Peripheral neuroimmune dialogues underlying pain states

Pain is profoundly shaped by neuroimmune interactions within peripheral tissues. Nociceptors are specialized sensory neurons that express receptors for cytokines, lipid mediators, complement components, antibodies and microbial signals, enabling immune mediators to directly modulate neuronal excitability. In turn, nociceptors influence immune cell and stromal cell activity through the release of neuropeptides and cytokines. Some of these pathways are shared across multiple tissues in pathological pain states, whereas others reflect the distinct immune and stromal environments of the skin, joints, muscles, gut, peripheral nerves, sensory ganglia and meninges. Across these sites, immune-to-neuron signalling orchestrates the initiation and amplification of pain, while maladaptive feedback loops reinforce hypersensitivity. In concert, coordinated neuroimmune signalling also contributes to pain resolution by restoring homeostasis. Emerging human studies reveal convergent neuroimmune signatures across nociceptive, neuropathic and nociplastic pain conditions, underscoring their translational relevance. By integrating both shared mechanisms and tissue-specific mechanisms, this Review highlights how peripheral neuroimmune crosstalk shapes pain across diverse contexts. Furthermore, it outlines therapeutic opportunities to rebalance these pathways, offering prospects for durable and mechanism-based analgesia.