Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

Abstract

Opioid drugs are prescribed extensively for pain treatment but when used chronically they induce constipation that can progress to opioid-induced bowel dysfunction. Opioid drugs interact with three classes of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DOR), and kappa opioid receptors (KORs), but opioid drugs mostly target the MORs. Upon stimulation, opioid receptors couple to inhibitory Gi/Go proteins that activate or inhibit downstream effector proteins. MOR and DOR couple to inhibition of adenylate cyclase and voltage-gated Ca channels and to activation of K channels resulting in reduced neuronal activity and neurotransmitter release. KORs couple to inhibition of Ca channels and neurotransmitter release. In the gastrointestinal tract, opioid receptors are localized to enteric neurons, interstitial cells of Cajal, and immune cells. In humans, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and motor neurons and purine/nitric oxide release from inhibitory motor neurons causing inhibition of propulsive motility patterns. MOR and DOR activation also results in inhibition of submucosal secretomotor neurons reducing active Cl secretion and passive water movement into the colonic lumen. Together, these effects on motility and secretion account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differences in trafficking and downstream signaling in enteric nerves in the colon compared to the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drug or other treatment strategies of opioid-induced bowel dysfunction.

Central and peripheral modulation of gastrointestinal transit in mice by DN‐9, a multifunctional opioid/NPFF receptor agonist

“…5 Previous reports have indicated that the activation of these three opioid receptors is all associated with the inhibition of the acetylcholine and purine/nitric oxide release from the enteric neurons, causing gastrointestinal (GI) inhibition. 6 The MOP (eg, morphine and DAMGO) and DOP (eg, DPDLE) receptor agonists were reported to inhibit GI transit dose-dependently. 7 KOP receptor is expressed primarily in the myenteric plexus.…”

Effects of naloxegol on whole gut transit in opioid‐naïve healthy subjects receiving codeine: A randomized, controlled trial

“…Lembo et al showed that the μ‐opioid agonist, fentanyl, inhibits the perception of phasic rectal distention in a dose‐dependent fashion. In addition, activation of μ and δ opioid receptors reduces active Cl − secretion and passive water movement into the colonic lumen by inhibiting submucosal secretomotor neurons, which can result in stool of more solid consistency …”

“…In addition, activation of μ and δ opioid receptors reduces active Cl − secretion and passive water movement into the colonic lumen by inhibiting submucosal secretomotor neurons, which can result in stool of more solid consistency. 11 Peripherally active μ-opioid receptor antagonists (PAMORA) have emerged as a treatment option for chronic opioid-induced constipation (OIC). 12 Naloxegol is a novel PAMORA which is efficacious in the treatment of chronic OIC when administered orally at a dose of 25 mg daily.…”

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar‐potency inhibitor of calcium‐activated chloride channel TMEM16A

“…This idea is supported by our findings that both TMEM16A inhibitor and loperamide delay gastric emptying, whereas only loperamide slowed whole-gut transit. Opioids have multiple actions on gut, including inhibition of ICCs by activating K + -ATP channels and suppression of enteric neurons and intestinal secretion, which indirectly inhibits stretch-induced motility (30). Because TMEM16A is not expressed in enterocytes or enteric neurons, TMEM16A inhibition is not expected to affect the determinants of gut motility other than ICC activity.…”

“…Mice were administered TM inh -23 at 10 mg/kg (in saline containing 5% DMSO and 10% Kolliphor HS 15) either intraperitoneally or by oral gavage. Blood samples were collected at 15,30,60,120, and 240 min by orbital puncture and centrifuged at 5000 rpm for 15 min at 25°C to separate serum. Solid-phase extraction columns (C18, HyperSep 60108-304; Thermo Fisher Scientific, Waltham, MA, USA) were conditioned with methanol (2 ml) followed by PBS (2 ml).…”