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...

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

“…MOR, DOR and KOR are expressed by myenteric and submucosal plexus neurons in the enteric nervous system (ENS)(Bagnol et al , 1997; Poonyachoti et al , 2002; Ho et al , 2003; Sternini et al , 2004; Gray et al , 2006; Poole et al , 2011; Lay et al , 2016), with some species differences. In the rat, MOR neurons are more abundant in the submucosal than myenteric plexus, whereas KOR are more numerous in the myenteric plexus, with both MOR and KOR myenteric neurons being more abundant in the stomach and proximal colon compared to other regions of the GI tract (Bagnol et al , 1997).…”

“…In the mouse GI tract, MOR and DOR but not KOR are expressed by ICC ((Kim et al , 2016). In the guinea pig, MOR are localized to interneurons controlling the peristaltic reflex and to submucosal secretomotor neurons (Ho et al , 2003; Lay et al , 2016). In the guinea pig stomach, MOR are located in nitrergic inhibitory motorneurons and cholinergic secretomotor neurons (Lay et al , 2016).…”

“…In the guinea pig, MOR are localized to interneurons controlling the peristaltic reflex and to submucosal secretomotor neurons (Ho et al , 2003; Lay et al , 2016). In the guinea pig stomach, MOR are located in nitrergic inhibitory motorneurons and cholinergic secretomotor neurons (Lay et al , 2016). In the guinea pig ileal myenteric plexus, MOR are localized to cholinergic, excitatory motor neurons and vasoactive intestinal peptide (VIP) expressing inhibitory motor neurons, and excitatory, cholinergic/VIPergic interneurons (Ho et al , 2003; Lay et al , 2016).…”

“…In the guinea pig stomach, MOR are located in nitrergic inhibitory motorneurons and cholinergic secretomotor neurons (Lay et al , 2016). In the guinea pig ileal myenteric plexus, MOR are localized to cholinergic, excitatory motor neurons and vasoactive intestinal peptide (VIP) expressing inhibitory motor neurons, and excitatory, cholinergic/VIPergic interneurons (Ho et al , 2003; Lay et al , 2016). The density of MOR nitrergic neurons is much higher than that of MOR cholinergic neurons in the myenteric plexus of both the proximal (Anselmi and Sternini, unpublished), and distal colon (Anselmi and Sternini, unpublished; (Lay et al , 2016).…”

“…In the guinea pig ileal myenteric plexus, MOR are localized to cholinergic, excitatory motor neurons and vasoactive intestinal peptide (VIP) expressing inhibitory motor neurons, and excitatory, cholinergic/VIPergic interneurons (Ho et al , 2003; Lay et al , 2016). The density of MOR nitrergic neurons is much higher than that of MOR cholinergic neurons in the myenteric plexus of both the proximal (Anselmi and Sternini, unpublished), and distal colon (Anselmi and Sternini, unpublished; (Lay et al , 2016). In the submucosal plexus, MOR are confined to VIP non-cholinergic secretomotor neurons of the ileum and distal colon (Lay et al , 2016).…”