Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice.In vivoelectrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity.SIGNIFICANCE STATEMENTChronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.

Comorbidity is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration and higher service utilization. Therefore, identifying key clusters of comorbidity and exploring the underlying pathophysiological mechanisms represent important steps towards improving mental health care. In the present review, we focus on the frequent association between addiction and depression. In particular, we summarize the large body of evidence from preclinical models indicating that the kappa opioid receptor (KOR), a member of the opioid neuromodulatory system, represents a central player in the regulation of both reward and mood processes. Current data suggest that the KOR modulates overlapping neuronal networks linking brainstem monoaminergic nuclei with forebrain limbic structures. Rewarding properties of both drugs of abuse and natural stimuli, as well as the neurobiological effects of stressful experiences, strongly interact at the level of KOR signalling. In addiction models, activity of the KOR is potentiated by stressors and critically controls drug-seeking and relapse. In depression paradigms, KOR signalling is responsive to a variety of stressors, and mediates despair-like responses. Altogether, the KOR represents a prototypical substrate of comorbidity, whereby life experiences converge upon common brain mechanisms to trigger behavioural dysregulation and increased risk for distinct but interacting psychopathologies.