title: Evidence for a distinct neuro-immune signature in rats that develop behavioural disability after nerve injury.
abstract: BACKGROUND
  Chronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances (e.g., reduced social interactions, sleep-wake cycle disruption, anhedonia, and depression). The role of the immune system in altered sensation following nerve injury is well documented. However, its role in the development of affective-motivational disturbances remains largely unknown. Here, we aimed to characterise changes in the immune response at peripheral and spinal sites in a rat model of neuropathic pain and disability.
  
  
  METHODS
  Sixty-two rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either Pain and disability, Pain and transient disability or Pain alone on the basis of sensory threshold testing and changes in post-CCI dominance behaviour in resident-intruder interactions. Nerve ultrastructure was assessed and the number of T lymphocytes and macrophages were quantified at the site of injury on day six post-CCI. ATF3 expression was quantified in the dorsal root ganglia (DRG). Using a multiplex assay, eight cytokines were quantified in the sciatic nerve, DRG and spinal cord.
  
  
  RESULTS
  All CCI rats displayed equal levels of mechanical allodynia, structural nerve damage, and reorganisation. All CCI rats had significant infiltration of macrophages and T lymphocytes to both the injury site and the DRG. Pain and disability rats had significantly greater numbers of T lymphocytes. CCI increased IL-6 and MCP-1 in the sciatic nerve. Examination of disability subgroups revealed increases in IL-6 and MCP-1 were restricted to Pain and disability rats. Conversely, CCI led to a decrease in IL-17, which was restricted to Pain and transient disability and Pain alone rats. CCI significantly increased IL-6 and MCP-1 in the DRG, with IL-6 restricted to Pain and disability rats. CCI rats had increased IL-1β, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1β.
  
  
  CONCLUSIONS
  This study has defined individual differences in the immune response at peripheral and spinal sites following CCI in rats. These changes correlated with the degree of disability. Our data suggest that individual immune signatures play a significant role in the different behavioural trajectories following nerve injury, and in some cases may lead to persistent affective-motivational disturbances.
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. paustin@anatomy.usyd.edu.au.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Austin
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. aber4607@uni.sydney.edu.au.
authors.forename: Annika M
authors.initials: AM
authors.lastname: Berglund
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. ssiu5308@uni.sydney.edu.au.
authors.forename: Sherman
authors.initials: S
authors.lastname: Siu
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. nfio4364@uni.sydney.edu.au.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Fiore
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. mbg@anatomy.usyd.edu.au.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Gerke-Duncan
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. slo@anatomy.usyd.edu.au.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Ollerenshaw
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. slei3376@uni.sydney.edu.au.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Leigh
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. priya.kunjan@gmail.com.
authors.forename: Priya A
authors.initials: PA
authors.lastname: Kunjan
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. jkan5634@uni.sydney.edu.au.
authors.forename: James W M
authors.initials: JW
authors.lastname: Kang
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia. keay@anatomy.usyd.edu.au.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Keay
mesh_terms: D059445:Anhedonia / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D003863:Depression / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D009437:Neuralgia / Q000503:physiopathology / Q000523:psychology; D015213:Neuroimmunomodulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries* / Q000503:physiopathology; D012684:Sensory Thresholds / Q000502:physiology; D020178:Sleep Disorders, Circadian Rhythm / Q000503:physiopathology* / Q000523:psychology; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D015850:Interleukin-6