Mechanism and modulation of spontaneous pain: from neural circuits to drug development

Abstract

Spontaneous pain, a pervasive and debilitating sensation occurring without external stimuli, represents a significant challenge in chronic pain management. Despite substantial advancements in the understanding of pain pathophysiology, current therapeutic strategies fail to adequately address spontaneous pain, contributing to the ongoing gap between preclinical findings and clinical outcomes. Historically, drug discovery has predominantly focused on the mechanisms underlying evoked pain, neglecting the unique neurobiology of spontaneous pain. This narrow focus has hindered progress in developing effective treatments. Emerging evidence from pharmacological and optogenetic studies underscores the involvement of sensory afferent fibers, descending pain pathways, cortical circuits, and thalamic and subthalamic nuclei in spontaneous pain processing. This review comprehensively explores the neurobiology of spontaneous pain, emphasizing the roles of these neural pathways and identifying novel druggable targets. Additionally, we examine the clinical implications of these findings and propose strategies to bridge the translational gap. To foster the development of innovative and effective pain therapies, we advocate for a paradigm shift in preclinical research that prioritizes robust assessments of spontaneous pain mechanisms. By aligning preclinical models with clinical symptomatology, we aim to advance the understanding and treatment of this underappreciated yet critical dimension of chronic pain. © The Author(s), under exclusive licence to Springer Nature B.V. 2025.