Differential antagonism of bremazocine- and U69,593-induced antinociception by quadazocine: further functional evidence of opioid kappa receptor multiplicity in the mouse.
In these studies, the antagonistic actions of (-)-1-Cyclopentyl-5-(1,2,3,4,5,-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6 -methano-3-benzazocin-11-yl)-3-pentanone methanesulfonate (quadazocine) were evaluated against the kappa-receptor-mediated antinociceptive effects of i.c.v. (5 alpha, 7 alpha, 8 beta)-(+)-N-methyl-N-(7-(1-pyrrolidinyl)- 1-oxaspiro(4,5)dec-8-yl)benzeneacetamide (U69,593) or bremazocine in the mouse warm water tail-flick test. Quadazocine produced no antinociceptive effects alone, and it selectively antagonized the actions of bremazocine, but not U69,593, in a dose- and time-related fashion, supporting previous suggestions of differences in kappa receptors mediating the antinociceptive effects of these agonists. Quadazocine, however, also antagonized the antinociceptive effects of both DAMGO (opioid mu agonist) and DPDPE (opioid delta agonist) at doses approximately 3-fold less than those needed to attenuate significantly the effects of bremazocine. The structurally diverse kappa opioids (+-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b]- thiophene-4-acetamide (PD 117,302), ethylketocyclazocine (EKC) and tifluadom were studied under kappa-selective conditions, and the sensitivity of their effects to 1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-[2(1- pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-UPHIT] (kappa 1 antagonist) or quadazocine (kappa 2 antagonist) was determined. On this basis PD 117,302, EKC and tifluadom were classified as acting at opioid kappa 1, kappa 1, and kappa 2 receptors, respectively; EKC and tifluadom were also shown to have significant activity at opioid mu, but not delta, receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Horan
P J
PJ
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson.
de Costa
B R
BR
Rice
K
K
Haaseth
R C
RC
Hruby
V J
VJ
Porreca
F
F
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000494:pharmacology*; D044482:Benzeneacetamides; D001569:Benzodiazepines / Q000494:pharmacology; D001575:Benzomorphans / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016314:Ethylketocyclazocine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000032:analysis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology
D000700:Analgesics; D001392:Azocines; D044482:Benzeneacetamides; D001575:Benzomorphans; D003510:Cyclohexanes; D009292:Narcotic Antagonists; D011758:Pyrroles; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013876:Thiophenes; C054718:PD 117302; C063077:2-isothiocyanato-4,5-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide; D001569:Benzodiazepines; D016314:Ethylketocyclazocine; C027248:bremazocine; C045444:U 69593; C035470:tifluadom; C035969:quadazocine