Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons

Ma, Weiya; Zheng, Wenhua; Kar, S.; Quirion, Rémi

doi:10.1016/s0306-4522(00)00226-8

Cited by 82 publications

(75 citation statements)

References 50 publications

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“…Thus, sustained morphine treatment was shown to enhance the content and release of excitatory neurotransmitters, including the pronociceptive neurotransmitter CGRP in the dorsal horn of the spinal cord (Menard 1995a(Menard , 1995bMa et al 2000;Gardell et al 2002;Trang et al 2005). Indeed, supporting the above observation, in the present work we demonstrate that 24 h morphine treatment significantly augments basal CGRP release from cultured neonatal rat primary sensory neurons (141% of control).…”

Section: Discussionsupporting

confidence: 84%

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

Yue

Tumati

Navratilova

et al. 2008

European Journal of Pharmacology

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Recent studies suggest that sustained morphine-mediated paradoxical pain may play an important role in the development of analgesic tolerance. The intracellular signal transduction pathways involved in sustained opioid mediated augmentation of spinal pain neurotransmitter (such as calcitonin gene-related peptide (CGRP)) release are not fully clarified. Cyclic AMP (cAMP)-dependent protein kinase (PKA) plays an important role in the modulation of presynaptic neurotransmitter release. Moreover, we have shown earlier that sustained opioid agonist treatment leads to a Raf-1-dependent sensitization of adenylyl cyclase(s) (AC superactivation), augmenting forskolin-stimulated cAMP formation upon opioid withdrawal (cAMP overshoot). Therefore, in the present study we examined the role of Raf-1 in sustained morphine-mediated regulation of cAMP formation and basal CGRP release in vitro, in cultured neonatal rat dorsal root ganglion (DRG) neurons. We found that sustained morphine treatment significantly augments intracellular cAMP production as well as basal CGRP release from cultured neonatal rat DRG neurons. The selective PKA inhibitor, H-89, attenuates the sustained morphine-mediated augmentation of basal CGRP release, indicating that the cAMP/PKA pathway plays an important role in regulation of CGRP release from sensory neurons. Since our present data also demonstrated that selective Raf-1 inhibitor, GW 5074, attenuated both the cAMP overshoot and the augmentation of CGRP release mediated by sustained morphine in neonatal rat DRG neurons, we suggest that Raf-1-mediated sensitization of the intracellular cAMP formation may play an important role in sustained morphine-mediated augmentation of spinal pain neurotransmitter release.

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Section: Discussionsupporting

confidence: 84%

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

Yue

Tumati

Navratilova

et al. 2008

European Journal of Pharmacology

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“…Interestingly, sustained morphine exposure enhances capsaicinevoked release of the spinal CGRP (Gardell et al, 2002). Given that these neurotransmitters are involved in morphine tolerance (Mao et al, 1994(Mao et al, , 1995bDunbar and Yaksh, 1996;Menard et al, 1996;Ma et al, 2000;King et al, 2005a,b;Ossipov et al, 2005;Vera-Portocarrero et al, 2007), we propose that chronic morphine activates TRPV1, which, at least partly, through modulation of neurotransmitters such as glutamate, CGRP, and SP, contributes to the tolerance and associated thermal hyperalgesia.…”

Section: Discussionmentioning

confidence: 67%

Activation of TRPV1 Contributes to Morphine Tolerance: Involvement of the Mitogen-Activated Protein Kinase Signaling Pathway

Chen¹,

Geis²,

Sommer³

2008

J. Neurosci.

145

141

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Tolerance to the analgesic effects of opioids occurs after their chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we investigated the role of TRPV1, which is crucial for the transduction of noxious chemical and thermal stimuli, in morphine tolerance and tolerance-associated thermal hyperalgesia. After chronic morphine treatment, a marked increase in TRPV1 immunoreactivity ( Chronic morphine exposure induced increases in phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK-IR, extracellular signal-regulated protein kinase (ERK)-IR, and c-Jun N-terminal kinase (JNK)-IR, in L4 DRG neurons.Intrathecal administration of the selective p38, ERK, or JNK inhibitors not only reduced morphine tolerance and associated thermal hyperalgesia but also suppressed the morphine-induced increase of TRPV1-IR in DRG neurons, spinal cord, and sciatic nerve and of mRNA levels in spinal cord and sciatic nerve. Together, we have identified a novel mechanism by which sustained morphine treatment results in tolerance and tolerance-associated thermal hyperalgesia, by regulating TRPV1 expression, in a MAPK-dependent manner. Thus, blocking TRPV1 might be a way to reduce morphine tolerance.

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“…Immunofluorescence in primary cultured neurons was performed as described previously with minor modifications (Ma et al, 2000). After various treatments, hippocampal cultured neurons were fixed in 4% paraformaldehyde in 0.1 M PB for 20 min with nonspecific labeling blocked using 5% normal donkey serum (NDS; Vector Laboratories) in 0.01 M PBS containing PBSϩT.…”

Section: Methodsmentioning

confidence: 99%

Insulin-Like Growth Factor-1–Induced Phosphorylation of Transcription Factor FKHRL1 Is Mediated by Phosphatidylinositol 3-Kinase/Akt Kinase and Role of This Pathway in Insulin-Like Growth Factor-1–Induced Survival of Cultured Hippocampal Neurons

2002

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Insulin-like growth factor-1 (IGF-1) is a trophic factor promoting cell survival by activating phosphatidylinositol 3-kinase (PI3K)/ Akt kinase pathway. FKHRL1, a member of the Forkhead family of transcription factors possibly involved in cell cycle and apoptosis, is a downstream target of Akt in fibroblasts. However, very little information is available concerning neurons. We report herein that IGF-1 rapidly induced the phosphorylation of endogenous FKHRL1 in hippocampal neurons. The PI3K/Akt kinase pathway mediates this action, as evidenced by the use of different kinase inhibitors, the expression of constitutively active Akt, and in vitro kinase assay. IGF-1 blocked the nuclear translocation of FKHRL1 in hippocampal neurons and promoted survival in parallel to the phosphorylation of Akt and FKHRL1. Similarly, the expression of constitutively active Akt in PC-12 cells increased the phosphorylation of FKHRL1 and promoted survival, whereas the expression of kinase dead Akt attenuated IGF-1-mediated survival of PC-12 cells. Moreover, the overexpression of wild-type FKHRL1 and its nonphosphorylated mutant induced apoptosis in cultured hippocampal neurons. Interestingly, IGF-1 and PI3-kinase inhibitors have no significant effect on the cell cycle inhibitor p27kip1 in hippocampal neurons. This finding suggests that in contrast to fibroblasts, FKHRL1 is unlikely to be involved in cell cycle in neurons. Taken together, these data reveal that endogenous FKHRL1 is a downstream substrate of PI3K/Akt in IGF-1 receptor signaling in hippocampal neurons and suggest that the phosphorylation of this transcription factor may play an important role in the neuronal survival properties of IGF-1.

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Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons

Cited by 82 publications

References 50 publications

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

Activation of TRPV1 Contributes to Morphine Tolerance: Involvement of the Mitogen-Activated Protein Kinase Signaling Pathway

Insulin-Like Growth Factor-1–Induced Phosphorylation of Transcription Factor FKHRL1 Is Mediated by Phosphatidylinositol 3-Kinase/Akt Kinase and Role of This Pathway in Insulin-Like Growth Factor-1–Induced Survival of Cultured Hippocampal Neurons

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