title: Persistent at-level thermal hyperalgesia and tactile allodynia accompany chronic neuronal and astrocyte activation in superficial dorsal horn following mouse cervical contusion spinal cord injury.
abstract: In humans, sensory abnormalities, including neuropathic pain, often result from traumatic spinal cord injury (SCI). SCI can induce cellular changes in the CNS, termed central sensitization, that alter excitability of spinal cord neurons, including those in the dorsal horn involved in pain transmission. Persistently elevated levels of neuronal activity, glial activation, and glutamatergic transmission are thought to contribute to the hyperexcitability of these dorsal horn neurons, which can lead to maladaptive circuitry, aberrant pain processing and, ultimately, chronic neuropathic pain. Here we present a mouse model of SCI-induced neuropathic pain that exhibits a persistent pain phenotype accompanied by chronic neuronal hyperexcitability and glial activation in the spinal cord dorsal horn. We generated a unilateral cervical contusion injury at the C5 or C6 level of the adult mouse spinal cord. Following injury, an increase in the number of neurons expressing ΔFosB (a marker of chronic neuronal activation), persistent astrocyte activation and proliferation (as measured by GFAP and Ki67 expression), and a decrease in the expression of the astrocyte glutamate transporter GLT1 are observed in the ipsilateral superficial dorsal horn of cervical spinal cord. These changes have previously been associated with neuronal hyperexcitability and may contribute to altered pain transmission and chronic neuropathic pain. In our model, they are accompanied by robust at-level hyperaglesia in the ipsilateral forepaw and allodynia in both forepaws that are evident within two weeks following injury and persist for at least six weeks. Furthermore, the pain phenotype occurs in the absence of alterations in forelimb grip strength, suggesting that it represents sensory and not motor abnormalities. Given the importance of transgenic mouse technology, this clinically-relevant model provides a resource that can be used to study the molecular mechanisms contributing to neuropathic pain following SCI and to identify potential therapeutic targets for the treatment of chronic pathological pain.
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Watson
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Hala
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Putatunda
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sannie
authors.affiliation: Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Lepore
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D003288:Contusions / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein; D006930:Hyperalgesia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009437:Neuralgia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D066148:Spinal Cord Dorsal Horn / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D027342:Excitatory Amino Acid Transporter 2; C483819:Fosb protein, mouse; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C493396:Slc1a2 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse