TREM2 and Pain Development: An Old Molecule, a New Target.

The essence of pain involves a multi-system interaction encompassing sensation, emotion, and cognition, with multi-level regulatory mechanisms such as peripheral sensitization, central plasticity, neuroimmune signal crosstalk, and glial cell activation playing critical roles. Among these mechanisms, microglia, as the primary immune effector cells in the central nervous system, contribute significantly to chronic pain by releasing pro-inflammatory factors and modulating synaptic remodeling. Nevertheless, significant gaps remain in our current understanding, including the molecular switch governing the transition from acute to chronic pain, the precise mechanisms regulating microglial phenotypic conversion, and the biological basis of endogenous pain resolution pathways. In this context, the triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a focal point of research due to its multifaceted regulation of microglial functions and its dual role in neuroimmune modulation. TREM2 dynamically balances pro-inflammatory and anti-inflammatory signals by modulating the complement system, regulating phagocytosis-related gene expression, and maintaining lipid metabolism homeostasis. While suppressing excessive inflammatory responses, TREM2 may also impair immune surveillance and potentially drive disease progression. However, significant gaps remain in our understanding of the specific mechanisms underlying TREM2's role in pain. The spatiotemporal dynamics of TREM2 signaling pathways, gender-specific effects, and interactions with pain-associated immune cell subsets remain to be systematically elucidated. Notably, loss-of-function mutations in TREM2 may influence the pathological process of pain by altering ligand-binding affinity; however, the precise molecular mechanisms require further experimental validation. These unresolved scientific questions underscore the translational medicine potential of TREM2 as a novel analgesic target while also highlighting the existing translational gap between current basic research and clinical applications. This review aims to comprehensively describe how TREM2 contributes to neuropathic pain (NP), chemotherapy-induced peripheral neuropathy pain (CIPN), inflammatory pain, and migraine, thereby providing theoretical support for developing novel analgesic drugs targeting TREM2.