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 pEC(50), 6.43 +/- 0.17, E-max 81.7 +/- 5.0%; longitudinal muscle pEC(50), 6.65 +/- 0.27, E-max 59.7 +/- 7.8%), the mu-opioid receptor-selective agonist, DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkephalin acetate) (circular pEC(50), 7.85 +/- 0.04, E-max 97.8 +/- 3.6%; longitudinal pEC(50), 7.35 +/- 0.09, E-max 56.0 +/- 6.1%), the delta-selective agonist DADLE ([D-Ala(2), D-Leu(5)]enkephalin acetate) (circular pEC(50), 7.41 +/- 0.17, E-max, 93.3 +/- 8.4%; longitudinal pEC(50), 6.31 +/- 0.07, E-max 66.5 +/- 5.2%) and the kappa-selective agonist U 50488H (trans-(7)3,4- dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeneacetamide methanesulphonate) (circular pEC(50), 5.91 +/- 0.41, E-max, 83.5 +/- 26.8%; longitudinal pEC(50), 5.60 +/- 0.08, E-max 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 mu M) of naltrexone caused apparent potentiation of U 50488H effects. 4 CTAP pK(B) estimates were consistent with previously reported values for m receptor antagonism (circular 7.84 +/- 0.17, longitudinal 7.64 +/- 0.35). However, the naltrindole pKB estimates indicated lower antagonist potency than expected (circular 8.22 +/- 0.23, longitudinal 8.53 +/- 0.35). 5 It is concluded that m and possibly atypical d 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.