A Critical Role for alpha7 Nicotinic Acetylcholine Receptor Signaling in Myeloid Lineage Cells in Chronic Neuropathic and Inflammatory Pain Responses

J Pain. 2026 Jun 1:106339. doi: 10.1016/j.jpain.2026.106339. Online ahead of print.

ABSTRACT

Neuroinflammation influences the development of chronic pain, an increasingly prevalent condition impacting the lives of many worldwide. Given the challenges of managing chronic pain, it is essential to explore new neuroimmune targets for the development of safe and effective analgesics. α7 nicotinic acetylcholine receptors (α7 nAChRs) have been explored for their role in pain and inflammation. It was hypothesized that α7 nAChR expression within myeloid cells mediates an anti-inflammatory response that mitigates pain states. Two mouse strains were engineered, with deletion of the α7 gene (Chrna7) globally and from myeloid lineage cells conditionally. These mice were characterized in chemotherapy-induced peripheral neuropathy (CIPN) using paclitaxel and acute and chronic inflammatory pain models. Spontaneous and evoked pain-related behaviors, gene expression of pro-inflammatory cytokines in peripheral nervous tissue, and other physiological parameters were measured. Additionally, RNA-sequencing and pathway enrichment analysis of spinal cord tissues from mice treated with paclitaxel were performed. Mice deficient for α7 nAChR in myeloid cells showed a marked increase in evoked pain behaviors in CIPN and chronic inflammatory models with a corresponding increase in gene expression of key pro-inflammatory cytokines in the peripheral sensory nervous system. Enrichment analysis identified changes in pathways pertaining to vascular function and enriched pathways associated with extracellular matrix function and angiogenesis in conditional knock-out mice treated with paclitaxel. This study suggests α7 nAChR expression in myeloid cells mediates an endogenous cholinergic anti-inflammatory pathway, which plays a critical role in chronic neuropathic and inflammatory pain and is an important target for developing novel analgesic agents. PERSPECTIVE: This article presents evidence that α7 nicotinic receptors located on myeloid cells are critical for attenuating neuropathic and chronic inflammatory pain. This provides new insight into a cellular target for the treatment of these conditions.

PMID:42229868 | DOI:10.1016/j.jpain.2026.106339