Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain
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REVIEW
Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain Xu-Hui Li 1,2,3
&
Qi-Yu Chen 1,2 & Min Zhuo 1,2,3
Accepted: 1 September 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract Chronic pain is a major health problem and the effective treatment for chronic pain is still lacking. The recent crisis created by the overuse of opioids for pain treatment has clearly shown the need for non-addictive novel pain medicine. Conventional pain medicines usually inhibit peripheral nociceptive transmission and reduce central transmission, especially pain-related excitatory transmission. For example, both opioids and gabapentin produce analgesic effects by inhibiting the release of excitatory transmitters and reducing neuronal excitability. Here, we will review recent studies of central synaptic plasticity contributing to central sensitization in chronic pain. Neuronal selective adenylyl cyclase subtype 1 (AC1) is proposed to be a key intracellular protein that causes both presynaptic and postsynaptic forms of long-term potentiation (LTP). Inhibiting the activity of AC1 by selective inhibitor NB001 blocks behavioral sensitization and injury-related anxiety in animal models of chronic pain. We propose that inhibiting injury-related LTPs will provide new mechanisms for designing novel medicines for the treatment of chronic pain and its related emotional disorders. Keywords Long-term potentiation . Chronic pain . ACC . Adenylyl cyclase subtype 1 . NB001
Abbreviations 5-HT Serotonin AC1 Adenylyl cyclase subtype 1 ACC Anterior cingulate cortex
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-020-00927-1) contains supplementary material, which is available to authorized users. * Min Zhuo [email protected] Xu-Hui Li [email protected] Qi-Yu Chen [email protected] 1
Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
2
Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, Shaanxi, China
3
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada
AMPARs BDNF CaM CFA CGRP CREB EPSCs EPSPs ERK GluN1 GluN2 HCN IBS IC KAR LC LTP NMDARs NMS PAG
2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoic acid receptors Brain-derived neurotrophic factor Calmodulin Complete Freund’s adjuvant Calcitonin gene-related peptide cAMP response element-binding protein Excitatory postsynaptic currents Excitatory postsynaptic potentials Extracellular signal-regulated kinase Glutamate NMDA receptor subunit 1 Glutamate NMDA receptor subunit 2 Hyperpolarization-activated cyclic nucleotidegated Irritable bowel syndrome Insular cortex Kainate receptor Locus coeruleus Long-term potentiation N-Methyl-D-aspartate receptors Neonatal maternal separation Periaqueductal gray
Li et al.
PFC PKA PKC PKMζ RVM TBS
Prefrontal corte
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