RT Journal Article
SR Electronic
T1 Differentiation of Kappa Opioid Agonist-Induced Antinociception by Naltrexone Apparent pA2 Analysis in Rhesus Monkeys
,
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 518
OP 526
VO 285
IS 2
A1 Mei-Chuan Ko
A1 Eduardo R. Butelman
A1 John R. Traynor
A1 James H. Woods
YR 1998
UL http://jpet.aspetjournals.org/content/285/2/518.abstract
AB Naltrexone (NTX) exhibited approximately 3-fold higher affinity for sites labeled by [3H]U69,593 (putative κ1-selective ligand) than [3H]bremazocine (non-selective ligand) in the presence of mu anddelta receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for κ1-versus non-κ1-mediated effects. Six opioid agonists were characterized by NTX apparent pA2 analysis in a 50°C water tail-withdrawal assay in rhesus monkeys. Constrained NTX pA2 values (95% confidence limits) were: alfentanil, 8.66 (8.47–8.85); ethylketocyclazocine, 7.97 (7.93–8.01); U69,593, 7.64 (7.49–7.79); U50,488, 7.55 (7.42–7.67); bremazocine, 6.92 (6.73–7.12); enadoline, 6.87 (6.69–7.05). Pretreatment with clocinnamox, an irreversible mu antagonist, confirmed that mu receptors were not involved in the antinociception produced by the kappa agonists, U69,593, U50,488, bremazocine and enadoline; however, both mu andkappa receptors mediated the antinociceptive effects of ethylketocyclazocine. The apparent NTX pA2 profile of opioid agonists correlated highly with the radioligand binding studies, which indicates that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functional evidence ofkappa opioid receptor multiplicity in primates and suggests that NTX may be a useful tool to study this phenomenonin vivo. The American Society for Pharmacology and Experimental Therapeutics