A guinea pig ileum preparation devoid of functional kappa receptors: a new in vitro pharmacologic assay for mu-opioid ligands.
Guinea pig ileum longitudinal muscle/myenteric plexus preparations contain functional mu- and kappa-opioid receptors. A preparation with blocked kappa receptors was obtained by pretreating guinea pigs with 0.1-10.0 mg/kg intraperitoneal doses of a new kappa-selective affinity label, DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S-1-(-3-isothiocyanatophenyl)-2-(-1 -pyrrolidinyl) ethyl] acetamide). Determination of IC50 values for the mu-selective agonist DAMGO ([D-Ala2,MePhe4,Gly(ol)5]-enkephalin) and the kappa-selective agonist U 69,593 ([5alpha,7alpha,8beta]-(+)-N-methyl-N-[7-(1-pyrrolidin yl)-1-oxaspiro-(4,5)-dec-8-yl]) showed that 0.5 mg/kg DIPPA at 48 h produced reliable, near-complete blockade of kappa-opioid activity but a minimal shift for kappa-opioid agonism. This new assay should be useful for studying mixed agonists/antagonists that produce strong kappa-opioid receptor agonism, which prevents determination of mu-opioid receptor antagonism.
Schwartz
R W
RW
Department of Neuroscience, SRI International, Menlo Park, CA 94025, USA.
Chang
A C
AC
Portoghese
P S
PS
Berzetei-Gurske
I P
IP
D000081:Acetamides / Q000494:pharmacology*; D000345:Affinity Labels / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism*; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*
D000081:Acetamides; D000345:Affinity Labels; D000700:Analgesics; D044482:Benzeneacetamides; D004745:Enkephalins; D017879:Isothiocyanates; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C087549:2-(3,4-dichlorophenyl)-N-methyl-N-(1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl)acetamide; C045444:U 69593