Friday, May 9, 2025
5/9/2025
Translation Control of Pain Plasticity - In neurons, synaptic and intrinsic plasticity is dependent on the regulated control of mRNA translation. Over the past decade our work has focused on how translation regulation signaling is involved in neuronal plasticity that drives chronic pain. Our findings demonstrate that inflammatory and neuropathic injuries stimulate translation regulation signaling pathways in dorsal root ganglion (DRG) nociceptors, neurons that detect injurious or potentially injurious stimuli. The result of activation of these pathways is increased excitability of nociceptors, behavioral signs of ongoing pain and sensitization to mechanical and thermal stimulation. This body of work, supports the idea that therapeutics targeting translation regulation signaling pathways can be used for the efficacious treatment of chronic pain. Our overarching hypothesis for this continuing project is that MNK1 activation in nociceptors is the key regulatory factor for the translation of a subset of mRNAs that encode proteins that augment the excitability of nociceptors causing enhanced pain phenotypes. We will test this hypothesis using new transgenic mouse lines, cell type-specific translating ribosome affinity purification (TRAP), highly specific inhibitors of MNK1/2 and new generation inhibitors that are specific for MNK1. Our preliminary data indicates that the key MNK isoform for nociceptive behavioral plasticity is MNK1. Based on our electrophysiology experiments we hypothesize that the site of action for this kinase is in DRG neurons. Our first specific aim will test the hypothesis that MNK1 expression in nociceptors is a key driver of behavioral expression of chronic pain. We have created a TRAP line that expresses L10a-tagged ribosomes in neurons that express the Scn10a gene (Scn10aTRAP). In our second specific aim we will examine how translation of specific mRNAs is regulated in preclinical neuropathic pain models with and without genetic or pharmacological manipulations of MNK-eIF4E signaling. This will yield unprecedented molecular insight into plasticity-driven changes in gene expression in nociceptors in neuropathic pain. The third specific aim will focus on pharmacologically or genetically targeting mechanisms discovered using approaches in aims 1 and 2. For instance, our TRAP approach captures translational upregulation of the Mrgrpd receptor in a neuropathic model. We will use knockout mice to investigate the role of this receptor in sensory neuron excitability in neuropathic pain. The proposed specific aims will highlight a key regulatory pathway for neuropathic pain and give new insight into novel therapeutic targets for neuropathic pain.
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