The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia

Abstract

Although pain is regarded as a global public health priority, analgesic therapy remains a significant challenge. Pain is a hypersensitivity state caused by peripheral and central sensitization, with the latter considered the culprit for chronic pain. This study summarizes the pathogenesis of central sensitization from the perspective of neuroglial crosstalk and synaptic plasticity and underlines the related analgesic mechanisms of acupuncture. Central sensitization is modulated by the neurotransmitters and neuropeptides involved in the ascending excitatory pathway and the descending pain modulatory system. Acupuncture analgesia is associated with downregulating glutamate in the ascending excitatory pathway and upregulating opioids, 𝛾-aminobutyric acid, norepinephrine, and 5-hydroxytryptamine in the descending pain modulatory system. Furthermore, it is increasingly appreciated that neurotransmitters, cytokines, and chemokines are implicated in neuroglial crosstalk and associated plasticity, thus contributing to central sensitization. Acupuncture produces its analgesic action by inhibiting cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, and upregulating interleukin-10, as well as modulating chemokines and their receptors such as CX3CL1/CX3CR1, CXCL12/CXCR4, CCL2/CCR2, and CXCL1/CXCR2. These factors are regulated by acupuncture through the activation of multiple signaling pathways, including mitogen-activated protein kinase signaling (e.g., the p38, extracellular signal-regulated kinases, and c-Jun-N-terminal kinase pathways), which contribute to the activation of nociceptive neurons. However, the responses of chemokines to acupuncture vary among the types of pain models, acupuncture methods, and stimulation parameters. Thus, the exact mechanisms require future clarification. Taken together, inhibition of central sensitization modulated by neuroglial plasticity is central in acupuncture analgesia, providing a novel insight for the clinical application of acupuncture analgesia.

Contralateral Acupuncture for the Treatment of Phantom Limb Pain and Phantom Limb Sensation in Oncologic Lower Limb Amputee: A Case Report

“…Acupuncture, as an ancient Chinese medical technique, has been widely applied in the treatment of various types of pain over 3,000 years, and accumulating experimental and clinical studies have demonstrated its benefit for chronic pain during the last decade (Vickers et al, 2018;Gao et al, 2021). Numerous reviews have summarized the analgesic effects of acupuncture regarding the peripheral, spinal, and supraspinal mechanisms (Zhang et al, 2014;Lai et al, 2019;Lyu et al, 2021). Several studies indicate that peripheral opioids, induced by acupuncture, act on peripheral opioid receptors to desensitize peripheral sensory nerves and reduce pro-inflammatory cytokines peripherally (Zhang et al, 2014).…”

“…Acupuncture inhibits the transmission of noxious inputs in the spinal cord with the involvement of spinal opioids, norepinephrine, serotonin, glutamate and glial cell (Zhang et al, 2014). Acupuncture analgesia is associated with downregulation of glutamate in the ascending excitatory pathway and upregulation of opioids, norepinephrine, and 5-hydroxytryptamine in the descending pain modulatory system, thus contributing to alleviate central sensitization (Lyu et al, 2021). From another perspective, affective disorders are interrelated with pain (Becker et al, 2018), and somatosensory pain memories may be revived after an amputation and lead to phantom limb pain (Katz and Melzack, 1990).…”

Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury

“…P38, a member of mitogen-activated protein kinases (MAPKs), is an important downstream kinase of CX3CL1/CX3CR1 signaling [72][73][74]. Activation of CX3CL1/CX3CR1/p38 MAPK pathway induces synthesis of proin ammatory cytokines such as TNF-α and IL-6 in the microglia [74,75].…”

The Effect of Natural Therapies in Combination with Usual Care for Depression: A Narrative Review

“…Acupuncture is involved in the modulation of neuroplasticity in the central nervous system [33] by raising the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF) that increase synaptic transmission [33,34]. Acupuncture upregulates neurotransmitters such as norepinephrine, dopamine, and serotonin [33,35] and facilitates endogenous opioid mechanisms that modulate the pain pathways involved in neuroglial crosstalk and plasticity [36,37]. It reduces associated oxidative stress and apoptosis [36] and the action of inflammatory pathways, especially the toll-like receptor, and tumour necrosis factor (TNF) signaling pathways that activate the nociceptive neurons [37,38].…”

“…Acupuncture upregulates neurotransmitters such as norepinephrine, dopamine, and serotonin [33,35] and facilitates endogenous opioid mechanisms that modulate the pain pathways involved in neuroglial crosstalk and plasticity [36,37]. It reduces associated oxidative stress and apoptosis [36] and the action of inflammatory pathways, especially the toll-like receptor, and tumour necrosis factor (TNF) signaling pathways that activate the nociceptive neurons [37,38].…”