The comorbidity of chronic pain and mood disorders represents a significant clinical challenge, yet the underlying neurobiological mechanisms within key brain regions like the ventral tegmental area (VTA) remain poorly understood. To address this, a multidisciplinary approach was employed, combining proteomics, phosphoproteomics, and lipidomics with behavioral and immunohistochemical analyses in a mouse model of neuropathic pain induced by partial sciatic nerve ligation (pSNL). The data reveal a temporal shift in the VTA proteome, progressing from an early (1-week) signature of metabolic reallocation and increased protein synthesis to a late (4-week) state of excitotoxic stress, characterized by impaired energy metabolism, autophagy, and cytoskeletal breakdown. This late maladaptive state was associated with two convergent mechanisms promoting hyperexcitability: sex-specific remodeling of Kv7 potassium channel subunit expression in VTA dopamine neurons and a deficit in the endocannabinoid 2-arachidonoylglycerol (2-AG). The development of passive coping behavior, a correlate of negative affect, was associated with these molecular changes. Notably, pharmacological restoration of 2-AG signaling or potentiation of Kv7 channel function reversed the pain-induced passive coping behavior. These findings delineate a progressive molecular pathology in the VTA and identify the 2-AG and Kv7 systems as therapeutically-relevant nodes linking chronic pain to the development of these behavioral states.