A Critical Role for a7 Nicotinic Acetylcholine Receptor Signaling in Myeloid Lineage Cells in Chronic Neuropathic and Inflammatory Pain Responses

Neuroinflammation influences the development of chronic pain, an increasinglyprevalent condition impacting the lives of many worldwide. Given the challenges ofmanaging chronic pain, it is essential to explore new neuroimmune targets for thedevelopment of safe and effective analgesics. Alpha 7 nicotinic acetylcholine receptors(a7 nAChRs) have been explored for their role in pain and inflammation. Wehypothesize that a7 nAChR expression within myeloid cells mediates an anti-inflammatory response that mitigates pain states. We engineered two mouse strains,with deletion of the a7 gene (Chrna7) globally and from myeloid lineage cellsconditionally. We characterized these mice in chemotherapy-induced peripheralneuropathy (CIPN) using paclitaxel and acute and chronic inflammatory pain models.We measured spontaneous and evoked pain-related behaviors, gene expression ofpro-inflammatory cytokines in peripheral nervous tissue, and other physiologicalparameters. Additionally, RNA-sequencing and pathway enrichment analysis of spinalcord tissues from mice treated with paclitaxel were performed. Mice deficient for a7nAChR in myeloid cells showed a marked increase in evoked pain behaviors in CIPNand chronic inflammatory models with a corresponding increase in gene expression ofkey pro-inflammatory cytokines in the peripheral sensory nervous system. Enrichmentanalysis identified changes in pathways pertaining to vascular function and enrichedpathways associated with extracellular matrix function and angiogenesis in conditionalknock-out mice treated with paclitaxel. Our study suggests a7 nAChR expression inmyeloid cells mediates an endogenous cholinergic anti-inflammatory pathway, whichplays a critical role in chronic neuropathic and inflammatory pain and is an importanttarget for developing novel analgesic agents.