Physiology and Anatomy, Komatsushima Aoba-ku, Sendai, Japan.
- Received February 25, 2007.
- Accepted May 8, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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