The persistent pain enigma: Molecular drivers behind acute-to-chronic transition

The transition from acute to chronic pain is a complex and multifactorial process that presents significant challenges in both diagnosis and treatment. Key mechanisms of peripheral and central sensitization, neuroinflammation, and altered synaptic plasticity contribute to the amplification of pain signals and the persistence of pain. Glial cell activation, particularly microglia and astrocytes, is pivotal in developing chronic pain by releasing pro-inflammatory cytokines that enhance pain sensitivity. This review explores the molecular, cellular, and systemic mechanisms underlying the transition from acute to chronic pain, offering new insights into the molecular and neurobiological mechanisms involved, which are often underexplored in existing literature. It also addresses emerging therapeutic strategies beyond traditional pain management, offering valuable perspectives for future research and clinical applications.