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

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.

Ascending contraction mediated by 5-hydroxytryptamine3 receptors in canine small intestine

We investigated the mechanism of ascending contraction induced by activation of 5-hydroxytryptamine3 (5-HT3) receptors in anesthetized dogs. Pressure-measuring balloons were inserted into a loop of extrinsically denervated jejunum. Drugs were administered via the arterial tree to the oral or the anal segment and the ensuing mechanical responses were monitored. Administration of 2-methyl-5-HT (440 pmol-44 nmol) to the anal segment caused contractions in the oral segment in a dose-dependent manner. This response was inhibited by treating the anal segment with ICS 205-930, cocaine, hexamethonium, or tetrodotoxin and by treating the oral segment with atropine or hexamethonium. The response persisted even after abolition of contraction in the anal segment by nifedipine. These results imply that activation of 5-HT3 receptors can induce an ascending contraction through an enteric excitatory pathway formed by a series of cholinergic interneurons and final cholinergic motor neurons, apart from the anal contraction.