TARGETING NLRP3 INFLAMMASOME SIGNALING TO ALLEVIATE STRESS-INDUCED PAIN SENSITIZATION

Chronic stress is a key contributor to the development and persistence of chronic pain diseases, like fibromyalgia (FM), which is still an unmet medical need condition. Neuroinflammatory mechanisms, such as proinflammatory cytokines like interleukin-1 (IL-1), are essential for stress-induced pain sensitization. Therefore, we tested the effects of MCC950, a potent inhibitor of the NLRP3 inflammasome, responsible for IL-1 release, in mouse models of stress-induced FM-like pain.
We tested two FM mouse models using the chronic restraint stress (CRS) and intermittent cold stress (ICS) protocols. Mechanical pain sensitivity and cold tolerance of the hind paw were measured continuously. MCC950 (10 mg/kg) or vehicle was administered daily intraperitoneally from the beginning of each stress protocol. To exclude nonspecific behavioural effects, the potential sedative properties of MCC950 were evaluated using the open field test (OFT).
CRS induced a progressive mechanical hyperalgesia, reaching maximum threshold reduction of approximately 15–20% by the second week of stress, ICS elicited a similar effect by 2^nd day post-stress, in vehicle-treated, but not in the MCC950-treated animals. Stress exposure induced a significant cold hyperalgesia of 70-80%, which emerged during the first week of CRS and immediately after the ICS protocol, and was not affected by MCC950 administration. MCC950 did not exhibit a sedative effect in the OFT.
These findings demonstrate that NLRP3 inflammasome inhibition selectively attenuates stress-induced mechanical sensitization across multiple FM rodent models, supporting NLRP3 inflammasome as a potential novel therapeutic target for the treatment of FM-like pain.
TKP2021-EGA-16 and 13,RRF-2.3.1-21-2022-00015,RRF-2.3.1-21-2022-00011,FK146283,FK137951,K138046,ÚNKP-23-3,EKÖP-24-3-II,EKÖP-25-4-I-PTE-414