beta-endorphin and Diarrhea

The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves.. Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents.. D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels.. Distinct patterns of immune dysfunction and interaction with sensory pathways occur in different patient groups and through different intracellular pathways. Our results indicate IBS patient subgroups would benefit from selective targeting of the immune system.

Topics: Adult; Animals; beta-Endorphin; Case-Control Studies; Cells, Cultured; Colon; Constipation; Culture Media, Conditioned; Cytokines; Diarrhea; Female; Ganglia, Spinal; Humans; Irritable Bowel Syndrome; Leukocytes, Mononuclear; Male; Mice; Middle Aged; Neuroimmunomodulation; Neurons, Afferent; Pain; Receptors, Cytokine

Opiates and opioid peptides can alter gastrointestinal motility and delay transit of intraluminal contents. These experiments were designed to characterize the effects of beta-endorphin and [D-Ala2,Met5]enkephalinamide (DALA) on small intestinal transit in the rat. Rats were implanted with a polyethylene cannula in the right lateral cerebral ventricle and a silastic cannula in the proximal duodenum. Drugs were administered via the cerebral cannula or intraperitoneally (i.p.) Interstitial transit was assessed by instilling radiochromium into the duodenum and calculating the geometric center of the distribution of marker in the small intestine. beta-Endorphin and DALA produced a dose-related decrease in intestinal transit when the peptides were given intracerebroventricularly (i.c.v.) however, neither peptide was effective when i.p. [D-Ala2,Leu5]enkephalinamide and dynorphin-(1-13) did not alter intestinal transit. The inhibitory effects of beta-endorphin and DALA were antagonized by pretreatment with naloxone or naltrexone. A quaternary amine containing opiate antagonist. N,N-diallylnormorphinium given i.p. did not alter the response to either peptide but was effective in blocking the antitransit effects of i.p. loperamide, a peripherally acting opioid agonist. In addition, DALA reduced the body weight loss produced by castor oil-induced diarrhea while beta-endorphin had no effect. These results indicate that opioid peptides can alter intestinal motility by an action within the central nervous system. While DALA and beta-endorphin produce quantitatively the same effects on small intestinal motility, qualitatively they may differ in their mechanisms of action.

Topics: Animals; beta-Endorphin; Central Nervous System; Diarrhea; Dynorphins; Endorphins; Female; Gastrointestinal Motility; Intestine, Small; Naloxone; Naltrexone; Rats; Rats, Inbred Strains