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TOXICOLOGY

Mechanisms Responsible for the Enhanced Antinociceptive Effects of µ-Opioid Receptor Agonists in the Rostral Ventromedial Medulla of Male Rats with Persistent Inflammatory Pain

Departments of Anesthesia (S.R.W., D.L.H.) and Pharmacology (K.T.S., D.L.H.) and the Medical Scientist Training Program (K.T.S.), The University of Iowa, Iowa City, Iowa; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (H.M., L.F.T.); and Department of Anesthesiology and Critical Care, The Johns Hopkins University, Baltimore, Maryland (R.W.H.)

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 -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 B_max nor the K_d 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 E_max value for DAMGO-induced stimulation of guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) 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]GTPS 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.

Address correspondence to: Dr. Donna L. Hammond, Department of Anesthesia, The University of Iowa, 200 Hawkins Dr. 6 JCP, Iowa City, IA 52242. E-mail: donna-hammond{at}uiowa.edu

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