This federal Project Grant award from the National Institute of Neurological Disorders and Stroke (NINDS), under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) program, provides $650,079.00 to Northeastern University to develop and optimize novel small-molecule probes targeting alpha9-containing nicotinic acetylcholine receptors (α9*-nAChRs) for the treatment of chronic inflammatory and neuropathic pain. The research aims to advance the understanding of α9*-nAChR's role in pain pathways and create non-addictive, effective pain relief options, addressing a critical unmet medical need. The 5-year project involves several key activities, including: 1) developing a series of α9*-nAChR agonists and antagonists using structure-activity relationship studies, 2) rigorously testing compound selectivity and functional activity, 3) evaluating pharmacokinetic properties of lead candidates, and 4) assessing the therapeutic potential and side-effect profile of the most promising probes in relevant mouse pain models. This interdisciplinary collaboration leverages Northeastern University's expertise in pharmacology, computational modeling, and in vivo research methodologies to advance the development of novel non-opioid pain treatments.