期刊
PAIN
卷 151, 期 1, 页码 194-205出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2010.07.006
关键词
Calcitonin gene-related peptide; Morphine tolerance; Transcription factor; N-methyl-D-aspartate receptor; Microglia; Astrocyte
资金
- Canadian Institutes of Health Research
Tolerance to morphine-induced analgesia is an intractable phenomenon, often hindering its prolonged applications in the clinics. The enhanced pronociceptive actions of spinal pain-related molecules such as calcitonin gene-related peptide (CGRP) may underlie this phenomenon and could be a promising target for intervention. We demonstrate here how CGRP regulates the development of morphine analgesic tolerance at the spinal level. A 7-day treatment with morphine led to tolerance to its analgesic effects and enhanced expression of CGRP and its receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1). Activation of several cell-type-specific kinase transcription factor cascades is required to mediate this tolerance, including calcium/calmodulin-dependent protein kinase II (CaMKII) and cAMP response element-binding protein (CREB) in neurons, p38 and nuclear factor kappa B (NF kappa B) in microglia and extracellular signal-regulated protein kinase (ERK) and signal transducer and activator of transcription 1 and 3 (Stat1/3) in astrocytes, because inhibitors of CaMKII, p38 and ERK pathways correspondingly reduced the increases in phosphorylated CREB, acetylated-NF kappa B and phosphorylated Stat1/3 levels and attenuated the development of tolerance. Interestingly, these cascades were linked to the regulation of glutamatergic N-methyl-D-aspartate (NMDA) receptor expression. Chronic morphine-induced behavioural responses and biochemical events were all subjugated to modulation by disrupting CGRP receptor signaling. Together, these data suggest that CGRP contributes to the development of tolerance to morphine-induced analgesia by regulating the activation of the neuronal CaMKII-CREB, microglial p38-NF kappa B and astroglial ERK-Stat1/3 cascades. Targeting CGRP-associated signaling molecules may prolong or restore morphine's analgesic properties upon a chronic exposure. Crown Copyright (c) 2010 Published by Elsevier B. V. on behalf of International Association for the Study of Pain. All rights reserved.
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