Chronic stress, sensory neurons, and chronic pain: integrating brain, periphery, and immune mechanisms

Chronic stress is a major risk factor for the development and persistence of chronic pain and is frequently associated with psychiatric comorbidities such as depression and post-traumatic stress disorder. However, the mechanisms linking stress exposure to pain chronification remain poorly integrated across peripheral and central levels. In this review, we examine chronic pain as a consequence of stress-driven brain–periphery–immune interactions, with a specific focus on primary sensory neurons as key integrators of immune, neuroendocrine, and neural signals. We discuss evidence showing that chronic stress reshapes immune function and promotes a pro-inflammatory milieu that directly targets nociceptors, increasing their excitability and susceptibility to peripheral sensitization. We then address how sustained nociceptive signaling and stress-related neuroimmune activation facilitate central sensitization within the spinal cord and limbic circuits, contributing to widespread pain and psychiatric vulnerability. By integrating findings from clinical and preclinical studies, this review highlights sensory neurons as a critical interface linking stress, immune dysregulation, and maladaptive pain processing across peripheral and central nervous system levels.