Abstract
Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium ion channel, TRPA1 plays an important role in pain and inflammation, thus becoming a new type of anti-inflammatory and analgesic target. However, there is no consensus on the role of this channel in mechanical hyperalgesia caused by inflammation. Here, we aim to explore the role and underlying mechanism of the inflammasome inhibitor CY-09 in two classic inflammatory pain models. We evaluated pain behavior on animal models, cytokine levels, intracellular Ca2+ levels, transient TRPA1 expression, NF-κB transcription, and NLPR3 inflammasome activation. Consistently, CY-09 reduced the production of inflammatory cytokines, intracellular Ca2+ levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury. Importantly, AITC (TRPA1 agonist) significantly reversed the analgesic effect of CY-09, indicating that TRPA1 was involved in the analgesic effect of CY-09. Our findings indicate that CY-09 relieves inflammation and pain via inhibiting TRPA1-mediated activation of NLRP3 inflammasomes. Thus, NLRP3 inflammasome may be a potential therapeutic target for pain treatment and CY-09 may be a pharmacological agent to relieve inflammatory pain, which needs further research.
Highlights
Pain is an unpleasant emotion and sensory experience resulting from tissue damage
In our study, based on the hypothesis that CY-09 can inhibit NLRP3 inflammasome formation and reduce Transient receptor potential ankyrin 1 (TRPA1) channel activation to alleviate inflammatory pain, we find that inhibition of TRPA1-mediated activation of NLRP3 inflammasomes is related to the analgesic effect of CY-09 on inflammatory pain
Mouse pain behavior was obvious and the foot tissue became swelling. 5 mg/kg of CY-09 obviously inhibited thermal hyperalgesia induced by LPS at 5 h (Figure 1(a)) and formalin 1 h (Figure 1(b)), respectively
Summary
Pain is an unpleasant emotion and sensory experience resulting from tissue damage. Inflammatory pain is mainly caused by intracellular ion accumulation and inflammatory mediator secretion, such as prostaglandin, serotonin, and bradykinin. Inflammatory pain is accompanied by many diseases, including diabetes, cancer, infection, autoimmune disease, chemotherapy, and trauma. Some inflammation, such as arthritis, can cause the central nervous system to be stressed too much, which leads to central sensitivity, and causes chronic pain and emotional distress to worsen [7]. People suffering from pain and inflammation are more depressed, leading to increased suicide rates and burden social and public security. Finding specific molecular targets and developing potent, safe, and low-tolerated analgesics become a hotspot in pain treatment research
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