Abstract
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.
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