rs-504393 and Pain

Acupuncture is an emerging alternative therapy that has been beneficial for the pain of osteoarthritis (OA). However, the underlying mechanism of protective effect remains unclear. MCP1/CCR2 axis can be stimulated in various periods of OA, and we hypothesize that acupuncture may treat OA by regulating the MCP1/CCR2 axis. This study aimed to explore the effect of acupuncture at points ST35 and ST36 on the effects of hyperalgesia and cartilage in OA rats including the expression of chemokines, nerve growth factor (NGF), and inflammatory-related proteins. OA was induced in male Sprague-Dawley rats by anterior cruciate ligament transection at the right knee. The first acupuncture intervention was performed on the seventh day after surgery and once a day for seven weeks. The knee-pain-related behaviors, histology, and related protein were examined in this study. We have found that electroacupuncture at ST35 and ST36 can significantly alleviate the hyperalgesia and cartilage degeneration as well as reducing nerve sprouting in OA knee joint. Moreover, acupuncture treatment may inhibit the MCP1/CCR2 axis as well as down-regulate inflaming factor and NGF in cartilage and synovial tissue. The data presented here indicate that acupuncture exerts a protective effect against hyperalgesia and cartilage degeneration, and the mechanism might involve in chemokines and NGF pathway.

Topics: Acupuncture Therapy; Animals; Benzoxazines; Cartilage, Articular; Chemokine CCL2; Cytokines; Ganglia, Spinal; Hyperalgesia; Inflammation Mediators; Knee Joint; Male; Nerve Growth Factor; Neurons; Osteoarthritis; Pain; Rats, Sprague-Dawley; Receptor, trkA; Receptors, CCR2; Signal Transduction; Spiro Compounds; Synovial Membrane

Previous studies have shown that CCL2 may cause chronic pain, but the exact mechanism of central sensitization is unclear. In this article, we further explore the presynaptic role of CCL2. Behavioral experiments show that intervertebral foramen injection CCR2 antagonists into dorsal root ganglion (DRG) can inhibit the inflammatory pain caused by CCL2 in spinal cord. We raised the question of the role of presynaptic CCR2 in the spinal dorsal horn. Subsequent electron microscopy experiments showed that CCR2 was expressed in the presynaptic CGRP terminal in the spinal dorsal horn. CCL2 can enhance presynaptic calcium signal. Whole-cell patch-clamp recordings showed that CCL2 can enhance NMDAR-eEPSCs through presynaptic effects, and further application of glutamate sensor method proved that CCL2 can act on presynaptic CCR2 to increase the release of presynaptic glutamate. In conclusion, we suggest that CCL2 can directly act on the CCR2 on presynaptic terminals of sensory neurons in the spinal dorsal horn, leading to an increase in the release of presynaptic glutamate and participate in the formation of central sensitization.

Topics: Animals; Benzoxazines; Calcitonin Gene-Related Peptide; Calcium Signaling; Chemokine CCL2; Ganglia, Spinal; Glutamic Acid; Hyperalgesia; Inflammation; Injections, Spinal; Mice, Inbred C57BL; Neurons; Nociceptors; Pain; Presynaptic Terminals; Protein Binding; Receptors, CCR2; Spinal Cord; Spinal Cord Dorsal Horn; Spiro Compounds; Synaptic Transmission; Up-Regulation