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The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain

Alba-Delgado, Cristinaa,b; Llorca-Torralba, Meritxella,c,d; Mico, Juan Antonioc,d,e; Berrocoso, Estherc,d,f

doi: 10.1097/j.pain.0000000000001372
Research Paper
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Neuropathic pain is a chronic condition that is challenging to treat. It often produces considerable physical disability and emotional distress. Patients with neuropathic pain often experience depression and anxiety both of which are known to be temporally correlated with noradrenergic dysfunction in the locus coeruleus (LC) as pain becomes chronic. Antidepressants are the first-line drug therapy for neuropathic pain, and the LC represents a potential target for such therapy. In this study, we evaluated the efficacy of the tricyclic antidepressant desipramine (DMI, a noradrenaline reuptake inhibitor) in preventing or relieving the noradrenergic impairment induced by neuropathic pain. The treatment started before or after the onset of the anxiodepressive phenotype (“early or late treatment”) in adult rats subjected to chronic sciatic constriction. Electrophysiological and western blotting assays showed LC dysfunction (increased bursting activity, alpha2-adrenoceptor sensitivity, tyrosine hydroxylase, and noradrenaline transporter expression) in chronic constriction injury at long term. These noradrenergic changes were concomitant to the progression of anxiety and despair-like features. Desipramine induced efficient analgesia, and it counteracted the despair-like behavior in chronic constriction injury-DMI animals, reducing the burst rate and tyrosine hydroxylase expression. Surprisingly, “early” DMI treatment did not modify pain-induced anxiety, and it dampened pain aversion, although these phenomena were abolished when the treatment commenced after noradrenaline impairment had been established. Hence, DMI seems to produce different outcomes depending when the treatment commences, indicating that the balance between the benefits and adverse effects of DMI therapy may shift as neuropathy progresses.

This study shows that desipramine can affect pain aversion and pain-induced anxiety in a distinct manner depending on the time of onset of treatment.

aNeuropsychopharmacology and Psychobiology Research Group, University of Cadiz, Cadiz, Spain

bINSERM/UCA U1107, Neuro-Dol Research Group, Université Clermont Auvergne, Clermont-Ferrand, France

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

dInstituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain

eNeuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain

fNeuropsychopharmacology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, Cadiz, Spain

Corresponding author. Address: Department of Psychology, Campus Universitario Río San Pedro s/n, 11510 Puerto Real, Cadiz, Spain. Tel.: +34956015224; fax: +34956015225. E-mail address: esther.berrocoso@uca.es (E. Berrocoso).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received January 10, 2018

Accepted August 06, 2018

© 2018 International Association for the Study of Pain
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