Effects of opioids on noncholinergic excitatory responses of the guinea-pig isolated ileum: inhibition of release of enteric substance P.

1 Experiments were carried out to determine whether opiates and opioid peptides could affect noncholinergic excitatory responses of the isolated guinea-pig ileum. 2 Transmural field stimulation (10-20 Hz) of an atropine pretreated, intact segment of gut produced a contracture that could be elicited repeatedly without significant variation in magnitude. 3 This noncholinergic contracture was significantly reduced 75.3 +/- 8.3% (mean +/- s.e. mean) by tetrodotoxin (TTX; 1 microgram/ml) and by desensitizing the preparation to substance P (76.3 +/- 10.1%). 4 Morphine (5 x 10(-6) M) as well as the opioid peptides D-Ala2, N-Phe4, Met-(0)-01 (FK 33-824; 9 x 10(-7) M), D-Met2-Pro5 enkephalin (3 x 10(-7) M) and D-Ala2-D-Leu5-enkephalin (5 x 10(-6) M) inhibited the magnitude of the noncholinergic contracture but did not alter contractile responses to exogenous substance P (4 x 10(-11) M--4 x 10(-10) M). 5 Pretreatment with the nicotinic receptor blocker, hexamethonium (10(-5)--10(-4) M) reduced by about 35% the magnitude of the atropine-resistant contracture but did not affect inhibitory responses to morphine or opioid peptides. Thus the inhibition produced by morphine on the 20 Hz contracture does not involve a nicotinic cholinergic mechanism. 6 Naloxone pretreatment (10(-6) M) in the presence of hexamethonium (10(-5)--10(-4) M) enhanced the magnitude of the noncholinergic contracture without affecting responses to exogenous substance P (4 x 10(-11)--4 x 10(-10) M). 7 These data suggest that substance P is the main, if not the sole, mediator of the atropine-resistant 20 Hz contracture and indicate further that exogenous as well as endogenous opioids can modulate the release of this enteric peptide.