RT Journal Article
SR Electronic
T1 Mechanisms Responsible for the Enhanced Antinociceptive Effects of μ-Opioid Receptor Agonists in the Rostral Ventromedial Medulla of Male Rats with Persistent Inflammatory Pain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 813
OP 821
DO 10.1124/jpet.107.121954
VO 322
IS 2
A1 Kenneth T. Sykes
A1 Stephanie R. White
A1 Robert W. Hurley
A1 Hirokazu Mizoguchi
A1 Leon F. Tseng
A1 Donna L. Hammond
YR 2007
UL http://jpet.aspetjournals.org/content/322/2/813.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics