Acupuncture—the stimulation of defined body points with needles—has been practiced for ~2,500 years and is recognized by the WHO for multiple indications. Electroacupuncture (EA), developed in the 1950s for surgical anesthesia, applies controlled electrical currents through needles and produces reliable analgesia. This lecture interprets the accompanying figure to propose an integrated CNS framework: EA activates peripheral afferents, reshapes spinal and supraspinal circuits, and engages both opioid and non-opioid mechanisms. Early work established endogenous opioids; recent studies define a parallel orexin endocannabinoid pathway that operates independently of opioids. Our new research identifies TRPM8 (transient receptor potential melastatin 8)—the cold/menthol-gated ion channel—as a mechanistic gate for EA: intact TRPM8 permits recruitment of endogenous opioids, whereas its inhibition or deletion shifts analgesia toward cannabinoid signaling. Converging on neuroimmune targets, EA suppresses microglial and astrocytic activation, lowers pro-inflammatory mediators, and mitigates central sensitization and GABAergic dysfunction—the drivers of allodynia, hyperalgesia, and pain chronification. These glial centric effects also confer neuroprotection after CNS injury (e.g., stroke, traumatic brain injury). Translationally, we show that: (i) EA at clinically relevant acupoints (e.g., PC6) alleviates pain via the orexin–endocannabinoid axis and retains efficacy in opioid-tolerant states; (ii) EA reduces glial reactivity and neuroinflammation after experimental brain trauma; and (iii) EA relieves severe dental pain and may limit the transition to chronic pain (e.g., irreversible pulpitis). Together, these data position EA as a multimodal, non-pharmacologic strategy that coordinates opioid and non-opioid systems while reprogramming neuroimmune responses—supporting evidence-based use of EA for pain management and neuroprotection.