Inflammation and pain are closely linked. Inflammation is a natural immune response to injury or infection, and pain is one of the cardinal signs of inflammation. Inflammatory pain is specifically the pain that occurs in the presence of inflammation, often due to increased sensitivity of nerve endings. Inflammation can cause pain, swelling or discoloration. These are signs your body is healing itself. Normal inflammation should be mild, and pain shouldn't be extreme. But inflammation can also affect parts of your body you can't see. Inflammatory reflexes, like the cholinergic anti-inflammatory pathway, can be harnessed to manage inflammation and pain, offering potential therapeutic avenues. By understanding the intricate connection between the nervous system and the immune system, researchers can develop strategies to modulate inflammation and potentially alleviate pain associated with inflammatory conditions. Acupuncture can help reduce inflammation by modulating the inflammatory response through various mechanisms, including activating specific nerve pathways like the vagus nerve, influencing the release of anti-inflammatory cytokines, and modulating the immune system's response. Animal studies have shown that acupuncture can effectively reduce systemic inflammation and even improve survival rates in models of sepsis. Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases Yaakov A Levine, Michael Faltys, David Chernoff Cold Spring Harb Perspect Med. 2020 Jan;10(1):a034330. Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the “inflammatory reflex.” We discuss various biomarkers developed and used to translate early physiological discoveries into dosing parameters used in experimental settings, from the treatment of animal models of disease through a proof-of-concept clinical study in rheumatoid arthritis (RA). Finally, we relate how unique aspects of this form of therapy enabled the design of a next-generation implanted pulse generator using integrated electrodes, currently under evaluation in a U.S.-based clinical study for patients with drug refractory RA. The bioelectronic medicine application of using neurostimulation in immune and inflammatory disorders began as an effort to harness the “inflammatory reflex” to treat underlying chronic inflammatory processes. This treatment paradigm-shifting endeavor was based on foundational scientific discoveries of how the immune system is centrally monitored and modulated by the nervous system. To pioneer such a wide-open field, we took a methodical approach using objective immunologic biomarkers to empirically interrogate a range of electrical stimuli to produce the desired clinical outcomes. Such a tool was new to the field of neurostimulation, allowing us to quickly discover what the therapy required. This led us to not only a groundbreaking treatment approach, but enabled development of a novel neurostimulation device that was fundamentally different than any commercially available system. This review relates the journey from concept to realization describing the process and discoveries made along the way. The Inflammatory Reflex and the Role of Complementary and Alternative Medical Therapies Stacey L Oke, Kevin J Tracey Ann N Y Acad Sci. 2009 Aug;1172:172–180. The body’s first defense against invading pathogens or tissue injury is the innate immune system. Since excessive immune responses can be damaging, anti-inflammatory mechanisms function to control the pro-inflammatory response and prevent injury. The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response. Knowledge concerning innervation of the immune system offers a unique opportunity to explore previously unrecognized techniques to treat disease. It also enables consideration of the neurological basis of complementary and alternative medical therapies, such as meditation and acupuncture. This evolving area of research has implications for the pathogenesis of chronic inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes, and other conditions of excessive cytokine release. The Anti-Inflammatory Actions and Mechanisms of Acupuncture from Acupoint to Target Organs via Neuro-Immune Regulation Ningcen Li, Yi Guo, Yinan Gong, Yue Zhang, Wen Fan, Kaifang Yao, Zhihan Chen, Baomin Dou, Xiaowei Lin, Bo Chen, Zelin Chen, Zhifang Xu, Zhongxi J Inflamm Res. 2021 Dec 21;14:7191–7224. Inflammation plays a significant role in the occurrence and development of multiple diseases. This study comprehensively reviews and presents literature from the last five years, showing that acupuncture indeed exerts strong anti-inflammatory effects in multiple biological systems, namely, the immune, digestive, respiratory, nervous, locomotory, circulatory, endocrine, and genitourinary systems. It is well known that localized acupuncture-mediated anti-inflammatory effects involve the regulation of multiple populations and functions of immune cells, including macrophages, granulocytes, mast cells, and T cells. In acupuncture stimulation, macrophages transform from the M1 to the M2 phenotype and the negative TLR4 regulator PPARγ is activated to inhibit the intracellular TLR/MyD88 and NOD signaling pathways. The downstream IκBα/NF-κB and P38 MAPK pathways are subsequently inhibited by acupuncture, followed by suppressed production of inflammasome and proinflammatory mediators. Acupuncture also modulates the balance of helper T cell populations. Furthermore, it inhibits oxidative stress by enhancing SOD activity via the Nrf2/HO-1 pathway and eliminates the generation of oxygen free radicals, thereby preventing inflammatory cell infiltration. The anti-inflammatory effects of acupuncture on different biological systems are also specific to individual organ microenvironments. As part of its anti-inflammatory action, acupuncture deforms connective tissue and upregulates the secretion of various molecules in acupoints, further activating the NF-κB, MAPK, and ERK pathways in mast cells, fibroblasts, keratinocytes, and monocytes/macrophages. The somatic afferents present in acupuncture-activated acupoints also convey sensory signals to the spinal cord, brainstem, and hypothalamic neurons. Upon information integration in the brain, acupuncture further stimulates multiple neuro-immune pathways, including the cholinergic anti-inflammatory, vagus-adrenal medulla-dopamine, and sympathetic pathways, as well as the hypothalamus-pituitary-adrenal axis, ultimately acting immune cells via the release of crucial neurotransmitters and hormones. This review provides a scientific and reliable basis and viewpoints for the clinical application of acupuncture in various inflammatory conditions. This is for informational purposes only. 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