title: Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases.
abstract: Neuropathic pain is induced by injury or disease of the nervous system. Studies aimed at understanding the molecular pathophysiology of neuropathic pain have so far focused on a few known molecules and signaling pathways in neurons. However, the pathophysiology of neuropathic pain appears to be very complex and remains poorly understood. A global understanding of the molecular mechanisms involved in neuropathic pain is needed for a better understanding of the pathophysiology and treatment of neuropathic pain. Towards this end, we examined global gene expression changes as well as the pathobiology at the cellular level in a spinal nerve ligation neuropathic pain model using DNA microarray, quantitative real-time PCR and immunohistochemistry. We found that the behavioral hypersensitivity that is manifested in the persistent pain state is accompanied by previously undescribed changes in gene expression. In the DRG, we found regulation of: (1) immediate early genes; (2) genes such as ion channels and signaling molecules that contribute to the excitability of neurons; and (3) genes that are indicative of secondary events such as neuroinflammation. In addition, we studied gene regulation in both injured and uninjured DRG by quantitative PCR, and observed differential gene regulation in these two populations of DRGs. Furthermore, we demonstrated unexpected co-regulation of many genes, especially the activation of neuroinflammation markers in both the PNS and CNS. The results of our study provide a new picture of the molecular mechanisms that underlie the complexity of neuropathic pain and suggest that chronic pain shares common pathobiology with progressive neurodegenerative disease.
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, WP26A-2000, West Point, PA 19486, USA. hao_wang@merck.com
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: K
authors.initials: K
authors.lastname: Della Penna
authors.forename: R J
authors.initials: RJ
authors.lastname: Benz
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: D L
authors.initials: DL
authors.lastname: Gerhold
authors.forename: D J
authors.initials: DJ
authors.lastname: Holder
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
mesh_terms: D000818:Animals; D002908:Chronic Disease; D005727:Ganglia, Spinal / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000502:physiology*; D008026:Ligation; D008297:Male; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D010146:Pain / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013127:Spinal Nerves / Q000293:injuries / Q000378:metabolism / Q000473:pathology