Morphine Induces μ Opioid Receptor Endocytosis in Guinea Pig Enteric Neurons Following Prolonged Receptor Activation

Patierno, Simona; Anselmi, Laura; Jaramillo, Ingrid; Scott, David F.; Garcia, R. V.; Sternini, Catia

doi:10.1053/j.gastro.2010.11.005

Cited by 36 publications

(51 citation statements)

References 51 publications

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“…All of the procedures with animals were approved by the Institutional Animal Care and Use Committee at Virginia Commonwealth University. Chronic parenteral exposure to morphine or saline was carried out over 7 days using the following schedule (Li et al, 2010;Patierno et al, 2011): morphine or saline was injected subcutaneously twice daily using the following paradigm: on day 1, 10 mg/kg b.i.d. ; days 2 and 3, 20 mg/kg b.i.d.…”

Section: Methodsmentioning

confidence: 99%

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

Kang¹,

Maguma²,

Smith³

et al. 2011

J Pharmacol Exp Ther

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␤-Arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant tolerance to constipation is a limiting side effect of chronic morphine treatment. Because tolerance to morphine develops in the mouse ileum but not the colon, we therefore examined whether the role of ␤-arrestin2 in the mechanism of morphine tolerance differs in the ileum and colon. In both guinea pig and mouse, chronic in vitro exposure (2 h, 10 M) to morphine resulted in tolerance development in the isolated ileum but not the colon. The IC 50 values for morphine-induced inhibition of electrical field stimulation contraction of guinea pig longitudinal muscle myenteric plexus shifted rightward in the ileum from 5.7 Ϯ 0.08 (n ϭ 9) to 5.45 Ϯ 0.09 (n ϭ 6) (p Ͻ 0.001) after morphine exposure. A significant shift was not observed in the colon. Similar differential tolerance was seen between the mouse ileum and the colon. However, tolerance developed in the colon from ␤-arrestin2 knockout mice. ␤-Arrestin2 and extracellular signal-regulated kinase 1/2 expression levels were determined further by Western blot analyses in guinea pig longitudinal muscle myenteric plexus. A time-dependent decrease in the expression of ␤-arrestin2 and extracellular signalregulated kinase 1/2 occurred in the ileum but not the colon after 2 h of morphine (10 M) exposure. Naloxone prevented the decrease in ␤-arrestin2. In the isolated ileum from guinea pigs chronically treated in vivo with morphine for 7 days, neither additional tolerance to in vitro exposure of morphine nor a decrease in ␤-arrestin2 occurred. We conclude that a decrease in ␤-arrestin2 is associated with tolerance development to morphine in the gastrointestinal tract.

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Section: Methodsmentioning

confidence: 99%

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

Kang¹,

Maguma²,

Smith³

et al. 2011

J Pharmacol Exp Ther

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“…Activated GPCRs may continue to signal from within endosomes as part of signaling complexes via G proteindependent and -independent mechanisms (30). In myenteric neurons MOR is internalized in response to agonists including [D-Ala 2 , MePhe 4 , Gly(ol) 5 ]enkephalin (DAMGO), whereas morphine does not induce MOR endocytosis unless neurons have been chronically exposed to this opiate (40,43,59). The inability of morphine to induce endocytosis has led to the hypothesis that agonists that weakly promote internalization are expected to lead to tolerance and dependence (4).…”

Section: This Article Provides a Detailed Characterization Of The -Opmentioning

confidence: 99%

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

Lay

Carbone

DiCello

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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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...

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“…Indeed, modulation of dynamin expression and localization was shown to be responsible for the increased ability of -opioid receptors to internalize in enteric neurons after chronic treatment (Patierno at al., 2011). Moreover, the lack of internalization in the majority of hippocampal neurons exposed to agonists is in line with previous results that demonstrated that no adaptive changes (desensitiza-…”

Section: Agonist-induced Internalization Of the 5-ht 1a Rmentioning

confidence: 99%

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

et al. 2013

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Morphine Induces μ Opioid Receptor Endocytosis in Guinea Pig Enteric Neurons Following Prolonged Receptor Activation

Abstract: Background & Aims-The μ opioid receptor (μOR) undergoes rapid endocytosis following acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of μOR affects morphine's ability to induce receptor endocytosis in enteric neurons.

Cited by 36 publications

References 51 publications

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

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

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

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Morphine Induces μ Opioid Receptor Endocytosis in Guinea Pig Enteric Neurons Following Prolonged Receptor Activation

Abstract: Background & Aims-The μ opioid receptor (μOR) undergoes rapid endocytosis following acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of μOR affects morphine's ability to induce receptor endocytosis in enteric neurons.

Cited by 36 publications

References 51 publications

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

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

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1ASerotonin Receptor

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Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor