EVIDENCE FOR TRYPTAMINERGIC AND NORADRENERGIC INVOLVEMENT IN THE ANTISECRETORY ACTION OF MORPHINE IN THE RAT JEJUNUM

Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) effect of morphine in the intestine is mediated by a direct action of morphine on enteric nerves. Rats were pretreated with 6‐hydroxydopamine (6‐OHDA) or p‐chlorophenylalanine (PCPA) to deplete intestinal stores of noradrenaline and 5‐hydroxytryptamine (5‐HT). Intraperitoneal injection of 6‐OHDA (3 doses at 50 mg kg−1) caused a selective reduction in the level of noradrenaline in the jejunum to 7ṁ3% of control. Intraperitoneal injection of PCPA (200 mg kg−1) selectively reduced the jejunal level of 5‐HT to 30ṁ5% of control. Groups of rats that had been treated as described above were anaesthetized and then injected intravenously with saline or with blocking doses of either atropine (0ṁ25 mg kg−1), hexamethonium (20 mg kg−1), ketanserin (30 μg kg−1), methysergide (30 μg kg−1), phentolamine (2 mg kg−1) or propranolol (1 mg kg−1). Following perfusion of the lumen of the jejunum, the rate of glucose absorption was measured to assess the integrity of the mucosa. Glucose absorption was unaltered in animals pretreated with hexamethonium and propranolol but there was a small enhancement in animals pretreated with atropine, PCPA, methysergide, 6‐OHDA and phentolamine. The rate of net water absorption from the lumen of the jejunum and the rate of fluid secretion into the lumen following intra‐arterial infusion of vasoactive intestinal peptide (VIP, 0ṁ8 μg min−1) were unaltered by any of the drug treatments. Intravenous injection of morphine (10 mg kg−1) did not alter the levels of noradrenaline or 5‐HT in the whole jejunum. However, this dose of morphine did cause a 63ṁ5% decrease in the VIP‐induced change in water transport. This antisecretory effect of morphine was unaltered in animals pretreated with atropine, hexamethonium and propranolol. In contrast, methysergide, ketanserin and 6‐OHDA abolished the antisecretory effect of morphine. PCPA and phentolamine produced a partial inhibition of morphine's antisecretory effect. It is concluded that morphine produces its antisecretory effect in the jejunum by activation of noradrenergic and tryptaminergic systems. 1987 Royal Pharmaceutical Society of Great Britain