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P2 × 7-NLRP3-Caspase-1 Signaling Mediates Activity-induced Muscle Pain in Male but Not Female Mice
Journal article   Peer reviewed

P2 × 7-NLRP3-Caspase-1 Signaling Mediates Activity-induced Muscle Pain in Male but Not Female Mice

Kazuhiro Hayashi, Joseph B. Lesnak, Lynn A. Rasmussen and Kathleen A. Sluka
The journal of pain, Vol.23(5), pp.58-58
05/2022
DOI: 10.1016/j.jpain.2022.03.217

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Abstract

We developed an animal model of activity-induced muscle pain that is dependent on local macrophage activation and release of interleukin-1β (IL-1β). Activation of purinergic type 2X (P2X) 7 receptors recruits the NOD-like receptor protein 3 (NLRP3) and activates caspase-1 release IL-1β. We hypothesized that pharmacological blockade of P2 × 7 receptors, NLRP3, and Caspase-1 would prevent the development of activity-induced muscle pain in vivo, and release of IL-1β in macrophages in vitro. Muscle pain was induced by 2, 20μl pH 5.0 injections, 5 days apart, in the gastrocnemius muscle combined with fatiguing muscle contractions in male and female C57BL6/J mice. To assess hyperalgesia, muscle withdrawal thresholds (MWT) of the gastrocnemius muscle were measured before and after induction of the model. Inhibitors of P2 × 7 (A740003), NLRP3 (MCC950), Caspase-1 (Z-WEHD-FMK) or IL-1β (antibody) were used to modulate the pathway. The decrease in MWT in male, but not female, mice was prevented by administration of P2 × 7, NLRP3, and Caspase-1 inhibitors prior to induction of the model, while blockade of Il-1β prior to induction attenuated hyperalgesia in both male and female mice (p<0.05). Blockade of P2 × 7, NLRP3, Capsase-1, or IL-1β 24h, but not 1 week, after induction of the model reversed hyperalgesia in male, but not female mice. Using multiplex, increases in IL-1β induced by combining ATP with pH 6.0 in LPS-primed male and female macrophages, were significantly lower with the presence of A740003 (male: 190.53pg/ml; female: 187.31pg/ml), MCC950 (male: 118.04pg/ml; female: 103.66pg/ml) and Z-WEHD-FMK (male: 307.19pg/ml; female: 219.88pg/ml) when compared to the vehicle (male: 624.99pg/ml, p<0.001; female: 467.47pg/ml, p<0.001). The current data suggests activation of P2 × 7, NLRP3, and Caspase-1 release IL-1β in male and female macrophages to initiate induction of activity-induced muscle pain only be in male mice. Grant support from NIH Grant AR073187, and JSPS Fellowship.

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