Mechanisms responsible for the enhanced antinociceptive effects of micro-opioid receptor agonists in the rostral ventromedial medulla of male rats with persistent inflammatory pain. J Pharmacol Exp Ther 2007 Aug;322(2):813-21
Date
05/15/2007Pubmed ID
17494863DOI
10.1124/jpet.107.121954Scopus ID
2-s2.0-34547119288 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
This study investigated three possible mechanisms by which the antinociceptive effects of the mu-opioid receptor (MOR) agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and the delta-opioid receptor (DOR) agonist [d-Ala(2),Glu(4)]-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 [(3)H]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 EC(50) nor the E(max) value for DAMGO-induced stimulation of guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) 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 [(3)H]DELT binding nor stimulation of [(35)S]GTPgammaS 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.
Author List
Sykes KT, White SR, Hurley RW, Mizoguchi H, Tseng LF, Hammond DLAuthor
Robert W. Hurley MD, PhD Adjunct Professor of Anesthesiology and CTSI in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnalgesicsAnimals
Cell Membrane
Dose-Response Relationship, Drug
Drug Synergism
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
Freund's Adjuvant
Guanosine 5'-O-(3-Thiotriphosphate)
Hindlimb
Hyperalgesia
Inflammation
Male
Medulla Oblongata
Oligopeptides
Pain
Pain Measurement
Rats
Rats, Sprague-Dawley
Reaction Time
Receptors, Opioid, delta
Receptors, Opioid, mu