TY - JOUR
T1 - Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT
T2 - Evidence of kappa opioid receptor multiplicity in mice
AU - Horan, P.
AU - de Costa, B. R.
AU - Rice, K. C.
AU - Porreca, F.
PY - 1991
Y1 - 1991
N2 - The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT {1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1 -pyrrolidinyl)cyclohexyl]benzeneacetamide}, on U69,593 {(5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl) -1-oxaspiro(4,5)dec-8-yl)benzeneacetamide}- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2,NMePhe4, Gly-ol]enkephalin-(mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significanlly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, β-funaltrxamine (mu antagonist) and ICI 174,864 {N,N,-diallyl-Tyr-(α-aminoisobutyric acid)2-Phe-Leu-OH} (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2,NMePhe4, Glyol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinocicieption produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.
AB - The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT {1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1 -pyrrolidinyl)cyclohexyl]benzeneacetamide}, on U69,593 {(5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl) -1-oxaspiro(4,5)dec-8-yl)benzeneacetamide}- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2,NMePhe4, Gly-ol]enkephalin-(mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significanlly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, β-funaltrxamine (mu antagonist) and ICI 174,864 {N,N,-diallyl-Tyr-(α-aminoisobutyric acid)2-Phe-Leu-OH} (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2,NMePhe4, Glyol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinocicieption produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.
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M3 - Article
C2 - 1646325
AN - SCOPUS:0025766286
SN - 0022-3565
VL - 257
SP - 1154
EP - 1161
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -