Potential molecular targets for prevention and treatment of persistent postoperative pain

Abstract

Introduction. Persistent postoperative pain is a clinically important complication of surgery that develops when acute nociceptive signaling fails to resolve and progresses toward sustained peripheral and central sensitization. Experimental evidence suggests that this transition is driven by coordinated changes in primary afferent excitability, spinal excitatory signaling, neuroimmune activation, and maladaptive synaptic plasticity. Study aims to summarize the main molecular targets involved in the development and persistence of postoperative pain and to highlight mechanism-based strategies for its prevention and treatment. Materials and Methods. This narrative analytical review summarizes primary mechanistic and translational studies on molecular pathways involved in postoperative pain persistence. Priority was given to studies investigating ion channels, glutamatergic signaling, spinal glial activation, inflammatory mediators, and neurotrophic factors in validated postoperative pain models. Results. The reviewed evidence supports a multifactorial model of persistent postoperative pain. At the peripheral level, increased nociceptor excitability is associated with transient receptor potential vanilloid 1-mediated heat hyperalgesia and upregulation of voltage-gated sodium channels, particularly NaV1.7, while selective sodium-channel blockade has shown analgesic potential in postoperative settings. At the spinal level, persistent sensitization is promoted by glutamatergic signaling through NMDA receptor subunits, enhanced NMDA receptor GluN2B/NR2B phosphorylation, and downstream activation of calcium/calmodulin-dependent protein kinase II and p38 mitogen-activated protein kinase pathways. Neuroimmune mechanisms are also central: activation of microglia and astrocytes, together with Toll-like receptor 4 and NF-kB signaling, increases the release of IL-1 beta, IL-6, TNF-α, further amplifying nociceptive transmission. In addition, elevated BDNF expression contributes to maladaptive synaptic plasticity and maintenance of pain hypersensitivity. Conclusions. Persistent postoperative pain results from the interaction of peripheral sensitization, spinal hyperexcitability, neuroinflammation, and pathological neuroplasticity. A mechanism-based therapeutic approach targeting these pathways may help prevent the transition from acute to chronic postoperative pain and support the development of more effective non-opioid perioperative analgesic strategies.