Counteracting effect of papaverine on morphine inhibition of gastrointestinal transit in mice

Oral papaverine has been shown to be capable of antagonizing the constipation induced by a single dose of oral morphine. The primary aim of the present study was to ascertain whether papaverine is also capable of counteracting morphine-induced decrease of upper gastrointestinal transit (UGT) after repeated parenteral administration of the opioid. We next investigated the mechanisms(s) responsible for the counteracting effect of papaverine, by analysing whether this effect was changed by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), dexamethasone, indomethacin or capsaicin. Papaverine, co-administered with morphine, counteracted the morphine-induced decrease in UGT in mice pretreated with morphine for 3 days but did not do so in naive animals. The counteracting effect of papaverine was antagonized by L-NAME, but not by indomethacin. In mice pretreated with both morphine and dexamethasone, papaverine failed to antagonize the effect of morphine. Capsaicin pretreatment completely abolished the effect of a single dose of morphine, the effect being partially restored by the 3 days pretreatment with morphine. In mice pretreated with both capsaicin and morphine, the UGT decrease elicited by morphine was lower than in the other experimental groups and was not modified by papaverine. Our results show that papaverine can counteract the morphine inhibition of UGT in mice repeatedly exposed to the opioid. Papaverine exerts its action through a nitric oxide synthase-mediated mechanism; this mechanism is only effective after repeated morphine administration and does not operate when capsaicin-sensitive afferent neurones are ablated.