Toll-like receptor 4 contributes to the inhibitory effect of morphine on colonic motility in vitro and in vivo

Abstract

Opioids rank among the most potent analgesic drugs but gastrointestinal side effects, especially constipation, limit their therapeutic utility. The adverse effects of opioids have been attributed to stimulation of opioid receptors, but emerging evidence suggests that opioids interact with the innate immune receptor Toll-like receptor 4 (TLR4) and its signalling pathway. As TLR4 signalling affects gastrointestinal motility, we examined the involvement of TLR4 in morphine-induced depression of peristaltic motility in the guinea-pig intestine in vitro and male C57BL/6N mice in vivo. While the TLR4 antagonist TAK-242 (0.1 μM and 1 μM) did not alter the morphine-induced inhibition of peristalsis in the isolated guinea-pig small intestine, the morphine-induced decrease in pellet propulsion velocity in colonic segments was attenuated by TAK-242 (0.1 μM). The ability of TAK-242 (4 mg/kg) to mitigate the morphine-induced suppression of colonic motility was replicated in mice in vivo by measuring the expulsion time of beads inserted in the distal colon. The inhibition of upper gastrointestinal transit of mice by morphine was not affected by pre-treatment with TAK-242 (4 mg/kg) in vivo. This is the first report that morphine-induced inhibition of colonic peristalsis is alleviated by TLR4 antagonism. We therefore conclude that TLR4 may contribute to opioid-induced constipation.

Activation of μ-opioid receptor and Toll-like receptor 4 by plasma from morphine-treated mice

“…The morphine metabolite, morphine-3-glucuronide (M3G), is able to activate TLR4 signalling (Hutchinson et al, 2010b). Activation of TLR4 by opioids is proposed to mediate some of the undesirable effects of opioids, such as neuro-inflammation through central innate immune and endothelial cells (Grace et al, 2014;Wang et al, 2012); contribution to the reinforcing/rewarding effects of opioids and to morphine-induced suppression of colon peristalsis (Farzi et al, 2015); but also to modulate peripheral endogenous opioid-mediated analgesia in the context of inflammation (Sauer et al, 2014).…”

Necrotizing enterocolitis and its association with the neonatal abstinence syndrome

“…It is hypothesized that upregulation of TLRs, specifically TLR4, in preterm, stressed intestinal epithelium allows for initiation of the pro-inflammatory cascade that results in the final common pathway of NEC [19]. Emerging evidence indicates that select opioids can activate TLR4 leading to elevated cytokine levels [20,21]. Our unproven hypothesis is that the upregulation of the immune system and release of cytokines by some opioids could be a factor in causation of NEC in these mature neonates after in utero exposure to opioids.…”

Immunologia dla specjalistów medycyny paliatywnej. Rola receptorów Toll-like w wywoływaniu objawów choroby

“…Opioids cause constipation by reacting with opioid receptors at the endings of entero-neurons in the gastrointestinal tract [63]. In addition to opioid receptors [64], TLR-4 are also located at the same nerve endings [65], the activation of which causes local inflammation and, as in irritable bowel syndrome [66], causes intestinal motility disorders and constipation. Naloxone administered orally together with opioids may also demonstrate effects by blocking TL receptors [67,68].…”

“…Opioidy powodują zaparcie poprzez reakcję z receptorami opioidowymi na zakończeniach entero neuonów w przewodzie pokarmowym [63]. Oprócz receptorów opioidowych [64], na tych samych zakończeniach nerwowych zlokalizowane są także TLR-4 [65], których aktywacja powoduje stan miejscowego zapalenia, i podobnie jak w zespole drażliwego jelita [66], powodują zaburzenia motoryki jelit i zaparcia. Nalokson podawany drogą doustną razem z opioidami może również wykazywać działanie poprzez blokadę receptorów TL [67,68].…”