Stage-Specific Mechanisms of Manual Acupuncture and Electroacupuncture in Inflammatory Pain: A Time-Dependent Review

This narrative review represents an important conceptual milestone in understanding the mechanisms of acupuncture for inflammatory pain, being the first to systematize evidence based on the temporal evolution of the disease process. The authors analyzed 54 preclinical studies that used the complete Freund's adjuvant (CFA) model in rodents, organizing the findings into three distinct phases of inflammatory pain. In the acute phase (1-3 days), manual acupuncture and electroacupuncture produce rapid analgesia primarily through activation of descending inhibitory pathways, involving μ-opioid, α2A-adrenergic, and 5-HT1A receptors. Simultaneously, modulation of peripheral TRP channels (TRPV1, TRPA1, TRPM8) and purinergic pathways occurs, particularly through release of extracellular ATP that is hydrolyzed to adenosine, activating A1 receptors.

During the subacute phase (4-14 days), the therapeutic focus shifts to reversing established central sensitization. Mechanisms include reprogramming the immune microenvironment by promoting M2 microglial polarization via AMPK/SIRT1, regulation of anti-inflammatory (IL-10) and pro-inflammatory (IL-1β, TNF-α) cytokines, and modulation of synaptic plasticity through dephosphorylation of AMPA GluR2 receptors. The chronic phase (>14 days) represents a strategic expansion of therapeutic objectives beyond simple pain relief. In this phase, acupuncture acts on remodeling of limbic circuits, promoting neuroplasticity through the BDNF/TrkB/CREB pathway in the hippocampus, regulating the rACC-CaMKII-DRN-5-HT pathway for anxiety symptoms, and initiating systemic repair through metabolic reprogramming and inhibition of programmed cell death such as ferroptosis.

The analysis reveals that manual acupuncture and electroacupuncture have complementary roles: manual acupuncture acts primarily as a peripheral initiator, converting mechanical force into local biological signals, while electroacupuncture is a more potent central and systemic modulator. This 'peripheral to central, low-level to high-level' pattern demonstrates the stage-specific adaptability of acupuncture. The authors propose a 'temporal window optimization' model, in which stimulation parameters, duration, and point selection should match the dominant pathological processes in each phase. This theoretical framework provides a basis for precise intervention strategies, suggesting that in the acute phase high-frequency electroacupuncture should be used for rapid relief, in the subacute phase treatment should have sufficient duration to accumulate immunomodulatory effects, and in the chronic phase treatment should be extended to address neuropsychiatric comorbidities.

Limitations include heterogeneity of evidence due to differences in stimulation parameters, methodological inconsistencies between studies, and the fact that the findings are limited to the CFA model, which may not fully capture the clinical complexity of mixed pain or affective comorbidities. The work establishes critical directions for future research, including the need for clinical trials to validate stage-specific strategies, application of multi-omics technologies to discover new targets, and development of standardized reporting guidelines to address heterogeneity of evidence.