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Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: An in vitro and in vivo study
Ma W.2; Zheng W.-H.2; Powell K.4; Jhamandas K.4; Quirion R.2
2001-12-01
Source PublicationEuropean Journal of Neuroscience
ISSN0953816X
Volume14Issue:7Pages:1091-1104
Abstract

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 μM) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.

KeywordCalcitonin Gene-related Peptide Cell Culture Naloxone Opiates Substance p Tolerance
DOI10.1046/j.0953-816X.2001.01731.x
URLView the original
Language英語English
WOS IDWOS:000171795700006
Scopus ID2-s2.0-0035783434
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Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.McGill University
2.Douglas Hospital Research Center
3.Wake Forest University School of Medicine
4.Queen's University, Kingston
Recommended Citation
GB/T 7714
Ma W.,Zheng W.-H.,Powell K.,et al. Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: An in vitro and in vivo study[J]. European Journal of Neuroscience, 2001, 14(7), 1091-1104.
APA Ma W.., Zheng W.-H.., Powell K.., Jhamandas K.., & Quirion R. (2001). Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: An in vitro and in vivo study. European Journal of Neuroscience, 14(7), 1091-1104.
MLA Ma W.,et al."Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: An in vitro and in vivo study".European Journal of Neuroscience 14.7(2001):1091-1104.
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