title: Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density.
abstract: Nerve growth factor (NGF) is involved in the long-term sensitization of nociceptive processing linked to chronic pain. Functional and structural ("sprouting") changes can contribute. Thus, humans report long-lasting hyperalgesia to mechanical and electrical stimulation after intradermal NGF injection and NGF-induced sprouting has been reported to underlie cancer bone pain and visceral pain. Using a human-like animal model we investigated the relationship between the structure and function of unmyelinated porcine nociceptors 3 weeks after intradermal NGF treatment. Axonal and sensory characteristics were studied by in vivo single-fiber electrophysiology and immunohistochemistry. C fibers recorded extracellularly were classified based on mechanical response and activity-dependent slowing (ADS) of conduction velocity. Intraepidermal nerve fiber (IENF) densities were assessed by immunohistochemistry in pigs and in human volunteers using the same NGF model. NGF increased conduction velocity and reduced ADS and propagation failure in mechano-insensitive nociceptors. The proportion of mechano-sensitive C nociceptors within NGF-treated skin areas increased from 45.1% (control) to 71% and their median mechanical thresholds decreased from 40 to 20 mN. After NGF application, the mechanical receptive fields of nociceptors increased from 25 to 43 mm(2). At the structural level, however, IENF density was not increased by NGF. In conclusion, intradermal NGF induces long-lasting axonal and mechanical sensitization in porcine C nociceptors that corresponds to hyperalgesia observed in humans. Sensitization is not accompanied by increased IENF density, suggesting that NGF-induced hyperalgesia might not depend on changes in nerve fiber density but could be linked to the recruitment of previously silent nociceptors.
authors.affiliation: Department of Anesthesiology, Medical Faculty Mannheim, Heidelberg University, 68135 Mannheim, Germany Institute of Molecular and Cell Biology, Faculty for Biotechnology, University of Applied Sciences, 68163 Mannheim, Germany Institute of Neuroanatomy, CBTM, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany Faculty of Mathematics and Computer Science, Bethel University, MN 55112, USA Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA Integrated Tissue Dynamics, LLC, Rensselaer, NY 12208, USA R&D AstraZeneca, Södertälje, Sweden Department of Neurosurgery, Johns Hopkins University, Baltimore, MA 21287, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hirth
authors.forename: Roman
authors.initials: R
authors.lastname: Rukwied
authors.forename: Alois
authors.initials: A
authors.lastname: Gromann
authors.forename: Brian
authors.initials: B
authors.lastname: Turnquist
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weinkauf
authors.forename: Klaus
authors.initials: K
authors.lastname: Francke
authors.forename: Philip
authors.initials: P
authors.lastname: Albrecht
authors.forename: Frank
authors.initials: F
authors.lastname: Rice
authors.forename: Björn
authors.initials: B
authors.lastname: Hägglöf
authors.forename: Matthias
authors.initials: M
authors.lastname: Ringkamp
authors.forename: Maren
authors.initials: M
authors.lastname: Engelhardt
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Martin
authors.initials: M
authors.lastname: Schmelz
authors.forename: Otilia
authors.initials: O
authors.lastname: Obreja
mesh_terms: D000328:Adult; D000818:Animals; D001369:Axons / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism; D003080:Cold Temperature; D004558:Electric Stimulation; D004817:Epidermis / Q000187:drug effects* / Q000294:innervation*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D008465:Mechanoreceptors / Q000502:physiology; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism; D009412:Nerve Fibers / Q000187:drug effects*; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects*; D013552:Swine; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568317:SCN10A protein, human; C486866:SCN9A protein, human; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D050051:Transient Receptor Potential Channels; D020932:Nerve Growth Factor
keywords: Axon; Hyperalgesia; Nerve growth factor; Sensitization; Sprouting
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