15-LOX-1 as a druggable target in the acute to chronic pain transition of rheumatoid arthritis

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PROJECT SUMMARY Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with a 0.5-1% worldwide incidence. Current therapies including steroids, biologics and nonsteroidal anti-inflammatory drugs (NSAIDs) targeting cyclooxygenases (COX) alleviate clinical signs of inflammation; however, joint pain characterized by mechanical hypersensitivity (allodynia) and functional disabilities (grip strength deficit, locomotor depression) along with psychiatric comorbidities (anxiety, depression) often remain well beyond resolution of peripheral inflammation. Thus, there exists a critical need for new therapeutics for the management of persistent arthritic pain. In the K/BxN serum transfer model of RA, allodynia during the early inflammatory phase is attenuated by conventional therapeutics (NSAIDs, the antiepileptic gabapentin, the TNFa receptor antibody etanercept, the partial mu opioid receptor agonist buprenorphine), but is only modestly reduced by gabapentin in the late post-inflammatory phase, indicating that the pathways targeted by these agents likely do not drive the chronification of arthritic pain. Transition to the neuropathic post-inflammatory allodynia is mediated by spinal Toll-like receptor 4 (TLR4), and intrathecal (IT) delivery of the TLR4 agonist Lipopolysaccharide (LPS) to model this transition phase produces tactile allodynia and grip strength deficits (a widely utilized rheumatological measure of musculoskeletal function) in both sexes. The lipoxygenase 15-LOX-1 has emerged as a viable target in disease models, and its bioactive metabolites (12/15-lipoxygenase metabolites; 12/15-LMs) contribute to allodynia at the spinal level. Our published and preliminary data demonstrate a critical role of spinal 12/15-LMs in mechanical pain hypersensitivity in rodents: i) 12/15-LMs activate multiple targets expressed in nociceptors; ii) intrathecal (IT) LPS (TLR4 agonist) produces allodynia in rodents and increases 15-LOX-1 expression; iii) spinal or systemic inhibition of 15-LOX-1, but not of COX, abrogates TLR4-mediated allodynia in rats and mice and iv) peripheral inflammation in rats or K/BxN serum transfer arthritis in mice induces spinal synthesis of 12/15-LMs and allodynia via several receptors. Given these observations, the proposed studies herein will test the overarching hypothesis that spinal 15-LOX activation mediates the transition from acute to chronic pain during K/BxN arthritis in males and females via 3 aims by investigating 1) the role of spinal 15-LOX-1 in the acute to chronic transition of pain in K/BxN arthritis 2) the cellular source(s) of spinal 15-LOX-1 and 3) the spinal receptor-mediated nociceptive effects of 15-LOX-1 metabolites using a variety of behavioral (tactile, grip strength, open field, clinical signs of inflammation), molecular and biochemical assays. Collectively, the expected results will address significant gaps in understanding of the mechanisms underlying sensory and affective components of chronic pain and interrogate 15-LOX-1 as a novel druggable target to impede activation of multiple downstream receptors in an alternative therapeutic strategy for treating arthritic pain states persisting after resolution of inflammation.