Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

Abstract

Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract.

Fig. 1

General structure of G protein-coupled receptors. Opioid receptors are integral membrane proteins, coupled to heterotrimeric G proteins. The structure of opioid receptors consists of seven hydrophobic transmembrane domains TM I–VII, three intracellular hydrophobic (i1–i3) and three extracellular (e1–e3) loops, a glycosylated amino and a carboxyl terminus

Fig. 2

Opioid receptor-related intracellular signal transduction pathways. Opioid receptors are coupled with Gαi, Gαo and Gαz proteins. Secondary transmitters include adenylyl cyclase (AC), GPCR kinase 2/3 (GRK), phospholipase Cβ (PLCβ), and phospatidyloinositol-3-kinase (PI3K). The release of Gβγ subunit also inhibits voltage-gated Ca²⁺ channels (VGCC, L-type and N-type) and activates K⁺ channels

Fig. 3

Interaction of opioids with neurotransmitters in the enteric nervous system. Opioids reduce tonic/segmental contractions and impair peristalsis by inhibition of the release of ACh and SP. The decrease of GI secretion is caused by the inhibition of the activity of ACh and VIP containing neurons

Fig. 4

Pharmacological and clinical effects of opioids

Fig. 5

Structures of anti-diarrheal agents, loperamide and acetorphan

Fig. 6

Structure of lubiprostone

Fig. 7

Principle of action of peripherally acting MOR antagonists (PAMORA)

Fig. 8

Structures of clinically used peripherally acting MOR antagonists (PAMORA): alvimopan and methylnaltrexone

Fig. 9

Structure of trimebutine