Translational Control Mechanisms in Persistent Pain

• Published in: Trends in neurosciences (Regular ed.) Vol. 41; no. 2; pp. 100 - 114
• Main Authors: Khoutorsky, Arkady, Price, Theodore J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2018
• Subjects: Animals; Chronic Pain - metabolism; Chronic Pain - physiopathology; Humans; local protein synthesis; mRNA translation; Nociception - physiology; Nociceptors - metabolism; pain; Protein Biosynthesis - physiology; sensitization; Sensory Receptor Cells - metabolism; Signal Transduction - physiology; pain; mRNA translation; sensitization; local protein synthesis
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2017.11.006

Persistent pain, which is poorly treated and estimated to afflict one third of the world’s population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics. Persistent pain is largely mediated by the sensitization of nociceptive neurons. This sensitization relies on de novo gene expression to support biochemical and structural changes that maintain amplified pain signaling. Nerve injury and peripheral inflammation stimulate local translation from pre-existing mRNAs in nociceptive sensory neurons. The newly synthesized proteins act locally to increase neuronal excitability or are transported to the cell body to activate transcriptional gene expression programs. Eukaryotic initiation factor 4F (eIF4F) complex formation is a convergent point downstream of mammalian target of rapamycin (mTOR) and extracellular-signal-regulated kinase (ERK) signaling pathways to regulate cap-dependent translation and promote neuronal excitability, synaptic transmission, and pain. A cellular energy status sensor AMP-activated protein kinase (AMPK) emerges as an attractive target to normalize aberrant mRNA translation in pathological pain conditions. Metformin, an AMPK activator and US Food and Drug Administration (FDA)-approved antidiabetic drug, corrects abnormal mRNA translation and reverses enhanced neuronal excitability and pain hypersensitivity in a variety of animal models of chronic pain.