Differential inhibition of cholinergic and noncholinergic neurogenic contractions by mu opioid and alpha-2 adrenergic agonists in guinea pig ileum.

The actions of clonidine, 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)-6-quinoxalinamine (UK 14304), D-Ala2, N-MePhe4, Gly-ol5 enkephalin (DAGOL), and morphine on neurogenic contractions were studied in guinea pig ileum longitudinal muscle myenteric plexus in vitro. Cholinergic contractions were evoked by 0.1 and 10 Hz transmural electrical stimuli; noncholinergic contractions (1 microM scopolamine present) were evoked only by trains of stimuli. Noncholinergic contractions were mediated largely by substance P (SP). DAGOL and morphine inhibited 0.1 Hz contractions; pD2 values were 8.0 and 6.0, respectively. DAGOL also inhibited 10-Hz cholinergic contractions (pD2 = 7.5). The actions of DAGOL were blocked by naloxone (Kb approximately 5 nM) indicative of an action at mu opioid receptors. DAGOL (1 microM) reduced by 50% noncholinergic responses evoked by 5 Hz but not 10- or 20-Hz stimulation. Morphine did not inhibit noncholinergic contractions. Clonidine and UK 14304 inhibited 0.1 Hz contractions with pD2 values of 8.1 and 7.4, respectively. Clonidine and UK 14304 also inhibited 10-Hz cholinergic contractions. UK 14304 inhibited equally well noncholinergic contractions evoked by 5-, 10- and 20-Hz stimuli. The actions of UK 14304 were blocked by idazoxan (Kb approximately 5 nM). UK 14304 and DAGOL Ka values were determined using null methods and were used to construct occupancy-response curves to measure coupling efficiency (efficacy) between agonist-occupied receptor and response. The relative efficacy of UK 14304 was: 10 Hz noncholinergic > or = 0.1 Hz cholinergic > 10 Hz cholinergic. The relative efficacy for DAGOL was: 0.1 Hz cholinergic > 10 Hz cholinergic >>> 10 Hz noncholinergic.(ABSTRACT TRUNCATED AT 250 WORDS)