title: 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.
abstract: 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.
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada H4H 1R3.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Chabot
authors.forename: Remi
authors.initials: R
authors.lastname: Quirion
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058286:Calcitonin Receptor-Like Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058262:Receptor Activity-Modifying Protein 1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000701:Analgesics, Opioid; D050882:CREB-Binding Protein; D015740:Calcitonin Gene-Related Peptide; D058286:Calcitonin Receptor-Like Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009020:Morphine; D009419:Nerve Tissue Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D058262:Receptor Activity-Modifying Protein 1; D016194:Receptors, N-Methyl-D-Aspartate; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C545508:Ramp1 protein, rat; C494088:Stat3 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C406305:olcegepant