Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain

Neuropathic pain is a complex condition that arises when the nervous system is damaged or dysfunctional, and it is considered one of the most difficult types of pain to treat among all painful conditions. This form of pain can be spontaneous or evoked, manifesting as an increased response to painful stimuli (hyperalgesia) or as pain in response to normally innocuous stimuli (allodynia). In addition to direct physical suffering, neuropathic pain is frequently accompanied by symptoms such as anxiety and depression, significantly affecting patients' quality of life. Although current pain control medications have made impressive advances, the existing treatment modalities are still not ideal for neuropathic pain, presenting high costs and adverse effects that further compromise patients' quality of life.

This scientific review examined studies published between 2017 and 2021 to better understand how acupuncture and electroacupuncture produce analgesic effects in neuropathic pain. The researchers analyzed 49 basic scientific articles that investigated the mechanisms by which acupuncture relieves neuropathic pain, focusing specifically on studies with animal models that allowed understanding the biological processes involved. The methodology included the analysis of different neuropathic pain models, such as chronic constriction injury, peripheral nerve injury, spinal nerve ligation, and diabetic neuropathy, among others. The most studied acupuncture parameters included electrical stimulation frequencies of 2 Hz and 100 Hz, intensities of 1 to 3 mA, and treatment time of 30 minutes, with the points ST-36 (Zusanli) and GB-34 (Yanglingquan) being the most frequently used.

The results revealed that acupuncture acts through multiple integrated mechanisms to produce analgesia in neuropathic pain. In the ascending excitatory system, acupuncture inhibits the transmission of painful signals by reducing neurotransmitters such as glutamate and its NMDA receptors, P2X purinergic receptors, substance P, and calcitonin gene-related peptide (CGRP), in addition to ion channels such as TRPV1 and HCN. Simultaneously, the technique activates the descending inhibitory pain system, increasing opioid peptides such as beta-endorphin, mu-opioid receptors (MOR), gamma-aminobutyric acid (GABA) and its receptors, and bidirectionally regulating serotonin (5-HT) — increasing 5-HT1A receptors and decreasing 5-HT7R. Acupuncture also stimulates appetite-modifying neurons in the hypothalamus, contributing to pain relief through activation of the endocannabinoid system.

The research also demonstrated that acupuncture exerts important control over neuroinflammation, a crucial factor in the development of neuropathic pain. The technique inhibits the JAK2/STAT3 and PI3K/mTOR inflammatory pathways, reduces the expression of the chemokine receptor CX3CR1 on microglia, and increases A1R adenosine receptors on astrocytes, thus suppressing the activation of glial cells and reducing inflammatory substances such as tumor necrosis factor-alpha (TNF-α). Additionally, mechanisms related to neuronal metabolism have been identified, in which acupuncture inhibits neuronal glucose metabolism through the reduction of the glucose transporter GLUT-3 in the medial prefrontal cortex, and promotes beneficial metabolic alterations in the brain. The regulation of oxidative stress also proved relevant, with acupuncture increasing antioxidant pathways such as Nrf2-ARE and superoxide dismutase, while reducing oxidative stress products.

For patients and healthcare professionals, these findings offer robust scientific evidence on the efficacy of acupuncture in the treatment of neuropathic pain. The results suggest that acupuncture may be a valuable therapeutic option, potentially reducing the need for analgesic medications and their associated side effects. For professionals, understanding these mechanisms allows for more targeted application of the technique, with better selection of acupuncture points and stimulation parameters. The identification that points such as ST-36 and GB-34, with frequencies of 2 Hz and 100 Hz for approximately 30 minutes, are effective provides practical guidelines for clinical treatment.

In addition, the understanding that acupuncture acts through multiple systems simultaneously — neural, inflammatory, metabolic, and antioxidant — explains its efficacy in a condition as complex as neuropathic pain.

It is important to recognize some limitations of this study. The research was primarily based on animal models, which may limit the direct translation of the results to humans. Although the acupuncture parameters used in animal studies are similar to those applied clinically, facilitating the translation of experimental results, more clinical studies are still needed to confirm these mechanisms in human patients. In addition, the heterogeneity of the neuropathic pain models studied, while providing a comprehensive view, may also make it difficult to generalize the findings to all types of human neuropathic pain.

Despite these limitations, this review provides a solid scientific basis for understanding the mechanisms of acupuncture in neuropathic pain and establishes important foundations for future clinical research and more effective therapeutic applications.