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.

Figure 1

Flow chart of the search processes.

Figure 2

Role of neuroglial crosstalk and synaptic plasticity mediated central sensitization in acupuncture analgesia. The titles of neurotransmitters, neuropeptides, and immune factors are presented in red, blue, and purple, as the figure shows. Factors in red are upregulated by acupuncture, while factors in blue are downregulated by acupuncture. Factors in purple are activated or inhibited in the central sensitization process but are not regulated by acupuncture. ACC: anterior cingulate cortex; PAG: periaqueductal gray; RVM: rostral ventromedial medulla; GABA: 𝛾-aminobutyric acid; 5-HT: 5-hydroxytryptamine; 5-HTR: 5-hydroxytryptamine receptor; NE: norepinephrine; AR: adrenergic receptor; GAT1: GABA transporter 1; Glu: glutamate; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDAR: N-methyl-d-aspartate receptor; mGluR: metabotropic glutamate receptors; CGRP: calcitonin gene-related peptide; CRLR: calcitonin receptor-like receptor; ATP: adenosine triphosphate; P2X: P2X receptor; P2Y: P2Y receptor; NK1: neurokinin-1; NK1 receptor: neurokinin-1 receptor; SP: substance P; SPR: substance P receptor; CX3CL1: C-X3-C motif chemokine ligand 1; CX3CR1: C-X3-C chemokine receptor 1; ERK: extracellular signal-regulated kinases; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; IL-1β: interleukin-1β; GT: glutamate transporter; TLR4: toll-like receptor 4; JNK: c-Jun-N-terminal kinase; CCL2: C-C motif chemokine ligand 2; CCL4: C-C motif chemokine ligand 4; CCL20: C-C motif chemokine ligand 20; CCR2: C-C chemokine receptor 2; CXCL1: C-X-C motif chemokine ligand 1; CXCR2: C-X-C chemokine receptor 2; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor 4. Red, promoted by acupuncture; blue, inhibited by acupuncture.