Mechanisms underlying morphine analgesic tolerance and dependence

Ueda, Hiroshi

doi:10.2741/3596

Cited by 101 publications

(55 citation statements)

References 73 publications

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“…Many investigators choose to study the effects of morphine on immune functions because morphine is an opioid that is given clinically, even though morphine has good affinity for all opioid receptors (24,39). We have shown here that MOR and DOR constitutively produce and function in innate immune cells, and activation of these receptors leads to increased NK cell functions.…”

Section: Discussionmentioning

confidence: 99%

Opiate Antagonist Prevents μ- and δ-Opiate Receptor Dimerization to Facilitate Ability of Agonist to Control Ethanol-altered Natural Killer Cell Functions and Mammary Tumor Growth

Sarkar

Sengupta

Zhang

et al. 2012

Journal of Biological Chemistry

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Background: Chronic treatment with a -receptor antagonist increases the ␦ ability of the agonist to promote natural killer cell functions in alcohol-and non-alcohol-treated animals. Results: Opiate receptor antagonist reduces the receptor heterodimerization but increases ligand sensitivity. Conclusion: Receptor dimerization controls feedback interaction between -and ␦-opiate receptors. Significance: Studying opiate receptor feedback interaction will promote better opiate-based therapy for immune diseases.

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Section: Discussionmentioning

confidence: 99%

Opiate Antagonist Prevents μ- and δ-Opiate Receptor Dimerization to Facilitate Ability of Agonist to Control Ethanol-altered Natural Killer Cell Functions and Mammary Tumor Growth

Sarkar

Sengupta

Zhang

et al. 2012

Journal of Biological Chemistry

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“…1A). It is generally agreed that neural adaptations implicated in addiction by many drugs, including opiates, are brought about by modification of synaptic plasticity mechanisms that can feature neuronal glia interactions (85)(86)(87). Therefore, the TSP1-dependent mechanism suggested here (Fig.…”

Section: Discussionmentioning

confidence: 99%

Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation

Ikeda

Miyatake

Koshikawa

et al. 2010

Journal of Biological Chemistry

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Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGF␤1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.Astrocytes are the source of a diverse group of molecules that are required for synapse formation, function, and maintenance in neurons (1-7). Thrombospondin (TSP) 3 is a member of the astrocyte-derived intercellular signaling components that have been implicated in synaptogenesis and other neuronal glial interactions of the developing brain (8 -17). In addition, synaptic plasticity and other neuroadaptations involving astrocyte neuron interactions are thought to play a role in reward learning and addiction (18). Some chronic morphine-responsive genes (Homer1, PSD-95, and synaptotagmin1) may subserve the long lived neuronal and behavioral plasticity observed in regions of the mesolimbic reward system, and they are involved in synaptogenesis (19 -26).TSPs are multidomain, multimeric glycoproteins that are secreted into the extracellular matrix of many cells and serve as bridging molecules in cell-cell interactions (27,28). First discovered in platelet ␣-granules and secreted upon platelet activation, the superfamily of TSPs modulate varied functions of cell signaling and cell adhesion in a broad array of cell types. The five TSP genes are expressed in the CNS and peripheral nervous system where they play important roles in neural development. T...

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“…Prolonged signaling of an endocytosis-resistant receptor that maintains an analgetic tonus may be favorable in a situation of long-term noxious stimulation. In this scenario, treatment of chronic pain with synthetic hMrgX1 agonists might benefit from long-lasting analgetic signaling, being advantageous over the established opioid-based therapy, which suffers a significant loss of efficiency partly because of receptor desensitization (Ueda and Ueda, 2009). Considering algetic effects, prolonged hMrgX1 signaling could be the cause of chronic pain, which could then be treated with specific antagonists or inverse agonists.…”

Section: Discussionmentioning

confidence: 99%

Sensory Neuron-Specific Mas-Related Gene-X1 Receptors Resist Agonist-Promoted Endocytosis

Solinski

Boekhoff²,

Bouvier³

et al. 2010

Molecular Pharmacology

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Human sensory neuron-specific mas-related gene X1 receptors (hMrgX1s) belong to the superfamily of G protein-coupled receptors (GPCRs), bind cleavage products of pro-enkephalin with high affinity, and have been suggested to participate in pain sensation. Murine or rat MrgC receptors exhibit high similarities with hMrgX1 in terms of expression pattern, sequence homology, and binding profile. Therefore, rodents have been used as an in vivo model to explore the physiological functions and pharmacodynamics of the hMrgX1. Agonist-promoted receptor endocytosis significantly affects the pharmacodynamics of a GPCR but is not yet investigated for hMrgX1. Therefore, we analyzed the effects of prolonged agonist exposure on cell surface protein levels of hMrgX1 and murine or rat MrgC in human embryonic kidney 293, Cos, F11, and ND-C cells. We observed that hMrgX1 are resistant and both MrgC are prone to agonist-promoted receptor endocytosis. In Cos cells, coexpression of ␤-arrestins strongly enhanced endocytosis of murine MrgC but did not alter cell surface expression of hMrgX1 receptors. These data define the hMrgX1 as one of the few members within the superfamily of GPCRs whose signaling is not regulated by agonist-promoted endocytosis and reveal species-specific differences in the regulation of Mrg receptor signaling. Given the importance of receptor endocytosis for the pharmacodynamics of a given ligand, our results may have a strong impact on the development of future drugs that suppose to control pain in humans but were tested in rodents.

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Mechanisms underlying morphine analgesic tolerance and dependence

Cited by 101 publications

References 73 publications

Opiate Antagonist Prevents μ- and δ-Opiate Receptor Dimerization to Facilitate Ability of Agonist to Control Ethanol-altered Natural Killer Cell Functions and Mammary Tumor Growth

Opiate Antagonist Prevents μ- and δ-Opiate Receptor Dimerization to Facilitate Ability of Agonist to Control Ethanol-altered Natural Killer Cell Functions and Mammary Tumor Growth

Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation

Sensory Neuron-Specific Mas-Related Gene-X1 Receptors Resist Agonist-Promoted Endocytosis

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