EFFECTS OF OPIOIDS ON NONCHOLINERGIC EXCITATORY RESPONSES OF THE GUINEA‐PIG ISOLATED ILEUM: INHIBITION OF RELEASE OF ENTERIC SUBSTANCE P

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Abstract
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 μg/ml) and by desensitizing the preparation to substance P (76.3 ± 10.1%). 4 Morphine (5 × 10−6 m) as well as the opioid peptides d-Ala2, N-Phe4, Met-(0)-01 (FK 33–824; 9 × 10−7 m), d-Met2-Pro5 enkephalin (3 × 10−7 m) and d-Ala2-d-Leu5-enkephalin (5 × 10−6 m) inhibited the magnitude of the noncholinergic contracture but did not alter contractile responses to exogenous substance P (4 × 10−11 m-4 × 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 × 10−11-4 × 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.