title: Chronic pain leads to concomitant noradrenergic impairment and mood disorders.
abstract: BACKGROUND
  Patients suffering chronic pain are at high risk of suffering long-lasting emotional disturbances characterized by persistent low mood and anxiety. We propose that this might be the result of a functional impairment in noradrenergic circuits associated with locus coeruleus (LC) and prefrontal cortex, where emotional and sensorial pain processes overlap.
  
  
  METHODS
  We used a chronic constriction injury of sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats to assess the time-dependent changes that might potentially precipitate mood disorders (2, 7, 14, and 28 days after injury). This was measured through a combination of behavioral, electrophysiological, microdialysis, immunohistochemical, and Western blot assays.
  
  
  RESULTS
  As expected, nerve injury produced an early and stable decrease in sensorial pain threshold over the testing period. By contrast, long-term neuropathic pain (28 days after injury) resulted in an inability to cope with stressful situations, provoking depressive and anxiogenic-like behaviors, even more intense than the aversiveness associated with pain perception. The onset of these behavioral changes coincided with irruption of noradrenergic dysfunction, evident as: an increase in LC bursting activity; in tyrosine hydroxylase expression and that of the noradrenaline transporter; and enhanced expression and sensitivity of α2-adrenoceptors in the LC.
  
  
  CONCLUSIONS
  Long-term neuropathic pain leads to anxio-depressive-like behaviors that are more predominant than the aversion of a painful experience. These changes are consistent with the impairment of noradrenergic system described in depressive disorders.
authors.affiliation: Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alba-Delgado
authors.forename: Meritxell
authors.initials: M
authors.lastname: Llorca-Torralba
authors.forename: Igor
authors.initials: I
authors.lastname: Horrillo
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Ortega
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Mico
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
mesh_terms: D000200:Action Potentials / Q000502:physiology; D059331:Adrenergic Neurons / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D059350:Chronic Pain / Q000150:complications / Q000503:physiopathology* / Q000523:psychology*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism / Q000502:physiology; D008297:Male; D019964:Mood Disorders / Q000150:complications / Q000503:physiopathology* / Q000523:psychology*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000096:biosynthesis; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine