A Role for Protein Kinase C-Dependent Upregulation of Adrenomedullin in the Development of Morphine Tolerance in Male Rats

Yu, Hong; Wang, Dongmei; Chabot, Jean‐Guy; Ma, Weiya; Chen, Peiwen; Quirion, Rémi

doi:10.1523/jneurosci.0306-10.2010

Cited by 23 publications

(35 citation statements)

References 46 publications

(46 reference statements)

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“…Interestingly, a 24 h-treatment with AM increases CGRP content in cultured ganglion explants while similar treatment with CGRP does not change AM content (Hong et al, 2010). A similar phenomenon was observed in human adipocyte tissue (Linscheid et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats

Wang

Ruan

et al. 2013

Experimental Neurology

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Section: Discussionsupporting

confidence: 63%

Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats

Wang

Ruan

et al. 2013

Experimental Neurology

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“…Importantly, inhibition of the AM receptor signalling by co‐administration of the AM receptor antagonist AM 22–52 (Hay et al, ) completely abolished the morphine‐induced alteration in μ receptor‐coupled Gi and Gs proteins. These data were comparable with the behavioural observations showing that the blockade of AM receptors inhibits morphine tolerance (Hong et al, ; Wang et al, ). Given that the chronic AM exposure mimics morphine‐induced analgesic tolerance and hyperalgesia (Wang et al, ) and alterations in μ receptor‐coupled Gi and Gs proteins (present study), we suggest that the switch from Gi protein to Gs protein coupled to μ receptors underlies the contribution of AM receptor signalling to the development of morphine tolerance during its chronic use.…”

Section: Discussionsupporting

confidence: 91%

“…Previous studies have shown that the mechanisms underlying AM's contribution to morphine tolerance involve a nociception‐facilitating property (Hong et al, ) and the recruitment of CGRP and nNOS (Hong et al, ; Wang et al, ; Wang et al, ), as well as the activation of spinal microglia and astrocytes (Zeng et al, ). We now examined if AM activity was involved in the chronic morphine‐induced alteration in Gi and Gs proteins/ μ receptor coupling.…”

Section: Discussionmentioning

confidence: 99%

“…The development of morphine tolerance is attributed to the up‐regulation of pronociceptive mediators in the spinal cord, such as glutamate (Zeng et al, ), CGRP (Menard et al, ), substance P (Powell et al, ), NO (Kielstein et al, ), TRPV1 (Chen et al, ) and AM (Hong et al, ). It is generally believed that the mechanism underlying the contribution of these mediators to morphine tolerance is the prolonged excitation of dorsal horn neurons (King et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…AM is a newly demonstrated pronociceptive mediator (Ma et al, 2006) and a member of CGRP family (Poyner et al, 2002). The expression and release of this peptide are increased in the spinal dorsal horn and/or dorsal root ganglia (DRG) following the chronic administration of morphine (Hong et al, 2010), while chronic exposure to AM induces a decline of morphine analgesic potency, referred to as 'naive morphine tolerance' or naive tolerance and hyperalgesia (Wang et al, 2014b). The inhibition of AM receptor signalling abolishes morphine-induced increase in CGRP (Hong et al, 2010) and neuronal NOS (nNOS) (Wang et al, 2014b) as well as the activation of spinal microglia and astrocytes (Zeng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Contribution of adrenomedullin to the switch of G protein‐coupled μ‐opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats

Wang

Zeng

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEChronic exposure to morphine increases spinal adrenomedullin (AM) bioactivity resulting in the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked alteration in μ-opioid receptor-coupled G proteins. EXPERIMENTAL APPROACHAgents were administered intrathecally (i.t.) in rats. Nociceptive behaviours and cumulative dose-response of morphine analgesia were assessed. Neurochemicals in the spinal dorsal horn were assayed by immunoprecipitation, Western blot analysis and ELISA. KEY RESULTSIntrathecal injection of AM (8 μg) for 9 days decreased and increased the levels of μ receptor-coupled Gi and Gs proteins respectively. Morphine stimulation (5 μg) after chronic treatment with AM also induced an increase in cAMP production in the spinal dorsal horn. Co-administration of the selective AM receptor antagonist AM 22-52 inhibited chronic morphine-evoked switch of G protein-coupled μ receptor from Gi to Gs. Chronic exposure to AM increased the phosphorylation of cAMP-responsive element-binding protein (CREB) and ERK. Co-administration of the PKA inhibitor H-89 (5 μg) or MEK1 inhibitor PD98059 (1 μg) reversed the AM-induced thermal/mechanical hypersensitivity, decline in morphine analgesic potency, switch of G proteincoupled μ receptor and increase in cAMP. CONCLUSIONS AND IMPLICATIONSThe present study supports the hypothesis that an increase in AM activity in the spinal dorsal horn contributes to the switch of the μ receptor-coupled G protein from Gi to Gs protein via the activation of cAMP/PKA/CREB and ERK signalling pathways in chronic morphine use. AbbreviationsAM, adrenomedullin; IPP, immunoprecipitation; MPE, maximum possible efffect; MEK, MAP kinase kinase; TFL, tail flick latency; TRPV1, Transient receptor potential vanilloid 1

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Involvement of adrenomedullin in spinal glial activation following chronic administration of morphine in rats

Zeng

Lin

Wang

et al. 2014

European Journal of Pain

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Background: Adrenomedullin (AM) belongs to the calcitonin generelated peptide (CGRP) family. Our previous studies show that chronic exposure to morphine increases spinal AM bioactivity, contributing to the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked gliosis. Methods: Real-time polymerase chain reaction was performed to determine interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α (TNF-α) mRNAs in the spinal dorsal horn and cultured sensory ganglion explants. Immunohistochemistry was performed to identify spinal microglia and astrocytes. Results: Repetitive intrathecal (i.t.) injection of morphine (20 μg) increased the expression of IL-1β, IL-6 and TNF-α mRNAs in the spinal dorsal horn. The co-administration of the selective AM receptor antagonist AM22-52 (36 μg) markedly attenuated chronic morphine-evoked increase in IL-1β and IL-6, but not TNF-α, mRNA levels. Exposure of cultured dorsal root ganglion (DRG) explants to morphine (3.3 μmol/L) for 6 days up-regulated IL-1β and IL-6 mRNA expressions. The depletion of AM gene using small interfering RNA (siRNA) approach abolished morphine-evoked increase in IL-1β and IL-6 syntheses in the cultured DRG. The blockade of AM receptors by i.t. AM22-52 also inhibited chronic morphine-evoked cell hypertrophy of microglia and astrocytes as well as an increase in OX-42 and GFAP (glial fibrillary acidic protein) immunoreactivities. Furthermore, the 6-day treatment with AM (10 μg, i.t.) induced morphological changes of microglia and astrocytes as well as an increase in IL-1β, IL-6 and TNF-α mRNA levels in the spinal dorsal horn. Conclusion: The present study supports the idea that up-regulation of the pronociceptive mediator AM can recruit spinal glial cells, resulting in an increase in cytokines during chronic use of morphine.

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A Role for Protein Kinase C-Dependent Upregulation of Adrenomedullin in the Development of Morphine Tolerance in Male Rats

Cited by 23 publications

References 46 publications

Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats

Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats

Contribution of adrenomedullin to the switch of G protein‐coupled μ‐opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats

Involvement of adrenomedullin in spinal glial activation following chronic administration of morphine in rats

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