Abstract:

Chronic pain is a complex disorder sustained by multilevel mechanisms， including peripheral sensitization， central sensitization， neuroinflammation， synaptic plasticity， and epigenetic regulation. Current analgesic strategies remain constrained by substantial interindividual efficacy heterogeneity， inadequate long-term safety profiles， and the absence of disease-modifying effects. Traditional investigations into pain signal transduction have historically focused primarily on protein kinases； however， the association between sustained kinase activation and pain chronification is critically governed by the dynamic antagonism and homeostatic balance between kinases and phosphatases. Protein phosphatase 2A （PP2A）， a serine/threonine protein phosphatase highly expressed in the central nervous system， counteracts protein kinase-mediated signal amplification via dephosphorylation and regulates key signaling molecules including N-methyl-D-aspartate receptors （NMDAR）， α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors （AMPAR）， Ca²⁺/calmodulin-dependent protein kinase Ⅱ （CaMK Ⅱ）， protein kinase A （PKA）， protein kinase C （PKC）， extracellular signal-regulated kinase （ERK）， cAMP response element-binding protein （CREB）， and histone deacetylases （HDAC）. Its substrate specificity is tightly modulated by subunit composition， post-translational modifications， endogenous inhibitory proteins， and exogenous regulators. Current， research targeting endogenous negative regulators of PP2A-including protein phosphatase methylesterase 1 （PME-1）， SE translocation protein （SET）， and Cancerous Inhibitor of Protein Phosphatase 2A （CIP2A） along with advances in the development of small-molecule PP2A activators， covalent modulators， and holoenzyme- and substrate-specific interventions， has yielded novel insights into the mechanisms underlying chronic pain. Collectively， these advances indicate that the development of chronic pain interventions is transitioning from non-specific global activation or inhibition toward holoenzyme-selective and substrate-selective targeting. This review focuses on the regulatory role of PP2A in synaptic plasticity and central sensitization， summarizing its molecular mechanisms， inactivation pathways， and therapeutic potential during chronic pain progression. Additionally， we discuss the translational barriers and future prospects of diverse PP2A-targeted pharmacological strategies， with the aim of providing a novel perspective for the development of targeted interventions for chronic pain.

Key words: protein phosphatase 2A, chronic pain, synaptic plasticity, central sensitization, targeted intervention