Electroacupuncture and P2X receptors: purinergic mechanisms in pain modulation : A narrative review with structured evidence mapping.

Acupuncture and electroacupuncture (EA) are used for pain modulation, but the molecular events linking needling to analgesia remain incompletely defined. Purinergic signaling provides a biologically coherent framework because mechanical stimulation at acupoints releases extracellular adenosine triphosphate (ATP), which can activate P2X receptors and is subsequently metabolized into adenosine. Importantly, the receptor-level literature synthesized here is dominated by EA studies, whereas key local ATP-adenosine evidence derives from manual or traditional acupuncture. This review synthesizes evidence on purinergic mechanisms involved in acupuncture-related analgesia, with primary emphasis on EA modulation of P2X3, P2X4, and P2X7 receptors across dorsal root ganglion (DRG), spinal dorsal horn, and supraspinal cortical compartments, while distinguishing manual/traditional acupuncture evidence at the acupoint level. A narrative review with structured evidence mapping was conducted. The synthesis prioritizes mechanistic studies of manual/traditional acupuncture and EA in inflammatory, neuropathic, diabetic neuropathic, visceral, and cancer pain models, and integrates the limited available human data on acupoint adenosine signaling. Evidence is interpreted according to stimulation modality, receptor subtype, and anatomical compartment. The best-supported local pathway is the ATP-adenosine cascade: manual or traditional needling induces ATP release and CD39/CD73-mediated conversion to adenosine, activating anti-nociceptive adenosine A1 receptors (A1R). Most receptor-specific evidence, however, derives from EA. P2X3 receptors in nociceptive DRG neurons are the most consistently reproduced EA-associated target, with reduced receptor expression, membrane trafficking, and ATP-evoked currents. P2X4R-related evidence links EA analgesia with reduced spinal microglial activation, BDNF signaling, and central sensitization, but direct receptor-specific causal confirmation remains limited. P2X7R findings are compartment-specific and must be interpreted alongside EA stimulation parameters and the receptor's requirement for relatively high or sustained extracellular ATP exposure. Purinergic signaling offers a compelling mechanistic bridge between needling-based stimulation and pain relief. The receptor-level evidence is predominantly preclinical, male-biased, and EA-centred; manual acupuncture and EA should not be treated as mechanistically interchangeable. Human receptor-level studies, sex-balanced designs, standardized reporting of EA parameters, and direct causal interrogation of receptor function are needed before P2X modulation can be considered clinically validated.