title: Keratinocytes acting on injured afferents induce extreme neuronal hyperexcitability and chronic pain.
abstract: Keratinocytes play an important role in the dialog between skin and cutaneous sensory neurons. They are an essential source of cutaneous nerve growth factor (NGF), a neurotrophin that contributes to persistent pain in inflammation and neuropathy. We studied the interaction of human keratinocytes (hKTs) and regenerating afferent nerve fibers by transplanting hKTs into a ligated and transected peripheral nerve. The hKTs self-assembled into a multi-laminar spheroid cellular structure resembling the stratum spinosum of epidermis. Axonal sprouts surrounded the structure although they were excluded from entry. Levels of NGF were elevated at the transplant site. Whole cell patch-clamp recordings from primary afferent neurons whose cut axons were present near the transplanted hKTs displayed extreme hyperexcitability. These neurons generated high frequency trains of action potentials during step depolarization stimuli, and they sometimes showed afterdischarge and fired spontaneously at resting membrane potential. This spontaneous firing originated from subthreshold membrane potential oscillations. The animals with the hKT transplants exhibited spontaneous pain behavior manifest as autotomy. The results demonstrate that an interaction between injured/regenerating nerve fibers and keratinocytes such as may occur during wound healing, results in afferent hyperexcitability and pain. These results have implications for persistent pain associated with burn and traumatic skin injuries.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA Department of Plastic, Hand and Reconstructive Surgery, Hannover Medical School, 30625 Hannover, Germany Department of Cell and Developmental Biology, Institute of Life Sciences, and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Christine
authors.initials: C
authors.lastname: Radtke
authors.forename: Peter M
authors.initials: PM
authors.lastname: Vogt
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Kocsis
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology* / Q000637:transplantation / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission / Q000379:methods; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009463:Neuroma / Q000473:pathology / Q000648:ultrastructure; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D011189:Potassium Chloride / Q000494:pharmacology; D012585:Sciatica / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D011984:Sensory Receptor Cells / Q000502:physiology / Q000648:ultrastructure
chemical_list: D016900:Neurofilament Proteins; D011189:Potassium Chloride; D020932:Nerve Growth Factor