Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

Abstract

Lay J, Carbone SE, DiCello JJ, Bunnett NW, Canals M, Poole DP. Distribution and trafficking of the -opioid receptor in enteric neurons of the guinea pig. Am J Physiol Gastrointest Liver Physiol 311: G252-G266, 2016. First published June 30, 2016 doi:10.1152/ajpgi.00184.2016.-The -opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons. In the stomach MOR was mainly localized to nitrergic neurons (ϳ88%), with some overlap with neuropeptide Y (NPY) and no expression by cholinergic neurons. These neurons are likely to have inhibitory motor and secretomotor functions. MOR was restricted to noncholinergic secretomotor neurons (VIP-positive) of the ileum and distal colon submucosal plexus. MOR was mainly detected in nitrergic neurons of the colon (nitric oxide synthase positive, 87%), with some overlap with choline acetyltransferase (ChAT) OPIATES HAVE BEEN USED FOR millennia for their analgesic properties and continue to be routinely used for the treatment of moderate to severe pain. Although opiate analgesics are effective, their use is associated with opioid-induced bowel dysfunction (OBD), a collection of on-target side effects that grossly impact gastrointestinal tract function. OBD can severely limit the use of opiates to treat pain, reducing patient quality of life and compliance, with intractable constipation the most significant problem (28).The direct inhibitory actions of opiates on the isolated colon were first demonstrated nearly a century ago by Trendelenburg. It is now established that opioids and opiates mediate their effects through actions at the ␦-, -, and -opioid G proteincoupled receptors (DOR, KOR, and MOR). These receptors are activated by over 20 endogenous opioid peptides that are generated by differential processing and cleavage of larger precursors, many of which are expressed within the gut (63). Endogenous opioid peptides, including endorphins, enkephalins, and dynorphins, are important regulators of gastrointestinal function and have dampening effects on motility and secretomotor function (70). Opiates, including morphine, mediate their effects on the gut through activation of the MOR expressed by enteric neurons, as demonstrated by mechanistic studies using selective MOR-targeting drugs and oprm1 Ϫ/Ϫ mice (reviewed by Refs. 52,70). In addition, peripherally restricted MOR antagonists, such as methylnaltrexone, have proven clinically efficacious in treating opiate-induced constipation. MOR agonists, including the peripherally restricted agonist loperamide, are commonly used as antidiarrheals.A large...

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

“…This matches our previous description of MOR immunolabeling in the guinea pig intestine. 10 In direct contrast to our study, Smith et al 32 recorded MOR-dependent responses from dissociated neurons with AH electrophysiological properties (ie, putative IPANs) from the mouse ileum and colon. However, putative interneurons and motoneurons, which functionally express MOR, 21 did not respond to morphine.…”

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

“…This matches our previous description of MOR immunolabeling in the guinea pig intestine. 10 In direct contrast to our study, Smith et al 32 recorded MOR-dependent responses from dissociated neurons with AH electrophysiological properties (ie, putative IPANs) from the mouse ileum and colon. However, putative interneurons and motoneurons, which functionally express MOR, 21 did not respond to morphine.…”

Tupaia belangeri (Wagner, 1841), a Northern Treeshrew is an Animal Model of Metabolic Healthy Obesity

“…In the colon, the distribution of MORs is significantly denser than in the stomach and small intestine areas (Lay et al, 2016). In the GI tract, MORs show a wide distribution pattern in the nerve cells of the intestinal muscular plexus and is involved in regulating the movement of intestinal smooth muscles, mainly for modulating the release of neurotransmitters, particularly the inhibitory ones (Kurz and Sessler, 2003).…”

Antidiarrheal effect of Psidium guajava L. extract in acute diarrhea: a systematic review

“…This drug acts at the μ ‐opioid receptor in the enteric nervous system, causing decreased propulsive motility and increased transit time and rectal tone. Loperamide also hyperpolarizes secretomotor neurons in the submucosal plexus, in which predominates the δ ‐opioid subtype, reducing secretion and resulting in lower liquidity of the small and large intestinal contents by reducing Ach and PG release 57,58 . However, despite its peripheral mode of action, loperamide is an avid substrate for efflux pump P‐glycoprotein, increasing the risk of drug–drug interactions and central adverse effects.…”

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

“…This matches our previous description of MOR immunolabeling in the guinea pig intestine. 10 In direct contrast to our study, Smith et al 32 recorded MOR-dependent responses from dissociated neurons with AH electrophysiological properties (ie, putative IPANs) from the mouse ileum and colon. However, putative interneurons and motoneurons, which functionally express MOR, 21 did not respond to morphine.…”

Tupaia belangeri (Wagner, 1841), a Northern Treeshrew is an Animal Model of Metabolic Healthy Obesity

“…In the colon, the distribution of MORs is significantly denser than in the stomach and small intestine areas (Lay et al, 2016). In the GI tract, MORs show a wide distribution pattern in the nerve cells of the intestinal muscular plexus and is involved in regulating the movement of intestinal smooth muscles, mainly for modulating the release of neurotransmitters, particularly the inhibitory ones (Kurz and Sessler, 2003).…”

Antidiarrheal effect of Psidium guajava L. extract in acute diarrhea: a systematic review

“…This drug acts at the μ ‐opioid receptor in the enteric nervous system, causing decreased propulsive motility and increased transit time and rectal tone. Loperamide also hyperpolarizes secretomotor neurons in the submucosal plexus, in which predominates the δ ‐opioid subtype, reducing secretion and resulting in lower liquidity of the small and large intestinal contents by reducing Ach and PG release 57,58 . However, despite its peripheral mode of action, loperamide is an avid substrate for efflux pump P‐glycoprotein, increasing the risk of drug–drug interactions and central adverse effects.…”

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

“…This matches our previous description of MOR immunolabeling in the guinea pig intestine. 10 In direct contrast to our study, Smith et al 32 recorded MOR-dependent responses from dissociated neurons with AH electrophysiological properties (ie, putative IPANs) from the mouse ileum and colon. However, putative interneurons and motoneurons, which functionally express MOR, 21 did not respond to morphine.…”

Tupaia belangeri (Wagner, 1841), a Northern Treeshrew is an Animal Model of Metabolic Healthy Obesity

“…In the colon, the distribution of MORs is significantly denser than in the stomach and small intestine areas (Lay et al, 2016). In the GI tract, MORs show a wide distribution pattern in the nerve cells of the intestinal muscular plexus and is involved in regulating the movement of intestinal smooth muscles, mainly for modulating the release of neurotransmitters, particularly the inhibitory ones (Kurz and Sessler, 2003).…”

Antidiarrheal effect of Psidium guajava L. extract in acute diarrhea: a systematic review

“…This drug acts at the μ ‐opioid receptor in the enteric nervous system, causing decreased propulsive motility and increased transit time and rectal tone. Loperamide also hyperpolarizes secretomotor neurons in the submucosal plexus, in which predominates the δ ‐opioid subtype, reducing secretion and resulting in lower liquidity of the small and large intestinal contents by reducing Ach and PG release 57,58 . However, despite its peripheral mode of action, loperamide is an avid substrate for efflux pump P‐glycoprotein, increasing the risk of drug–drug interactions and central adverse effects.…”