Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

Abstract

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.

Graphical abstract

Fig. 1.

Regulation of eIF4E-mediated translation initiation. Extracellular factors, like cytokines and growth factors, induce intracellular signaling pathways that modulate eIF4E-dependent protein synthesis in a pathway-specific manner. Ras/Raf-MNK signaling phosphorylates eIF4E enhancing the expression of certain genes. Activation of mTORC1 relieves 4E-BP inhibition and thereby increases eIF4E-mediated translation. AMPK stimulation further fine-tunes translation initiation by inhibiting mTORC1 and Raf signaling. MEK, mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase.

Fig. 2.

Modulation of the integrated stress response. (A) The ternary complex, consisting of GTP-bound eIF2 and the initiator Met-tRNA_i, aids in the recognition of the start codon. The GTP bound to eIF2 is hydrolyzed upon encountering the start codon. The resulting GDP-eIF2 dissociates from the initiation complex and is recycled by eIF2B for the next round of initiation. Under cellular stress, four kinases (PERK, PKR, GCN2, and HRI) phosphorylate eIF2α at Ser51 and initiate the ISR, which inhibits global translation by sequestering available eIF2B. (B) Various small molecules are known to modulate the ISR, particularly by maintaining phosphorylation of eIF2α (e.g., salubrinal, guanabenz, and sephin1) or by activating eIF2B (e.g., ISRIB). (Ci) Phosphorylation of eIF2α stabilizes the interaction of two molecules of eIF2 with eIF2Bα and eIF2Bδ subunits of eIF2B, inducing a conformational rearrangement that prevents the GDP to GTP exchange and competes with the binding of Met-tRNA_i. In this manner, phospho-eIF2α acts as a noncompetitive inhibitor of eIF2B [Gordiyenko et al. (2019), PDB: 6QG0]. (Cii) ISRIB restores eIF2B levels by facilitating the binding of two tetramer subunits, particularly by interacting with eIF2Bδ and eIF2Bβ [Zyryanova et al. (2018), PDB: 6EZO]. (D) Although phosphorylation of eIF2α suppresses global translation, it induces the expression of certain genes, such as ATF4, CHOP, and GADD34. GADD34 is a stress-induced regulatory subunit of PP1, which dephosphorylates phospho-eIF2α to normalize translation. Recent structural and functional analysis shows that GADD34 promotes binding of PP1 and phospho-eIF2α via its lysine (K), valine (V), arginine (R), and phenylalanine (F).(KVRF) and proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) motifs, respectively [Choy et al. (2015), PDB: 4XPN]. The PEST sequences in GADD34 are not found in CreP, a constitutively active PP1 regulatory subunit, and may represent a novel target for the suppression of ISR-induced GADD34.

Fig. 3.

Other mechanisms of translation regulation. Despite a loss in the ternary complex after ISR, the synthesis of certain proteins, like CHOP and ATF4, is enhanced by leaky scanning (A) and delayed reinitiation (B) mechanism, respectively. The reduced availability of eIF2 in stressed conditions allows for the scanning ribosomes to bypass (i.e., leaky scanning) the uORF in the 5′ UTR and translate the mORF. This is the case for CHOP and GADD34. Some genes, like ATF4, contain multiple uORFs in which one of the uORFs overlaps with the mORF in an out-of-frame manner, thereby suppressing the expression of the main gene. During ISR, the delay in eIF2 recycling allows for the scanning ribosome to skip the start codon of uORF and instead translate the mORF.

Fig. 4.

Chemical structures of MNK inhibitors. LE, ligand efficiency; MW, molecular weight; TPSA, topological polar surface area.

Fig. 5.

(A) Key fragments and pyridone aminal 3. (B) Diversification points on pyridone aminal 4 and selected properties of eFT508. MW, molecular weight; TPSA, topological polar surface area.

Fig. 6.

Key scaffolds 5–7, optimized analogs 8–10, and selected properties of ETC-206.

Fig. 7.

The general structure of BAY 1143269 (11) and related analogs 12–15.

Fig. 8.

Evidence for localized translation in sensory axons in neuropathic pain. 1) Translation machinery is present in sensory neuron axons, such as mRNA, ribosomes, translation initiation factors (eIF2α, eIF4E, and eIF5), and translation regulators (ERK, p38, mTOR). 2) Sensory neuron mRNAs (ex: Nav1.8) are trafficked and translated locally in peripheral axons leading to ectopic activity. 3) Ribosomes and exosomes from Schwann cells (SCs) are trafficked into sensory axons (blue arrows). In myelinated axons, these ribosomes form ribosomal plaques that are located near the myelin-axon border. We hypothesize the same occurs between nonmyelinating SCs and nociceptive axons [i.e., in Remak bundles (top right panel)]. It is possible that the SC-axon cytoplasms become continuous after axotomy, forming a syncytium in which SCs aid in axonal translation during recovery.

Fig. 9.

Personalized treatment approaches for chronic pain. After injury and disease, translational regulation mechanisms alter protein synthesis, which forms the basis of enhanced excitability in sensory neurons and potentially also in central networks. As a result, patients with chronic pain experience evoked and spontaneous pain. Since the plasticity after injury and disease is unique to its pathology, we propose that individualized treatment avenues that specifically target the underlying pathology would best alleviate pain. To determine the course of treatment, skin biopsies can be obtained and analyzed for inflammatory mediators and translational regulators as well as sequenced for RNA profiling. Based on these personalized analyses of underlying molecular mechanisms, therapeutic development and decision making can be improved.