Calcitonin gene-related peptide as a regulator of neuronal CaMKII–CREB, microglial p38–NFκB and astroglial ERK–Stat1/3 cascades mediating the development of tolerance to morphine-induced analgesia

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• 作者：Zhiyong Wang ; Weiya Ma ; Jean-Guy Chabot ; Remi Quirion
• 关键词：Calcitonin gene-related peptide ; Morphine tolerance ; Transcription factor ; N-methyl-d-aspartate receptor ; Microglia ; Astrocyte
• 刊名：Pain
• 出版年：2010
• 出版时间：October 2010
• 年：2010
• 卷：151
• 期：1
• 页码：194-205
• 全文大小：1827 K

文摘

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 (NFκB) 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-NFκB 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–NFκB and astroglial ERK–Stat1/3 cascades. Targeting CGRP-associated signaling molecules may prolong or restore morphine’s analgesic properties upon a chronic exposure.