Aside from movement initiation and control, the primary motor cortex (M1) has been implicated in pain modulation mechanisms. A large body of clinical data has demonstrated that stimulation and behavioral activation of M1 result in clinically important pain relief in patients with specific chronic pain syndromes. However, despite its clinical importance, the full range of circuits for motor cortex-related analgesia (MCRA) remains an enigma. This review draws on insights from experimental and clinical data and provides an overview of the neurobiological mechanisms of MCRA, with particular emphasis on its neurocircuitry basis. Based on structural and functional connections of the M1 within the pain connectome, neural circuits for MCRA are discussed at different levels of the neuroaxis, specifically, the endogenous pain modulation system, the thalamus, the extrapyramidal system, non-noxious somatosensory systems, and cortico-limbic pain signatures. We believe that novel insights from this review will expedite our understanding of M1-induced pain modulation and offer hope for successful mechanism-based refinements of this interventional approach in chronic pain management.

Ku70 and Ku80 form Ku, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway.1 Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., LIG4, DNA-PKcs). While Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated-DNA-PKcs on ribosomal RNA (rRNA),3,4 the physiological role on Ku-RNA interaction in otherwise wildtype cells remains unclear. Intriguingly, Ku is dispensable for murine development5,6 but essential in human cells.7 Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ - possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10~100 times weaker than dsDNA.2,8 Investigating Ku's essentiality in human cells, we found that Ku-depletion - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and MAVS. Prolonged Ku-degradation further activates other dsRNA sensors, especially PKR (suppressing translation) and OAS/RNaseL (cleaving rRNA), leading to growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed Ku binding to diverse dsRNA, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3'-UTRs. Ku expression rose sharply in higher primates, correlating tightly with Alu-expansion (r = 0.94/0.95). Thus, Ku plays a vital role in accommodating Alu-expansion in primates by limiting dsRNA-induced innate immunity, explaining both Ku's elevated expression and its essentiality in human cells.