CAPS Research
Permanent URI for this collectionhttps://hdl.handle.net/10735.1/7128
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Browsing CAPS Research by Author "Price, Theodore J."
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Item The Antidiabetic Drug Metformin Prevents and Reverses Neuropathic Pain and Spinal Cord Microglial Activation in Male but not Female Mice(Academic Press Ltd- Elsevier Science Ltd, 2018-11-01) Inyang, Kufreobong E.; Szabo-Pardi, Thomas; Wentworth, Emma; McDougal, Timothy A.; Dussor, Gregory; Burton, Michael D.; Price, Theodore J.; 0000-0002-6971-6221 (Price, TJ); Dussor, Gregory; Price, Theodore J.; Inyang, Kufreobong E.; Szabo-Pardi, Thomas; Wentworth, Emma; McDougal, Timothy A.Metformin is a widely prescribed drug used in the treatment of type II diabetes. While the drug has many mechanisms of action, most of these converge on AMP activated protein kinase (AMPK), which metformin activates. AMPK is a multifunctional kinase that is a negative regulator of mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling. Activation of AMPK decreases the excitability of dorsal root ganglion neurons and AMPK activators are effective in reducing chronic pain in inflammatory, post-surgical and neuropathic rodent models. We have previously shown that metformin leads to an enduring resolution of neuropathic pain in the spared nerve injury (SNI) model in male mice and rats. The precise mechanism underlying this long-lasting effect is not known. We conducted experiments to investigate the effects of metformin on SNI-induced microglial activation, a process implicated in the maintenance of neuropathic pain that has recently been shown to be sexually dimorphic. We find that metformin is effective at inhibiting development of neuropathic pain when treatment is given around the time of injury and that metformin is likewise effective at reversing neuropathic mechanical hypersensitivity when treatment is initiation weeks after injury. This effect is linked to decreased Iba-1 staining in the dorsal horn, a marker of microglial activation. Importantly, these positive behavioral and microglia effects of metformin were only observed in male mice. We conclude that the neuropathic pain modifying effects of metformin are sex-specific supporting a differential role for microglial activation in male and female mice.Item Transcriptome Analysis of the Human Tibial Nerve Identifies Sexually Dimorphic Expression of Genes Involved in Pain, Inflammation, and Neuro-Immunity(Frontiers Media S.A.) Ray, Pradipta R.; Khan, Jawad; Wangzhou, Andi; Tavares-Ferreira, Diana; Akopian, A. N.; Dussor, Gregory; Price, Theodore J.; Ray, Pradipta R.; Khan, Jawad; Wangzhou, Andi; Tavares-Ferreira, Diana; Dussor, Gregory; Price, Theodore J.Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms. © 2019 Ray, Khan, Wangzhou, Tavares-Ferreira, Akopian, Dussor and Price.