Molecular physiology of enteric opioid receptors

Abstract

Opioid drugs have powerful antidiarrheal effects and many patients taking these drugs for chronic pain relief experience chronic constipation that can progress to opioid-induced bowel dysfunction. Three classes of opioid receptors are expressed by enteric neurons: μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). MOR and DOR couple to inhibition of adenylate cylase and nerve terminal Ca(2+) channels and activation of K(+) channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca(2+) channels and inhibition of neurotransmitter release. In the human gastrointestinal tract, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and purine/nitric oxide release from inhibitory motorneurons. These actions inhibit propulsive motility. MOR and DOR also link to inhibition of submucosal secretomotor neurons, reducing active Cl(-) secretion and passive water movement into the colonic lumen. These effects 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 differential β-arrestin-2-dependent opioid receptor desensitization and internalization in enteric nerves in the colon compared with 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 drugs or other treatment strategies of opioid-induced bowel dysfunction.

Figure 1

Signaling pathways activated by opioid receptor agonists in the enteric nervous system. μ- and δ-opioid receptors couple to inhibition of adenylate cyclase via the inhibitory G-protein, Gi. These receptors also couple to activation of K⁺ channels and inhibition of Ca²⁺ channels via a Go-linked pathway. These mechanisms suppress enteric neuronal activity. κ-Opioid receptors link to inhibition of Ca²⁺ channels on enteric nerve terminals. This would inhibit neurotransmitter release. These pathways contribute to the constipating effects caused by opioid receptor agonists. cAMP, cyclic 3′,5′ adenosine monophosphate; PKA, protein kinase A.

Figure 2

Activation of μ-opioid receptor induces G-protein and β-arrestin-2 signaling pathways. G-protein activation allows for signaling to inhibition of adenylate cyclase and modulation of ion channels. Activation of the β-arrestin-2 pathway, in chronic activation, results in tolerance due to β-arrestin-2-mediated receptor degradation in the ileum, while maintained β-arrestin-2 levels prevent tolerance development in the colon. PKA, protein kinase A.