A Time-Dependent History of Mood Disorders in a Murine Model of Neuropathic Pain

Abstract

Chronic pain is clinically associated with the development of affective disorders. However, studies in animal models of neuropathic pain are contradictory and the relationship with mood disorders remains unclear. In this study, we aimed to characterize the affective consequences of neuropathic pain over time and to study potential underlying mechanisms. Neuropathic pain was induced by inserting a polyethylene cuff around the main branch of the right sciatic nerve in C57BL/6J mice. Anxiety- and depression-related behaviors were assessed over 2 months, using a battery of tests, such as elevated plus maze, marble burying, novelty suppressed feeding, splash test, and forced swimming test. Plasma corticosterone levels were assessed by radioimmunoassay. We also investigated changes in cyclic adenosine monophosphate response element (CRE) activity using CRE-LacZ transgenic mice. Mice developed anxiety-related behavior 4 weeks after induction of the neuropathy, and depression-related behaviors were observed after 6 to 8 weeks. Control and neuropathic mice did not differ for basal or stress-induced levels of corticosterone or for hypothalamic-pituitary-adrenal axis negative feedback. After 8 weeks, the CRE-mediated activity decreased in the outer granule layer of dentate gyrus of neuropathic mice but not in the amygdala or in the anterior cingulate cortex. Our results demonstrate that the affective consequences of neuropathic pain evolve over time, independently from the hypothalamic-pituitary-adrenal axis, which remains unaffected. CRE-mediated transcription within a limbic structure was altered at later time points of the neuropathy. These experiments provide a preclinical model to study time-dependent development of mood disorders and the underlying mechanism in a neuropathic pain context.