µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

Abstract

Background and Aims The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ‐opioid receptor (MOR), its ligand β‐endorphin (β‐END), and cannabinoid receptor‐2 (CB2) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception. Methods Mucosal biopsies were obtained from the left colon of 31 IBS patients (45% women) with predominant constipation (IBS‐C, 9) or diarrhea (IBS‐D, 10) or with mixed bowel habits (IBS‐M, 12) and 32 AC (44% women) and processed for qRT‐PCR, Western blotting, and immunohistochemistry. Key Results µ‐opioid receptor and CB2 mRNA and protein expression and β‐END protein levels were increased in patients with IBS compared to AC (all Ps=0.021). A significant sex by IBS interaction was found in relation to CB2 mRNA expression (P = .003) with women showing a markedly higher expression to men (P = .035). In contrast, in AC, men had higher expression than women (P = .033). β‐END, MOR, and CB2 immunoreactivities (IR) were localized to CD4+T cells including EMR‐1+ eosinophils and CD31+ T cells but not to mast cells. Conclusions The increased expression of MOR, β‐END, and CB2 in the mucosa of IBS patients, where they are localized to immune cells, suggests that opioid and cannabinoid systems play an immune‐related compensatory role in visceral pain in IBS patients. Further work is necessary to support this hypothesis.

Proteolytic Cleavage of Bioactive Peptides and Protease-Activated Receptors in Acute and Post-Colitis

“…Therefore, we first aimed to obtain cleavage patterns of naturally occurring substrates with a set of purified trypsin-like and elastase-like proteases present in the human colon (trypsin-1, -2, -3, tryptase, thrombin, cathepsin G, neutrophil elastase and pancreatic elastase). We focused on -endorphin, vasoactive intestinal peptide (VIP), neurotensin, enkephalins, substance P and bradykinin because these peptides are linked to pain sensitization or inflammation and, as such, are relevant in the pathophysiology of colitis [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Since a role for protease-activated receptors (PARs) in colitis and post-colitis has been described, the ability of the proteases to ‘unmask’ or ‘disarm’ PARs was assessed as well [ 31 , 32 , 33 , 34 ].…”

Overexpression of corticotropin-releasing factor in intestinal mucosal eosinophils is associated with clinical severity in Diarrhea-Predominant Irritable Bowel Syndrome

“…However, eosinophils also synthesize neuro-hormones and peptides and express receptors that may contribute to both, regulatory physiology and disease mechanisms. In fact, intestinal mucosal eosinophils contain substance P (SP), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide and corticotropin-releasing factor (CRF) 1 , 6 , 7 and have recently been identified as potential contributors to the opioid and cannabinoid systems by playing a compensatory role 8 . Moreover, as most immune cells in the lamina propria , eosinophils locate near nerves in pathological conditions 9 , which facilitates bidirectional communication between the immune and nervous systems.…”

Expression of Opioid Receptors in Cells of the Immune System

“…Microscopic analysis identified the presence of µ-OR and β-endorphin immunoreactivities in CD4+, EMR-1+, and CD31+ cells, indicating the expression of µ-OR and β-endorphin by mucosal T-helper lymphocytes, eosinophils, and leukocytes, respectively. This result suggests the involvement of the opioid system in the immune-related compensatory role in visceral pain in irritable bowel syndrome patients [ 102 ].…”