title: Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat.
abstract: Spinal cord injury (SCI) often results in intractable chronic central pain syndromes. Recently chemokines such as CCL2 were identified as possible key integrators of neuropathic pain and inflammation after peripheral nerve lesion. The focus of the current study was the investigation of time-dependent CCL2 and CCR2 expression in relation to central neuropathic pain development after spinal cord impact lesions of 100, 150, or 200 kdyn force on spinal cord level T9 in adult rats. Below-level pain was monitored with weekly sensory testing for 42 days after SCI. In parallel expression of CCL2/CCR2 on cervical, thoracic, and lumbar levels was investigated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry early (7 days [7d]), intermediate (15d), and late (42d) after lesion. Cellular source and anatomical pain related expression was determined by double-immunohistochemistry. Force-defined SCI led to acute mechanical hypersensitivity in all lesion groups, and to persistent below-level pain in severely injured animals. While in the early post-operative time course, CCL2 and CCR2 were expressed in astroglia and granulocytes only on level T9; there was additional astroglial CCL2 expression in dorsal columns and dorsal horns above and below T9 of severely injured animals 42d after lesion. In dorsal horns (level L3-L5) of animals exhibiting chronic below-level pain CCL2 was co-expressed with transmitters and receptors that are involved in nociceptive processing like calcitonin gene-related peptide (CGRP), Substance-P, vanilloid-receptor-1, and its activated phosphorylated form. These data demonstrate lesion grade dependence of below-level pain development and suggest chemokines as potential candidates for integrating inflammation and central neuropathic pain after SCI.
authors.affiliation: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Knerlich-Lukoschus
authors.forename: Mathias
authors.initials: M
authors.lastname: Juraschek
authors.forename: Ulrike
authors.initials: U
authors.lastname: Blömer
authors.forename: Ralph
authors.initials: R
authors.lastname: Lucius
authors.forename: Hubertus M
authors.initials: HM
authors.lastname: Mehdorn
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D015870:Gene Expression; D006930:Hyperalgesia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008161:Lumbosacral Region; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020332:Rats, Inbred LEC; D054390:Receptors, CCR2 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013373:Substance P / Q000096:biosynthesis; D050916:TRPV Cation Channels / Q000096:biosynthesis; D013904:Thoracic Vertebrae; D013995:Time
chemical_list: C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D012333:RNA, Messenger; D054390:Receptors, CCR2; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide