Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain.
Date
2023-04
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Attention Stats
Abstract
The origin of chronic pain is linked to inflammation, characterized by increased levels of pro-inflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of pro-inflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the COMT inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the dorsal root ganglia of Gcamp3 mice. In all three models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of pro-inflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments.
Type
Department
Description
Provenance
Subjects
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Scarneo, Scott, Xin Zhang, Yaomin Wang, Jose Camacho-Domenech, Jennifer Ricano, Philip Hughes, Tim Haystead, Andrea G Nackley, et al. (2023). Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain. The journal of pain. p. S1526-5900(23)00402-9. 10.1016/j.jpain.2023.04.011 Retrieved from https://hdl.handle.net/10161/27524.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Xin Zhang
Dr. Xin Zhang is an Adjunct Assistant Professor in the Department of Anesthesiology’s Center for Translational Pain Medicine (CTPM) at Duke University and a Professor at Nanjing Medical University in China. With a doctoral degree in the pain field and 20 years of clinical experience, he possesses a unique perspective on translating preclinical research to patient care. During his postdoctoral fellowship in Dr. Andrea Nackley's lab, Xin’s research focused on chronic primary ‘overlapping’ pain syndromes (CPPCs). He demonstrated the involvement of peripheral β2- and β3-adrenergic receptors in driving nociception and persistent pain, and the link between CPPCs and depressive disorders mediated by heightened catecholaminergic tone. Xin continues to collaborate on the development and validation of novel CPPC mouse models for in vivo discovery and screening of novel analgesic therapeutics.
Timothy Arthur James Haystead
Haystead, Timothy. Using chemical biology approaches to define novel drug targets for the treatment of hypertension, obesity, cancer, inflammatory and infectious disease.
Research Interests
The major focus of my laboratory is the discovery and development of novel small molecule inhibitors targeting purine-utilizing proteins involved in various aspects of human disease. Specific targets of interest include heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), fatty acid synthase, acetyl CoA Carboxylase, DAPK3 (ZIPK), PIM kinases, dengue fever non-structural protein 5 (NS5) and TAK1 (haysteadlab.com). Hsp90, Hsp70 and fatty acid synthase all have cancer and antiviral therapeutic indications and we are actively developing a series molecules specifically targeting these proteins that were scratch discovered in our laboratory. We have also developed a series of novel imaging molecules based on our Hsp90 inhibitor series that have utility as both diagnostics and potentially curative strategies for a number human cancers and viral infections. Our DAPK(ZIPK) and PIMK inhibitors have shown indications as anti-hypertensive agents as well as having utility in preventing reperfusion injury after stroke. Our TAK1 inhibitor program (discovered with the Derbyshire Laboratory, Department of Chemistry, Duke) has defined a highly potent and selective inhibitor of TAK1 kinase an important protein kinases thought to mediate the actions of proinflammatory cytokines such as TNFa, IL1 and TGFb. The foundations of these programs are based on the development a chemoproteomic strategy utilizing affinity methods combined with in house organic synthetic chemistry.
Andrea Gail Nackley
Pain is a multidimensional sensory and emotional experience that is important for our survival, but once pain becomes chronic it is no longer beneficial and, instead, becomes a disorder in and of itself. Chronic pain remains one of our nation’s most significant healthcare problems due to a limited understanding of the underlying genetic and environmental factors. There are three main objectives of our lab’s research in this area:
- To determine the factors that put some people, but not others, at risk for maladaptive chronic pain conditions. To achieve this objective, we study genetic, biological, and environmental factors associated with the initial onset of pain as well as its severity and duration. In addition, we are beginning to study factors associated with patient-centered outcomes, which may have the power to predict optimal management strategies for different individuals.
- To elucidate the mechanism(s) whereby genetic, biological, and environmental factors drive chronic pain. To achieve this objective, we integrate molecular genetics, animal models, and clinical epidemiologic measures in order to reveal pathogenic processes that are unique to as well as common across a particular condition or individual(s). This line of inquiry will provide novel targets for the development of individualized therapeutics for the management of chronic pain.
- To improve pharmacologic management of pain. To achieve this objective, we conduct pre-clinical studies to test the efficacy of new compounds and to optimize the efficacy of existing compounds in patient-relevant animal models.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.