title: Neuropathy-induced spinal GAP-43 expression is not a main player in the onset of mechanical pain hypersensitivity.
abstract: Structural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. In the present study, the spatiotemporal expression of growth-associated protein-43 (GAP-43), a protein which has been traditionally implicated in nerve fiber growth and sprouting, was investigated in relation to mechanical pain hypersensitivity. An L5 spinal nerve transection model was validated by the presence of mechanical pain hypersensitivity and an increase in the early neuronal activation marker cFos within the superficial spinal dorsal horn upon innocuous hindpaw stimulation. Spinal GAP-43 was found to be upregulated in the superficial L5 dorsal horn from 5 up to 10 days after injury. GAP-43 was co-localized with calcitonin-gene related peptide (CGRP), but not vesicular glutamate transporter-1 (VGLUT-1), IB4, or protein kinase-γ (PKC-γ), suggesting the regulation of GAP-43 in peptidergic nociceptive afferents. These GAP-43/CGRP fibers may be indicative of sprouting peptidergic fibers. Fiber sprouting largely depends on growth factors, which are typically associated with neuro-inflammatory processes. The putative role of neuropathy-induced GAP-43 expression in the development of mechanical pain hypersensitivity was investigated using the immune modulator propentofylline. Propentofylline treatment strongly attenuated the development of mechanical pain hypersensitivity and glial responses to nerve injury as measured by microglial and astroglial markers, but did not affect neuropathy-induced levels of spinal GAP-43 or GAP-43 regulation in CGRP fibers. We conclude that nerve injury induces structural plasticity in fibers expressing CGRP, which is regarded as a main player in central sensitization. Our data do not, however, support a major role of these structural changes in the onset of mechanical pain hypersensitivity.
authors.affiliation: Pain Management and Research Center, Department of Anesthesiology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Robby J
authors.initials: RJ
authors.lastname: Jaken
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Gorp
authors.forename: Elbert A
authors.initials: EA
authors.lastname: Joosten
authors.forename: Mario
authors.initials: M
authors.lastname: Losen
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez-Martínez
authors.forename: Marc
authors.initials: M
authors.lastname: De Baets
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marcus
authors.forename: Ronald
authors.initials: R
authors.lastname: Deumens
mesh_terms: D000818:Animals; D005260:Female; D019922:GAP-43 Protein / Q000096:biosynthesis*; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D010452:Peptide Biosynthesis / Q000502:physiology; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019922:GAP-43 Protein