Journal article
P2X7-NLRP3-Caspase-1 signaling mediates activity-induced muscle pain in male but not female mice
Pain (Amsterdam), Vol.164(8), pp.1860-1873
08/2023
DOI: 10.1097/j.pain.0000000000002887
PMCID: PMC10363217
PMID: 36930885
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 (NLRP) 3 and activates Caspase-1 to release IL-1β. We hypothesized that pharmacological blockade of P2X7, NLRP3, and Caspase-1 would prevent development of activity-induced muscle pain in vivo and release of IL-1β from macrophages in vitro. The decrease in muscle withdrawal thresholds in male, but not female, mice was prevented by the administration of P2X7, NLRP3, and Caspase-1 inhibitors before induction of the model, whereas blockade of IL-1β before induction prevented muscle hyperalgesia in both male and female mice. Blockade of P2X7, NLRP3, Capsase-1, or IL-1β 24 hours, but not 1 week, after induction of the model alleviated muscle hyperalgesia in male, but not female, mice. mRNA expression of P2X7, NLRP3, Caspase-1, and IL-1β from muscle was increased 24 hours after induction of the model in both male and female mice. Using multiplex, increases in IL-1β induced by combining adenosine triphosphate with pH 6.5 in lipopolysaccharide-primed male and female macrophages were significantly lower with the presence of inhibitors of P2X7 (A740003), NLRP3 (MCC950), and Caspase-1 (Z-WEHD-FMK) when compared with the vehicle. The current data suggest the P2X7/NLRP3/Caspase-1 pathway contributed to activity-induced muscle pain initiation and early maintenance phases in male but not female, and not in late maintenance phases in male mice.
Details
- Title: Subtitle
- P2X7-NLRP3-Caspase-1 signaling mediates activity-induced muscle pain in male but not female mice
- Creators
- Kazuhiro Hayashi - University of IowaJoseph B LesnakAshley N PlumbLynn A RasmussenKathleen A Sluka
- Resource Type
- Journal article
- Publication Details
- Pain (Amsterdam), Vol.164(8), pp.1860-1873
- DOI
- 10.1097/j.pain.0000000000002887
- PMID
- 36930885
- PMCID
- PMC10363217
- NLM abbreviation
- Pain
- ISSN
- 0304-3959
- eISSN
- 1872-6623
- Language
- English
- Electronic publication date
- 03/15/2023
- Date published
- 08/2023
- Academic Unit
- Iowa Neuroscience Institute; Nursing; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology
- Record Identifier
- 9984380460602771
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