ABSTRACT Osteoarthritis (OA), also known as degenerative joint disease, is a progressive disease that eventually leads to a functional disability making it the 11th most debilitating ailment worldwide and one of the greatest pressing current issues in public health. The most notable clinical symptom of OA is chronic joint pain that is gradual in onset and that worsens over time. The pain-related functional impairment is characterized by interference with many aspects of daily activity significantly decreasing quality of life. Despite reserved controversial recommendations by current guidelines due to dependency, abuse, tolerability and toxicity concerns, opioids are frequently prescribed for pain control when other pain management options have failed. The negative consequences of opioids evince a necessity for alternative route options for OA pain management. OA is a multifactorial disorder, which involves low-grade, chronic inflammation that is mediated, in part, by interleukin- 6/glycoprotein 130 (IL-6/gp130) cascade leading to gradual matrix degradation and irreversible destruction of articular cartilage. Recent studies have reported that IL-6/gp130 signaling is implicated in the development of inflammatory, pathological pain. Previously, we have demonstrated that manipulation of intracellular residues within gp130 receptor and its context specific downstream signaling can be deconstructed to selectively bypass the pro-inflammatory consequences of this axis while promoting beneficial outcomes. Our group has identified a signaling residue (Y814) within gp130 that represents an initiating factor responsible for the activation of a highly detrimental arm of gp130 and constitutive ablation of Y814 in mice inhibits development of injury-induced OA. To manipulate the destructive outputs downstream of gp130, including those regulated by Y814, we have synthesized a new class of small molecule compounds capable of selective inactivation of gp130 signaling and consequently protect articular cartilage in the knee from matrix degradation and reduce pain in rat and canine models of post-traumatic OA. Through multiple rounds of optimization, an analog that we termed R159 has shown the most potent and selective inhibition of gp130Y814 as well as an excellent absorption, distribution, metabolism, and excretion (ADME) profile. Current grant application is designed to systematically investigate the significance of gp130Y814 in the pathogenesis of OA and interrogate whether pharmacologically targeting this residue will attenuate OA-associated chronic pain. For this, we will first define the systemic pharmacokinetic parameters for R159 after oral and intraperitoneal administration to rats. Subsequently, we will determine the efficacy of systemically administered R159 in mitigating pain and functional and affective behaviors in a pre- clinical CFA-induced ankle OA rat and generalized OA guinea pig models. No conducted clinical trials till date have provided adequa...