Neuroimmune Interactions and Novel Therapeutic Targets in Neuropathic Pain

Neuropathic pain remains a formidable clinical challenge. Current treatments often provide inadequate relief, largely due to our incomplete understanding of its underlying mechanisms. Accumulating evidence underscores the indispensable role of dynamic, bidirectional communication between neurons and non-neuronal cells in the initiation and chronicity of neuropathic pain. In the dorsal root ganglia (DRG) and trigeminal ganglia (TG), critical crosstalk between sensory neurons and non-neuronal cells (including satellite glial cells, macrophages, and other immune cells) lowers neuronal activation thresholds, enhances excitability, and increases spontaneous activity, leading to peripheral sensitization. In the spinal cord, this amplified peripheral input triggers the activation of astrocytes and microglia, prompting the release of glial mediators. These glial-derived signals enhance synaptic strength by increasing presynaptic neurotransmitter release and postsynaptic NMDA receptor efficacy, resulting in the hyperexcitability of spinal pain-projection neurons. Despite significant progress, critical questions regarding these neuron-non-neuronal interactions remain unresolved. This IASP Topical Workshop, "Neuroimmune Interactions and Novel Therapeutic Targets in Neuropathic Pain," aims to dissect these complex cellular dialogues and illuminate novel, translationally relevant signaling pathways.

This workshop brings together four leading experts to present cutting-edge research on neuroimmune signaling pathways and their therapeutic implications.

Prof. Ru-Rong Ji (Duke University, USA) will present recent findings demonstrating that GPR37L1 in astrocytes functions as a critical negative regulator of astrogliosis and neuropathic pain. Using single-cell transcriptomics, astrocyte morphological analysis, patch-clamp recordings, and genetic manipulations, he will highlight a protective role of GPR37L1 in suppressing astrocyte reactivity and mitigating neuropathic pain.

Prof. Marc R Suter (University of Lausanne, Switzerland) will detail how extracellular vesicles (EVs) and their miRNAs mediate bidirectional communication between nerve and immune cells in pain. He will present evidence that, after nerve injury, macrophages from the DRG release EVs that sensitize sensory neurons. Conversely, injured neurons release signals and EVs that influence microglia in the spinal cord, highlighting a differential effect based on injury status. This EV-mediated exchange is a central pain mechanism, and their miRNA content is a promising therapeutic target.

Prof. Yun Wang (Peking University, China) will delve into a self-amplifying circuit within the trigeminal system. Her talk will elucidate how NPY-Y2R signaling in trigeminal ganglia neurons drives a feedforward loop by recruiting and activating macrophages, which in turn exacerbate neuronal hyperexcitability. This mechanism underpins the persistence of severe conditions such as trigeminal neuralgia.

Finally, Prof. Yong-Jing Gao (Nantong University, China) will introduce a multi-component signaling pathway central to trigeminal neuropathic pain: UCN1-CRFR1-HSP-TLRs axis. Her research reveals how the stress peptide Urocortin 1 (UCN1) induces the production of the small heat shock protein, which is released via exosomes to activate Toll-like receptors on non-neuronal cells. This pathway creates a potent pro-inflammatory and pro-nociceptive cascade unique to orofacial pain.

Collectively, this workshop will provide a comprehensive and integrative view of novel neuroimmune and neuroglial regulations, spanning from GPCR signaling and EV-mediated intercellular communication to self-sustaining neuronal-immune circuits. By highlighting these novel pathways, our goal is to stimulate interdisciplinary discussion, foster collaborations, and accelerate the development of next-generation therapies for neuropathic pain.