Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain.

Gene
Vaskar DasHee-Jeong Im

Abstract

Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clea...Continue Reading

Citations

Jul 12, 2019·PLoS Computational Biology·Jennifer CrodelleVictoria Booth
Jan 3, 2020·Pain·Vinko PaladaEija Kalso
Nov 24, 2020·Experimental Gerontology·Francesco Dernie, Daniel Adeyoju
Jul 3, 2021·Journal of Cellular and Molecular Medicine·Xiaopeng SongLi Gao
Aug 11, 2021·Neuroscience and Biobehavioral Reviews·Jacob R BumgarnerRandy J Nelson

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