Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

Abstract

The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1β, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 μg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.

Oxidative Stress, Inflammation, Gut Dysbiosis: What Can Polyphenols Do in Inflammatory Bowel Disease?

“…These excessive ROS can act as upstream stimuli to evoke aberrant activation of the intestinal immune system, causing damage to the intestinal mucosal barrier, including a decrease in mucous secretion, antimicrobial peptide secretion, and the destruction of tight junctions [ 15 ]. Importantly, radical immune cells activate inflammatory signaling pathways such as NF-κB, JAK/STAT, and MAPK signaling pathways [ 16 , 17 , 18 ], promote the release of proinflammatory factors (e.g., TNF-α, IL-6, and IL-1β) and oxidases (e.g., iNOS, COX-2, and NOX [ 19 , 20 ]), and further increase the level of oxidative stress in the intestinal tract [ 21 ], which will remold the gut microbiota and form a loop of oxidative stress–ROS–inflammation–ROS–oxidative stress ( Figure 1 ). Accordingly, such a loop can be used as a potential therapeutic target to avoid the occurrence and progression of intestinal inflammation by alleviating oxidative stress in the intestine and reducing the stimulation of gut microbiota and immune cells by ROS, thereby recovering the intestinal mucosal barrier.…”

The effect of dalargin on growth factors content in experimental ulcerative colitis

“…Thus, an increase in leu-and met-enkephalins content in the blood plasma, as well as an increase in the expression and activity of opioid µ-receptors in opiorphin administration, led to the suppression of the activity of nuclear factor kB, p65 protein, and Toll-like receptor (TLR-4), induced NO-synthase and cyclooxygenase type 2 (Raeeszadeh-Sarmazdeh et al 2020). The involvement of opioid µ-receptors in the anti-inflammatory effect of opiorphin was confirmed by the fact that these effects were not observed in naloxone administration, which blocks the activity of opioid µreceptors (Luo et al 2022).…”

“…The use of the enkephalinase inhibitor opiorphin in experimental UC in mice caused a decrease in the concentration of proinflammatory cytokines (IL-1β, IL-6, TNFα) and an Table 1. Effect of dalargin on the concentrations of transforming growth factor-β and epidermal growth factor in the homogenate of the medial colon increase in the content of anti-inflammatory IL-10, both in the colonic wall and in the plasma, as well as a decrease in the activity index disease and reduction in the area of ulcers of the colonic mucosa (Luo et al 2022).…”