title: Sympathetic fibre sprouting in the skin contributes to pain-related behaviour in spared nerve injury and cuff models of neuropathic pain.
abstract: BACKGROUND
  Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive-NF200+) and peptidergic (calcitonin gene-related peptide positive-CGRP+) primary afferents and sympathetic fibres (dopamine β-hydroxylase positive-DBH+)
  
  
  RESULTS
  Cuff and SNI caused an early loss and later reinnervation of NF200 and CGRP fibres in the plantar hind paw skin. In both models, DBH+ fibres sprouted into the upper dermis of the plantar skin 4 and 6 weeks after injury. Despite these similarities, behavioural pain measures were significantly different in each model. Sympathectomy using guanethidine significantly alleviated mechanical allodynia 6 weeks after cuff, when peak sympathetic sprouting was observed, having no effect at 2 weeks, when fibres were absent. In SNI animals, mechanical allodynia in the lateral paw was significantly improved by guanethidine at 2 and 6 weeks, and the development of cold hyperalgesia, which roughly paralleled the appearance of ectopic sympathetic fibres, was alleviated by guanethidine at 6 weeks. Sympathetic fibres did not sprout into the dorsal root ganglia at 2 or 6 weeks, indicating their unimportance to pain behaviour in these two models.
  
  
  CONCLUSIONS
  Alterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Room 1215, Montreal, QC, H3G 1Y6, Canada. ney.pintodonascimento@gmail.com.|Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada. ney.pintodonascimento@gmail.com.
authors.forename: Francisney P
authors.initials: FP
authors.lastname: Nascimento
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Room 1215, Montreal, QC, H3G 1Y6, Canada. claire.magnussen@mail.mcgill.ca.|Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada. claire.magnussen@mail.mcgill.ca.
authors.forename: Claire
authors.initials: C
authors.lastname: Magnussen
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Room 1215, Montreal, QC, H3G 1Y6, Canada. noosha.yousefpour@mail.mcgill.ca.|Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada. noosha.yousefpour@mail.mcgill.ca.
authors.forename: Noosha
authors.initials: N
authors.lastname: Yousefpour
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Room 1215, Montreal, QC, H3G 1Y6, Canada. alfredo.ribeirodasilva@mcgill.ca.|Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada. alfredo.ribeirodasilva@mcgill.ca.|Department of Anatomy and Cell Biology, McGill University, Montreal, QC, H3A 0C7, Canada. alfredo.ribeirodasilva@mcgill.ca.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
mesh_terms: D000320:Adrenergic Fibers / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003080:Cold Temperature; D020405:Dermis / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006145:Guanethidine / Q000494:pharmacology; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology; D008297:Male; D009437:Neuralgia / Q000150:complications / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology*; D012867:Skin / Q000187:drug effects / Q000294:innervation* / Q000473:pathology; D013562:Sympathectomy
chemical_list: D004299:Dopamine beta-Hydroxylase; D015740:Calcitonin Gene-Related Peptide; D006145:Guanethidine