Histamine-induced ion transport in ileal mucosa: Neuroimmunomodulation by selective opioids

Histamine, an inflammatory mediator released from mucosal mast cells (MMC), evokes anion and fluid secretion in the small intestine, which in turn facilitates secretory IgA movement into the lumen and dilutes luminal pathogens. δ- and μ-Opioid agonists decrease mucosal anion secretion by reducing the release of enteric neurotransmitters. In this study, we tested the hypothesis that opioids suppress mucosal defense by decreasing anion secretion evoked by MMC products. Histamine (10 μM) or the MMC-degranulating compound 48/80 (10 ng/ml) produced transient increases in short-circuit current (I_SC) across sheets of porcine ileal mucosa mounted in Ussing chambers. Their effects were greatly attenuated by the neuronal blocker saxitoxin (100 nM) or the H₁-histamine antagonist diphenhydramine (10 μM). Histamine- or 48/80-evoked Isc changes were also reduced in tissues pretreated with selective opioid agonists. At 0.1 μM, the respective κ-and δ-opioid agonists U50,488 and DPDPE decreased mucosal Isc responses to histamine by approximately 62% in 4-7 tissues; in comparison, the μ-opioid agonist DAMGO decreased mucosal responses by 34 ± 5% in 5 tissues. Opioid activity was inhibited in tissues pretreated with saxitoxin or the opioid antagonist naloxone (0.1 μM). In pig ileum as in intestinal mucosae from other species, a portion of the intestinal secretory effect of histamine is mediated by histamine receptors residing on a subpopulation of submucosal enteric neurons. Neurotransmitter release from these neurons appears to be modulated by opioid receptors. Opioids may reduce defense function in the intestinal mucosa by inhibiting the actions of inflammatory mediators, such as histamine.