I managed to post this before it was ready, edited my post, then lost it all. So here's round two. A few pain related FTO papers for consideration for Race Therapeutics.
MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons
https://www.frontiersin.org/articles/10.3389/fphar.2021.673831/full
"Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis."
N6‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341103/
“This study explores the m6A epitranscriptional mechanism of neuropathic pain. Peripheral nerve injury produces the Runx1‐triggered FTO upregulation in the dorsal root ganglion (DRG). This upregulation contributes to nerve injury‐induced pain hypersensitivity through erasing Ehmt2 mRNA m6A, stabilizing Ehmt2 mRNA/G9a expression, and silencing mu opioid receptor expression in the injured DRG. FTO may be a new target for neuropathic pain treatment.”
“In summary, our study demonstrated that blocking the nerve injury‐induced DRG FTO increase mitigated neuropathic pain without changing basal or acute pain and locomotor function. This blockage also improved morphine analgesia and alleviated morphine analgesic tolerance development under neuropathic pain conditions. Given that the FTO inhibitor meclofenamic acid was approved by FDA as a nonsteroidal anti‐inflammatory drug,[ 59 , 60 ] blocking DRG FTO may have a potential clinical application in neuropathic pain management.”
Effect of Pharmacological Inhibition of Fat-Mass and Obesity-Associated Protein on Nerve Trauma-Induced Pain Hypersensitivities https://pubmed.ncbi.nlm.nih.gov/33829413/
"Genetic knockout or knockdown of fat-mass and obesity-associated protein (FTO), a demethylase that participates in RNA N6-methyladenosine modification in injured dorsal root ganglion (DRG), has been demonstrated to alleviate nerve trauma-induced nociceptive hypersensitivities. However, these genetic strategies are still impractical in clinical neuropathic pain management. The present study sought to examine the effect of intrathecal administration of two specific FTO inhibitors, meclofenamic acid (MA) and N-CDPCB, on the development and maintenance of nociceptive hypersensitivities caused by unilateral L5 spinal nerve ligation (SNL) in rats. Intrathecal injection of either MA or N-CDPCB diminished dose-dependently the SNL-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneous ongoing nociceptive responses in both development and maintenance periods, without altering acute/basal pain and locomotor function. Intrathecal MA also reduced the SNL-induced neuronal and astrocyte hyperactivities in the ipsilateral L5 dorsal horn. Mechanistically, intrathecal injection of these two inhibitors blocked the SNL-induced increase in the histone methyltransferase G9a expression and rescued the G9a-controlled downregulation of mu opioid receptor and Kv1.2 proteins in the ipsilateral L5 DRG. These findings further indicate the role of DRG FTO in neuropathic pain and suggest potential clinical application of the FTO inhibitors for management of this disorder."
Anyone with any knowledge on pain science? Could this have any impact on chemotherapy-induced peripheral neuropathy? Or how SNL results translate to drugs in the clinic?
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