Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

1 In a voltage clamp setting (Ussing chamber), the antidiarrhoeal drug, loperamide (Lop) slightly augmented prostaglandin E1 (PGE1) plus theophylline‐stimulated net chloride secretion above control values at low concentrations (10−10 and 10−9 m) but inhibited it at higher concentrations (10−6 and 10−5 m). The apparently weak prosecretory action component of Lop was turned into a clear cut antisecretory effect by pretreatment with 2 times 10−7 m naloxonazine plus 10−7 m CTOP‐NH2 , two selective μ opioid receptor antagonists. This indicates a prosecretory effect of loperamide at μ opioid receptors. The antisecretory effect of low Lop concentrations, uncovered by μ opioid receptor blockade, was prevented by additional blockade of κ opioid receptors by 5 times 10−9 m nor‐binaltorphmiine (nor‐BNI). 2 The nonselective opioid antagonist, naloxone, at 10−6 m did not significantly reduce either PGE1 plus theophylline‐stimulated net chloride secretion in Lop‐free controls or the antisecretory action of Lop. By contrast, the partial agonist ethylketocyclazocine (EKC), which activates κ but blocks μ opioid receptors, concentration‐dependently inhibited PGE1 plus theophylline‐stimulated net chloride secretion without any consistent prosecretory action component. Nor‐BNI at 5 times 10−8 m significantly blocked the antisecretory action of EKC. 3 It is concluded that, in the guinea‐pig colonic mucosa under the present conditions, μ opioid receptors mediate enhancement and κ opioid receptors inhibition of PGE1‐stimulated net chloride secretion by low Lop concentrations. The two opposite actions are largely masked by superimposition. An opioid receptor‐independent mechanism of action contributes to the antisecretory effect of Lop at high concentrations.