Abstract
Acute pain serves as a protective mechanism, guiding the organism away from actual or potential tissue injury. In contrast, chronic pain is a debilitating condition without any obvious physiological function. The transition to, and the maintenance of chronic pain require new gene expression to support biochemical and structural changes within the pain pathway. The regulation of gene expression at the level of mRNA translation has emerged as an important step in the control of protein expression in the cell. Recent studies show that signaling pathways upstream of mRNA translation, such as mTORC1 and ERK, are upregulated in chronic pain conditions, and their inhibition effectively alleviates pain in several animal models. Despite this progress, mRNAs whose translation is altered in chronic pain conditions remain largely unknown. Here, we performed genome-wide translational profiling of dorsal root ganglion (DRG) and spinal cord dorsal horn tissues in a mouse model of neuropathic pain, spared nerve injury (SNI), using the ribosome profiling technique. We identified distinct subsets of mRNAs that are differentially translated in response to nerve injury in both tissues. We discovered key converging upstream regulators and pathways linked to mRNA translational control and neuropathic pain. Our data are crucial for the understanding of mechanisms by which mRNA translation promotes persistent hypersensitivity after nerve injury.
Highlights
Chronic pain debilitates over twenty percent of the population worldwide, and is the leading cause of long-term disability in humans (Souza et al, 2017)
We reasoned that the 30 day time point was appropriate for tissue collection in order to study the chronic phase of neuropathic pain
Translational control of gene expression has emerged as a prominent mechanism in the regulation of gene expression in pathological pain states (Price and Geranton, 2009; Melemedjian and Khoutorsky, 2015; Khoutorsky and Price, 2018)
Summary
Chronic pain debilitates over twenty percent of the population worldwide, and is the leading cause of long-term disability in humans (Souza et al, 2017). The most common chronic pain conditions include headache, low back pain, cancer pain, arthritis pain, and neuropathic pain, which can result from damage to peripheral nerves or to the central nervous system itself. The inadequate management of chronic pain is a consequence of our incomplete understanding of the mechanisms underlying the induction and maintenance of pain states, leading to treatments that only target symptomatology without addressing the etiology of the disease. Sensitization of nociceptive circuits, both in the central and peripheral nervous systems, leads to mechanical hypersensitivity (allodynia), which is a hallmark of many chronic pain conditions. This sensitization is supported by the expression of new genes, which are required for the biochemical and structural reorganization of the pain pathway.
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