Tracking the opioid receptors on the way of desensitization

Marie, Nicolas; Aguila, Benjamin; Allouche, Stéphane

doi:10.1016/j.cellsig.2006.03.015

Cited by 48 publications

(29 citation statements)

References 155 publications

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“…The reduced duration of the antiallodynic action of U50488 could also result from rapid desensitization of U50488-mediated KOR signaling. Opioid receptor systems, such as many seventransmembrane-spanning receptor systems, can undergo rapid, agonist-induced desensitization that can involve receptor phosphorylation, internalization, and down-regulation as well as postreceptor effects (Marie et al, 2006;Kelly et al, 2008). MOR signaling to voltage-gated calcium channels in dorsal root ganglion neurons desensitizes rapidly in response to agonist pretreatment of cultures (Nomura et al, 1994;Samoriski and Gross, 2000;Tan et al, 2003; König et al, Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of κ-Opioid Receptor Signaling in Peripheral Sensory Neurons In Vitro and In Vivo

Berg¹,

Rowan²,

Sanchez³

et al. 2011

J Pharmacol Exp Ther

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There is considerable interest in understanding the regulation of peripheral opioid receptors to avoid central nervous system side effects associated with systemically administered opioid analgesics. Here, we investigated the regulation of the -opioid receptor (KOR) on rat primary sensory neurons in vitro and in a rat model of thermal allodynia. Under basal conditions, application of the KOR agonist trans- (1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride hydrate (U50488) did not inhibit adenylyl cyclase (AC) activity nor release of calcitonin gene-related peptide (CGRP) in vitro and did not inhibit thermal allodynia in vivo. However, after 15-min pretreatment with bradykinin (BK), U50488 became capable of inhibiting AC activity, CGRP release, and thermal allodynia. Inhibition of AC by 5-hydroxytryptamine 1 or neuropeptide Y 1 receptor agonists and stimulation of extracellular signal-regulated kinase activity by U50488 did not require BK pretreatment. The effect of U50488 in BK-primed tissue was blocked by the KOR antagonist nor-binaltorphimine both in vitro and in vivo. The effect of BK in vitro was blocked by either indomethacin or bisindolylmaleimide, suggesting that an arachidonic acid (AA) metabolite and protein kinase C (PKC) activation mediate BK-induced regulation of the KOR system. Furthermore, the effect of U50488 in BK-treated tissue was blocked by a soluble integrin-blocking peptide (GRGDSP), but not the inactive reverse sequence peptide (GDGRSP), suggesting that, in addition to AA and PKC, RGD-binding integrins participate in the regulation of KOR signaling in response to U50488. Understanding the mechanisms by which peripheral KOR agonist efficacy is regulated may lead to improved pharmacotherapy for the treatment of pain with reduced adverse effects.

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Section: Discussionmentioning

confidence: 99%

Regulation of κ-Opioid Receptor Signaling in Peripheral Sensory Neurons In Vitro and In Vivo

Berg¹,

Rowan²,

Sanchez³

et al. 2011

J Pharmacol Exp Ther

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“…The opioid receptors are G-protein coupled receptors (GPCRs), and three types of receptors µ, δ and κ-opioid receptors (OPRM1, OPRD1 and OPRK1) are known to serve as receptors for morphine (2). Among them, OPRM1 generated the main analgesic effect induced by morphine in a knock-out study performed in mice (3).…”

Section: Introductionmentioning

confidence: 99%

“…Among them, OPRM1 generated the main analgesic effect induced by morphine in a knock-out study performed in mice (3). Agonists for opioid receptors induce the activation of GPCRs, triggering the activ ation of various downstream molecules (2). A regulator of the G-protein signaling (RGS)-protein family negatively regulates opioid-receptor signaling by accelerating the deactivation of G proteins, and the regulators RGS2 and RGS9 are thought to be involved in resistance to morphine (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

et al. 2012

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Abstract. Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

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“…However, the number of binding sites for opioids has been demonstrated to decrease in opioid tolerance without a similar decline in the expression of the opioid receptor as quantified by mRNA levels. 8 A plausible explanation for this came in 1996, when Keith et al 9 reported that different opioid agonists have varying abilities to cause MORs to desensitize and endocytose perhaps through the affinity of the agonist-receptor complex for binding arrestins. 10 MORs sequestered by endocytosis through clathrin-coated pits are then targeted 1) for dephosphorylation, re-sensitization, and recycling back to the cell surface ready to be activated again or 2) for degradation.…”

Section: Receptor Traffickingmentioning

confidence: 99%

“…Historically, tolerance by the quantitative loss of receptor expression on the cell surface has been hypothesized but never adequately shown to occur for opioid receptors 8 as it has for other G protein-coupled receptors such as β-adrenergic or dopamine receptors. However, the number of binding sites for opioids has been demonstrated to decrease in opioid tolerance without a similar decline in the expression of the opioid receptor as quantified by mRNA levels.…”

Section: Receptor Traffickingmentioning

confidence: 99%

Mechanisms of opioid tolerance: emerging evidence and therapeutic implications

Joo

2007

Can J Anesth/J Can Anesth

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Tracking the opioid receptors on the way of desensitization

Cited by 48 publications

References 155 publications

Regulation of κ-Opioid Receptor Signaling in Peripheral Sensory Neurons In Vitro and In Vivo

Regulation of κ-Opioid Receptor Signaling in Peripheral Sensory Neurons In Vitro and In Vivo

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

Mechanisms of opioid tolerance: emerging evidence and therapeutic implications

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