title: Cutaneous neurturin overexpression alters mechanical, thermal, and cold responsiveness in physiologically identified primary afferents.
abstract: Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRα2 receptor, a receptor found primarily in isolectin B4-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRα2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties.NEW & NOTEWORTHYGDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent.
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Jankowski
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Baumbauer
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Albers
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Davis
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania rkoerber@pitt.edu.
authors.forename: H Richard
authors.initials: HR
authors.lastname: Koerber
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000344:Afferent Pathways / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D051101:Neurturin / Q000235:genetics / Q000378:metabolism*; D010812:Physical Stimulation; D011601:Psychophysics; D012684:Sensory Thresholds / Q000502:physiology; D012867:Skin / Q000294:innervation* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013696:Temperature
chemical_list: D051101:Neurturin; C070614:neurobiotin; D001710:Biotin
keywords: mechanical sensitivity; neurturin; nociceptors; pain; thermal responsiveness