This study investigates the role of p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion (DRG) neurons in the development and progression of chemotherapy-induced peripheral neuropathy (CIPN). This research evaluates whether inhibiting activation of p38 MAPK could reduce neuropathic outcomes in a transgenic breast cancer mouse model (C3TAg) and wild-type mice (FVB/N) treated with cisplatin. Cisplatin treatment stimulated p38 MAPK phosphorylation and nuclear translocation in DRG neurons. Neflamapimod, a specific inhibitor of p38 MAPK alpha (p38α), proven to be safe in clinical trials, inhibited neuronal cisplatin-induced p38 MAPK phosphorylation in vitro and in vivo. Neflamapimod also reduced cisplatin-induced oxidative stress, mitochondrial dysfunction, and cleaved caspase-3 expression in DRG neurons in vitro, protecting neuronal integrity and preventing axonal damage. Functionally, neflamapimod improved mechanical and musculoskeletal hyperalgesia, and cold sensitivity in cisplatin-treated mice, reversing neuropathic pain and neurotoxicity. This study identifies p38 MAPK activation as a critical driver of CIPN and highlights its potential as a therapeutic target for CIPN. Targeting p38 MAPK activation with neflamapimod offers a promising strategy to mitigate neurotoxicity and hyperalgesia without exacerbating cancer progression, positioning it as a novel intervention for CIPN.

Pain is a debilitating feature of hemophilia A (HA), yet it remains understudied. We developed models of chronic and acute pain in factor VIII knock-out (FVIIIKO; B6;129S-FVIIItm1Kaz/J), demonstrating characteristic features of hemarthrosis pain and gait. Using these models, we examined the mechanisms involving inflammation and vascular changes triggered by bleeding to produce pain. To recapitulate hemarthrosis, we utilized an acute knee-injury model to assess acute pain. We observed an increase in nocifensive behaviors, mechanical and deep tissue hyperalgesia, impaired weight bearing and gait changes 4 days post-subpatellar injury which persisted through 8 weeks. The uninjured FVIIIKO mice showed similar changes in behaviors and gait at 10 weeks of age, suggestive of chronic pain. Dynamic gait changes indicated compensatory behavior. Hemarthropathy induced a significant elevation in circulating serum amyloid P (SAP) and interleukin (IL)-6 and the injured knee joint showed a significant increase in neutrophil elastase, myeloperoxidase, mast cell degranulation, substance P (SP) and calcitonin gene related peptide (CGRP) suggestive of global inflammation. SP and CGRP stimulate vascular permeability and arteriolar dilatation, respectively, but are also involved in the generation and maintenance of pain. Mast cell tryptase and neutrophil elastase activate protease-activated receptor 2, which causes nociceptor activation leading to pain. Recombinant FVIII treatment led to partial improvement in pain behaviors. Thus, pain may persist following current HA treatments. Our study shows that a mouse model of HA can be used to study the mechanisms of pain and gait, which will enable us to develop treatable targets for pain in HA.