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

• Published in: Pain (Amsterdam) Vol. 151; no. 1; pp. 194 - 205
• Main Authors: Wang, Zhiyong, Ma, Weiya, Chabot, Jean-Guy, Quirion, Remi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.10.2010; Elsevier
• Subjects: Analgesics; Analgesics, Opioid - administration & dosage; Analysis of Variance; Animals; Astrocyte; Biological and medical sciences; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - agonists; Calcitonin Gene-Related Peptide - antagonists & inhibitors; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Receptor-Like Protein - metabolism; CREB-Binding Protein - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance - physiology; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Male; Medical sciences; Microglia; Morphine - administration & dosage; Morphine tolerance; N-methyl- d-aspartate receptor; Nerve Tissue Proteins - metabolism; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; NF-kappaB-Inducing Kinase; p38 Mitogen-Activated Protein Kinases - metabolism; Pain Measurement - drug effects; Pharmacology. Drug treatments; Physical Stimulation - adverse effects; Piperazines - pharmacology; Protein Serine-Threonine Kinases - metabolism; Quinazolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 1 - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Spinal Cord - cytology; Spinal Cord - drug effects; Spinal Cord - metabolism; STAT3 Transcription Factor - metabolism; Transcription factor; Calcitonin gene-related peptide; Morphine tolerance; Astrocyte; Transcription factor; N-methyl- d-aspartate receptor; Microglia; Neuroglia; Tolerance; Morphine; Glutamate receptor; Calcitonin gene related peptide; Subunit; Neuropeptide; Analgesia; Binding protein; Analgesic; Pain; Treatment; Calcitonin receptor; Excitatory aminoacid; Neurotransmitter; N-methyl-D-aspartate receptor; CGRP receptor; Biological receptor
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2010.07.006

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.