title: Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord.
abstract: Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective-like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.
authors.affiliation: Department of Neurosurgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: C-L
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: P
authors.initials: P
authors.lastname: Heron
authors.affiliation: Department of Anesthesiology, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: S R
authors.initials: SR
authors.lastname: Hamann
authors.affiliation: Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, United States; Shriners Hospitals for Pediatric Research Center, Department of Neuroscience, Temple University, Philadelphia, PA 19140, United States. Electronic address: george.smith@temple.edu.
authors.forename: G M
authors.initials: GM
authors.lastname: Smith
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D005260:Female; D020932:Nerve Growth Factor / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism
chemical_list: D020932:Nerve Growth Factor
keywords: hyperalgesia; nerve growth factor; nociceptor; plasticity; regeneration