Pain mechanismμ-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to μ-opioid receptor agonists: Comparison between etorphine and morphine
Section snippets
Animals
The present study was conducted in accordance with the guidelines established by the Institutional Animal Investigation Committee at Hoshi University and the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the use of laboratory animals and to optimize their comfort. Male ICR mice weighing 25–30g (Tokyo Laboratory Animals Science Co., Ltd., Tokyo, Japan) were used. Animals were kept in a room with an ambient temperature of
Development of tolerance to etorphine- or morphine-induced antinociception
We first investigated the development of tolerance to etorphine- or morphine-induced antinociception using hot-plate test. Groups of mice were repeatedly s.c. injected with etorphine (10 μg/kg), morphine (10mg/kg) or saline once a day for seven consecutive days. The injection of etorphine or morphine produced about 70–90% antinociceptive effect on the first day. However, this antinociception was significantly decreased during consecutive exposure to etorphine or morphine, indicating the
Discussion
Following the binding of the agonist to MORs, the receptor signals via activation of heterotrimeric G proteins of the Gi/Go family. With continued exposure to agonist, MORs are rapidly phosphorylated by GRK, and this phosphorylation stimulates the binding of arrestins to the receptor. The MOR/arrestin complex is then recruited to a constitutive pathway that utilized clathrin-coated pits to endocytose a wide variety of cell surface proteins in a dynamin-dependent manner (Keith et al 1996, Chu et
Conclusion
In conclusion, the present data provide direct evidence for the distinct mechanisms between etorphine and morphine on the development of tolerance to antinociception. These findings raise the possibility that the increased astroglia response due to chronic morphine treatment may result in the morphine-specific receptor modulating profile, which could be related to the down-regulation of MOR function without receptor internalization and may actively participate in the development of morphine
Acknowledgments
This work was supported in part by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References (44)
- et al.
Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation
J Biol Chem
(2000) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding
Anal Biochem
(1976)- et al.
Specific G protein activation and μ-opioid receptor internalization caused by morphine, DAMGO and endomorphin I
Eur J Pharmacol
(1998) - et al.
Agonist-induced signaling and trafficking of the μ-opioid receptorrole of serine and threonine residues in the third cytoplasmic loop and C-terminal domain
FEBS Lett
(1997) - et al.
δ And κ opioid receptors are differentially regulated by dynamin-dependent endocytosis when activated by the same alkaloid agonist
J Biol Chem
(1997) - et al.
The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior
Exp Neurol
(1999) - et al.
Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons
Neuroscience
(2000) - et al.
Intrathecal morphine in micea new technique
Eur J Pharmacol
(1980) - et al.
Morphine activates opioid receptors without causing their rapid internalization
J Biol Chem
(1996) - et al.
μ And δ opioid receptors are differentially desensitized by the coexpression of β-adrenergic receptor kinase 2 and β-arrestin 2 in Xenopus oocytes
J Biol Chem
(1997)
Enhanced μ-opioid responses in the spinal cord of mice lacking protein kinase Cγ isoform
J Biol Chem
Suppression of the morphine-induced rewarding effect and G-protein activation in the lower midbrain following nerve injury in the mouseinvolvement of G-protein-coupled receptor kinase 2
Neuroscience
Agonist-induced desensitization of the μ opioid receptor is determined by threonine 394 preceded by acidic amino acids in the COOH-terminal tail
J Biol Chem
Neuroglial activation repertoire in the injured braingraded response, molecular mechanisms and cues to physiological function
Brain Res Rev
Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance
Pain
The involvement of glial cells in the development of morphine tolerance
Neurosci Res
Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family
J Biol Chem
Dissociation of functional roles of dynamin in receptor-mediated endocytosis and mitogenic signal transduction
J Biol Chem
Opioid agonist and antagonist treatment differentially regulates immunoreactive μ-opioid receptors and dynamin-2 in vivo
Eur J Pharmacol
μ Opioid receptor phosphorylation, desensitization, and ligand efficacy
J Biol Chem
Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization
Nature
Immune function of astrocytes
Glia
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2023, NeuropharmacologyCitation Excerpt :Tolerance to these agonists also differed (Pradhan et al., 2009, 2010). One interesting difference noted between DORs compared to MORs and KORs is their ability to be upregulated and/or trafficked to the plasma membrane in response to stress and inflammatory conditions (Bie et al., 2009a; Cahill et al., 2003; Chang et al., 2019; Morinville et al., 2003; van Rijn et al., 2012). In addition, chronic morphine treatment promotes movement of DORs to the cell surface in the dorsal horn of the rat spinal cord and hippocampus (Erbs et al., 2016), as well as the vlPAG (Hack et al., 2005) and RVM (Ma et al., 2006).
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2014, Biological PsychiatryMu opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes
2013, Journal of NeuroimmunologyCitation Excerpt :The current hypothesis is that biased agonism involves differential recruitement of beta-arrestin, which is due to different conformational states induced by different ligands (Shukla et al., 2008). In this context, it has been demonstrated that morphine induces minimal recruitment of beta-arrestin as compared to other agonists (Keith et al., 1996; Narita et al., 2006). Beta-arrestin itself is thought to to induce several signaling pathways or effects, which, in this way, consequently differ for certain μ opioid receptor agonists.
The kappa-opioid receptor is upregulated in the spinal cord and locus ceruleus but downregulated in the dorsal root ganglia of morphine tolerant rats
2010, Brain ResearchCitation Excerpt :However, the mechanisms of MOR's role during morphine tolerance have not been revealed, and many MOR related phenomena cannot be interpreted. Morphine seems more likely to induce tolerance than the more specific MOR agonists (etorphine, fentanyl, DAMGO, etc.), although morphine is less capable of promoting rapid endocytosis of MOR (Paronis and Holtzman, 1992; Sternini et al., 1996; Keith et al., 1998; Eisinger et al., 2002; Borgland et al., 2003; Koch et al., 2005; Narita et al., 2006; Martini and Whistler, 2007). Ligand competitive binding assays indicate that the affinities of morphine for three different opioid receptors are distinctive (MOR > KOR > DOR), with inhibition constant (Ki) values of 1.70 ± 0.50 nM for MOR, 65.5 ± 22.6 nM for KOR, and 104.57 ± 27.18 nM for DOR (Peckham and Traynor, 2006).
Tolerance to the antinociceptive effects of peripherally administered opioids. Expression of β-arrestins
2009, Brain ResearchCitation Excerpt :These results suggest that arrestin-mediated desensitization (and presumably endocytosis) of OR is induced by morphine in vivo. However, the effects of chronic morphine on β-arrestins activity remain controversial: while some studies suggest that morphine induces desensitization/internalization via β-arrestin 2 recruitment (Zuo, 2005), others propose that a compensatory increase in the activity of adenylyl cyclase isoenzymes in response to chronic opioid receptor stimulation (Nevo et al., 1998) or glial activation (Song and Zhao, 2001; Narita et al., 2006), are factors that may contribute to cellular opioid tolerance. The role of β-arrestins in peripheral tissues during chronic inflammatory pain has not been investigated.
Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence
2008, Current BiologyCitation Excerpt :All opioids, when given at high enough concentration for a long enough period of time, including methadone, can induce tolerance and dependence. However, when given at equi-antinociceptive doses, opioids induce different degrees of tolerance and dependence [29–31] (see Figure 4C), and some ligands even appear to cause these effects by different mechanisms [32, 33]. Hence, given the complex pharmacology of the various opioid ligands, it has been difficult to isolate the effect of endocytosis on tolerance and dependence.