Chronic Pain Leads to Concomitant Noradrenergic Impairment and Mood Disorders

  • Cristina Alba-Delgado
    Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
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  • Meritxell Llorca-Torralba
    Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain
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  • Igor Horrillo
    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Department of Pharmacology, University of the Basque Country, Bizkaia, Spain
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  • Jorge E. Ortega
    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Department of Pharmacology, University of the Basque Country, Bizkaia, Spain
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  • Juan Antonio Mico
    Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
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  • Pilar Sánchez-Blázquez
    Department of Neuropharmacology, Instituto Cajal CSIC, Madrid, Spain
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  • J. Javier Meana
    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Department of Pharmacology, University of the Basque Country, Bizkaia, Spain
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  • Esther Berrocoso
    Address correspondence to Esther Berrocoso, Ph.D., University of Cadiz, Department of Psychology, Neuropsychopharmacology Research Group, Psychobiology Area, Campus Universitario Río San Pedro, 11510 Puerto Real, Cadiz, Spain
    Neuropsychopharmacology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, Cadiz, Spain

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
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      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.


      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.


      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.


      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.

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