Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain

by Selleckchem | Aug 19 2023

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.

Comments:

The passage you provided describes a study that investigated the potential of a TAK1 small molecule inhibitor called takinib to alleviate pain and inflammation in various models of chronic pain. TAK1 (Transforming growth factor beta-activated kinase 1) is known to play a crucial role in pro-inflammatory cytokine signaling in conditions such as cancer and autoimmune disorders.

The study used different models to represent inflammatory, neuropathic, and primary pain. Inflammatory pain was induced using complete Freund's adjuvant (CFA) injected into the paw, neuropathic pain was modeled using chronic constriction injury (CCI), and primary pain was induced by systemic delivery of the COMT inhibitor OR486. The behavioral responses to mechanical and thermal stimuli were evaluated in mice that received takinib or a vehicle before pain induction and over specific time periods following pain induction.

The results of the study demonstrated that inhibiting TAK1 with takinib significantly reduced hypersensitivity to mechanical and thermal stimuli in all three pain models. This reduction in hypersensitivity was accompanied by a decrease in the expression of pro-inflammatory cytokines in the dorsal root ganglia (DRG), which are clusters of sensory nerve cells located near the spinal cord. The study also found that TAK1 inhibition reduced the activity of nociceptive neurons in the DRG that were primed with tumor necrosis factor (TNF) and stimulated with capsaicin, a compound that activates pain-sensing neurons.

The findings suggest that TAK1 inhibition holds therapeutic potential as a novel drug target for the treatment of chronic pain syndromes with different underlying causes. By reducing pain and inflammation, TAK1 inhibitors like takinib could provide an alternative treatment option for chronic pain, potentially reducing the reliance on opioid-based pain medications. This research offers new perspectives on the development of therapies for chronic pain and may contribute to improved pain management strategies in the future.