Characterisation of opioid receptors involved in modulating circular and longitudinal muscle contraction in the rat ileum.
1. The aim of the present investigation was to characterise the opioid receptor subtypes present in the rat ileum using a method that detects drug action on the enteric nerves innervating the circular and longitudinal muscles. 2. Neurogenic contractions were reversibly inhibited by morphine (circular muscle pEC50, 6.43+/-0.17, Emax 81.7+/-5.0%; longitudinal muscle pEC50, 6.65+/-0.27, Emax 59.7+/-7.8%), the mu-opioid receptor-selective agonist, DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin acetate) (circular pEC50, 7.85+/-0.04, Emax 97.8+/-3.6%; longitudinal pEC50, 7.35+/-0.09, Emax 56.0+/-6.1%), the delta-selective agonist DADLE ([D-Ala2,D-Leu5]enkephalin acetate) (circular pEC50, 7.41+/-0.17, Emax, 93.3+/-8.4%; longitudinal pEC50, 6.31+/-0.07, Emax 66.5+/-5.2%) and the kappa-selective agonist U 50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulphonate) (circular pEC50, 5.91+/-0.41, Emax, 83.5+/-26.8%; longitudinal pEC50, 5.60+/-0.08, Emax 74.3+/-7.2%). Agonist potencies were generally within expected ranges for activity at the subtype for which they are selective, except for U 50488H, which was less potent than expected. 3. The mu and delta receptor-selective antagonists, CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) and naltrindole, caused progressive, parallel rightward shifts in the DAMGO and DADLE curves, respectively. Analysis indicated conformity to theoretical simple competitive antagonist behaviour. U 50488H effects were insensitive to the kappa-selective antagonist, n-BNI. A high concentration (1 microM) of naltrexone caused apparent potentiation of U 50488H effects. 4. CTAP pK(B) estimates were consistent with previously reported values for mu receptor antagonism (circular 7.84+/-0.17, longitudinal 7.64+/-0.35). However, the naltrindole pK(B) estimates indicated lower antagonist potency than expected (circular 8.22+/-0.23, longitudinal 8.53+/-0.35). 5. It is concluded that mu and possibly atypical delta receptors (but not kappa receptors) mediate inhibition of contraction in this model. Nonopioid actions of U 50488H are probably responsible for the inhibitory effects seen with this compound.
Gray
Andrew C
AC
Department of Pharmaceutical Biology and Pharmacology, Faculty of Pharmacy, Victorian College of Pharmacy, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
White
Paul J
PJ
Coupar
Ian M
IM
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D017615:Enteric Nervous System / Q000187:drug effects / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051844:norbinaltorphimine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C055382:naltrindole