Expression of Spinal NMDA Receptor and PKCγ after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

Lim, Grewo; Wang, Shuxing; Zeng, Qing; Sung, Backil; Yang, Liling; Mao, Jianren

doi:10.1523/jneurosci.3768-05.2005

Cited by 85 publications

(64 citation statements)

References 68 publications

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“…This possibility is supported by our observations that these receptors are co-expressed in CeA neurons, and other reports that μOR activation has direct inhibitory actions on excitatory postsynaptic signaling in CeA neurons (Zhu and Pan, 2004). Morphine initiates an array of intracellular transduction pathways involving intracellular calcium, cAMP, protein kinases (Bernstein and Welch, 1998;Fan et al, 1999;Lim et al, 2005) and transcription factors (Rasmussen et al, 1995;Shaw-Lutchman et al, 2002). These pathways may impact intermediate-and longterm cellular processes including gene expression (Ammon-Treiber and Hollt, 2005), glutamate receptor trafficking (Glass et al, 2003;Glass et al, 2005), or neuronal morphology (Robinson and Kolb, 2004).…”

Section: Potential Mechanisms Mediating Nmda-μor Interactions and Depsupporting

confidence: 86%

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

Glass

Hegarty²,

Oselkin

et al. 2008

Experimental Neurology

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Preclinical behavioral pharmacological and neuropharmacological evidence indicates that the NMDA receptor plays an important role in opioid dependence, however, the neural substrates subserving these actions are poorly understood. The central nucleus of the amygdala (CeA) is a critical coordinator of autonomic, behavioral, and emotional systems impacted by opioids, however there is no evidence that the essential NMDA-NR1 (NR1) subunit gene in the amygdala plays a role in opioid dependence. To determine the role of the NR1 subunit gene in the amygdala with respect to physical and psychological opioid withdrawal, a spatial-temporal deletion of this gene was produced by microinjecting a recombinant adeno-associated virus (rAAV) expressing the GFP reporter and Cre recombinase (rAAV-GFP-Cre) into the CeA of adult "floxed" NR1 mice (fNR1). Amygdala microinjection of rAAV-GFP-Cre produced a decrease in NR1 gene expression and protein immunolabeling in postsynaptic sites of neurons without signs of compromised ultrastructural neuronal morphology. Amygdala NR1 gene deletion also did not affect locomotor, somatosensory, or sensory-motor behaviors. In addition, bilateral local NR1 gene deletion did not impact somatic or visceral withdrawal symptoms precipitated by naloxone in morphine-dependent mice. However, there was a significant deficit in the expression of an opioid withdrawal-induced conditioned place aversion in mice with amygdala NR1 deletion. These results indicate that functional amygdala NMDA receptors are involved in aversive psychological Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Section: Potential Mechanisms Mediating Nmda-μor Interactions and Depsupporting

confidence: 86%

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

Glass

Hegarty²,

Oselkin

et al. 2008

Experimental Neurology

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“…As has been reported [24] , the i.t. injection of morphine (10 μg) twice daily for 7 days significantly reduced the analgesic potency of morphine.…”

Section: Spinal Dorsal Hornsupporting

confidence: 75%

“…Morphine tolerance was induced following the methods described by Lim et al [24] . Briefly, to induce analgesic tolerance, rats were injected i.t.…”

Section: Induction Of Morphine Tolerance and Drug Deliverymentioning

confidence: 99%

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

et al. 2014

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Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-infl ammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphae roides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawalinduced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawalinduced pain hypersensitivity.

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“…In addition, PKC α and γ are up-regulated in the spinal cord of morphine tolerant rats (97,98). The NMDA NR1 sub-unit is also up-regulated in morphine tolerant animals (99) and blockade of the NMDA receptor can diminish the development of tolerance (100,101). These findings suggest overlap in nociception and opioid tolerance highlighting the potential dual utility of PKC isozyme specific inhibitors in the treatment of chronic pain and the prevention of opioid tolerance.…”

Section: C Spinal Cordmentioning

confidence: 89%

Protein kinase C in pain: Involvement of multiple isoforms

Velázquez

Mohammad

Sweitzer

2007

Pharmacological Research

130

125

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Pain is the primary reason that people seek medical care. At present chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than two months duration and can be of an inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally nonnoxious stimuli), and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional pain drugs or surgical intervention and thus the study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on protein kinase C involvement in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as the master regulator of peripheral and central sensitization that underlies many chronic pain conditions.

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Expression of Spinal NMDA Receptor and PKCγ after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

Cited by 85 publications

References 68 publications

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

Protein kinase C in pain: Involvement of multiple isoforms

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