While much attention has been paid to changes in transcription, the regulation of protein synthesis has only recently been recognized as an important contributor to nociceptive plasticity (Price and Geranton, 2009). Control of gene expression at the level of translation affords DRG neurons a rapid and local mechanism through which to generate new proteins involved in the amplification of nociceptive signaling. We hypothesize that algogenic compounds engage signaling to the translational machinery in nociceptors and their axons to enhance the efficiency of the rate-limiting step of translation, elongation initiation. This would lead to the rapid, de-novo synthesis of proteins that can mediate acute sensitization and act as positive retrograde signals to elicit long-lasting changes in gene expression sustaining sensitization. Our preliminary findings indicate that the pro-nociceptive cytokine, interleukin 6 (IL-6), stimulates translation-mediated changes in gene expression in DRG neurons via activation of the ERK-MNK pathway which phosphorylates and activates the eIF4E elongation initiation complex. We also show that IL-6 leads to CREB protein synthesis via this pathway suggesting that this transcription factor may act as a positive retrograde signal to the cell body linking local IL-6 effects in the periphery to transcriptional changes in the nucleus sustaining long- term sensitization of these neurons. In this proposal we will address the following questions through our specific aims: 1) How does IL-6 signal to the translation machinery in DRG neurons? 2) Does IL-6 stimulate translation within the axonal compartment to generate retrograde signaling to the neuronal nucleus? 3) What is the role of IL-6-mediated translation control in IL-6-induced acute and latent nociceptor sensitization in vivo? The proposed research will provide essential information on mechanisms of IL-6-induced translation regulation in DRG neurons and their axons leading to nociceptor sensitization, potentially unveiling new mechanisms and new targets for the management of chronic pain.
Chronic pain is a major clinical problem with significant barriers to treatment. Changes in gene expression upon injury or disease are known causes for the chronification of pain but mechanisms underlying these effects are poorly understood. Through this research, we intend to discover novel mechanisms of regulation of gene expression, linked to translation control, which will enhance our understanding of how pain becomes chronic and potentially lead to the discovery of novel treatment avenues.
|Melemedjian, Ohannes K; Tillu, Dipti V; Moy, Jamie K et al. (2014) Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity. Mol Pain 10:45|
|Mao-Ying, Qi-Liang; Kavelaars, Annemieke; Krukowski, Karen et al. (2014) The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One 9:e100701|
|Melemedjian, Ohannes K; Mejia, Galo L; Lepow, Talya S et al. (2014) Bidirectional regulation of P body formation mediated by eIF4F complex formation in sensory neurons. Neurosci Lett 563:169-74|
|Kusne, Yael; Goldberg, Emily L; Parker, Sara S et al. (2014) Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice. Age (Dordr) 36:199-212|
|Boitano, Scott; Hoffman, Justin; Tillu, Dipti V et al. (2014) Development and evaluation of small peptidomimetic ligands to protease-activated receptor-2 (PAR2) through the use of lipid tethering. PLoS One 9:e99140|
|Asiedu, Marina N; Mejia, Galo L; Hübner, Christian A et al. (2014) Inhibition of carbonic anhydrase augments GABAA receptor-mediated analgesia via a spinal mechanism of action. J Pain 15:395-406|
|Kaila, Kai; Price, Theodore J; Payne, John A et al. (2014) Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci 15:637-54|
|Melemedjian, Ohannes K; Yassine, Hussein N; Shy, Adia et al. (2013) Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment. Mol Pain 9:14|
|Melemedjian, Ohannes K; Tillu, Dipti V; Asiedu, Marina N et al. (2013) BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Mol Pain 9:12|
|Price, Theodore J; Dussor, Gregory (2013) AMPK: An emerging target for modification of injury-induced pain plasticity. Neurosci Lett 557 Pt A:9-18|
Showing the most recent 10 out of 33 publications