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. Author manuscript; available in PMC: 2020 Dec 7.
Published in final edited form as: Wiley Interdiscip Rev RNA. 2019 May 14;10(6):e1546. doi: 10.1002/wrna.1546

RNA Control in Pain: Blame it on the Messenger

June Bryan I de la Peña 1, Jane J Song 1, Zachary T Campbell 1
PMCID: PMC7721054  NIHMSID: NIHMS1651088  PMID: 31090211

Abstract

mRNA function is meticulously controlled. We provide an overview of the integral role that post-transcriptional controls play in the perception of painful stimuli by sensory neurons. These specialized cells, termed nociceptors, precisely regulate mRNA polarity, translation, and stability. A growing body of evidence has revealed that targeted disruption of mRNAs and RNA-binding proteins robustly diminishes pain-associated behaviours. We propose that the use of multiple independent regulatory paradigms facilitates robust temporal and spatial precision of protein expression in response to a range of pain-promoting stimuli.

Graphical Abstract

graphic file with name nihms-1651088-f0001.jpg

A key function of the peripheral nervous system is detection and amplification of pain promoting cues. Here we summarize multiple lines of evidence in support of the notion that mRNA localization, stability, and translation serve integral functions in pain signals originating from sensory neurons.

Introduction

Pain generates tremendous human suffering. Advances in our understanding of its origins have the potential to yield new targets for therapeutic development. The peripheral nervous system reacts to potentially harmful cues with appropriate behavioural responses through a process called nociception. This conserved process ensures survival through avoidance of additional tissue damage (Tracey, 2017). However, when pain transitions into a chronic phase, it greatly diminishes quality of life. A variety of cues promote pain including changes in temperature (e.g. heat or cold), certain chemicals (e.g. capsaicin), inflammatory mediators (e.g. nerve growth factor, interleukin 6), and mechanical stimuli (e.g. pressure, poke, etc…). Not all pain is nociceptive in origin. Damage to the nervous system can cause neuropathic pain, which unlike nociceptive pain, does not always have a clear stimulus (e.g. phantom limb pain). Here, we describe five lines of evidence supporting the notion that mRNA regulation is integral to pain signalling. They are: (1) identification of essential RNA-binding proteins for sustained changes is nociceptor activity, (2) pharmacology that implicates the structural features in mRNA as therapeutically relevant, (3) perturbations in cap-dependent mRNA translation result in reduced pain sensitivity, (4) discovery of miRNAs that regulate key mRNAs in nociceptors, and finally, (5) emerging evidence that targeted destabilization of mRNAs with therapeutic oligonucleotides can robustly diminish certain forms of pain.

A key role for nociceptors

Nociceptors are specialized sensory neurons tasked with receiving information from the environment and relaying it to the central nervous system (Figure 1). Nociceptors are not identical. Distinctive patterns of gene expression enable subspecialisation. Nociceptors vary with respect to conduction velocity, diameter, and responsiveness. These attributes form the basis of their classification (Table 1). The unusual anatomy of these neurons is intimately linked to their function. Their nuclei are housed in specialized tissues termed the trigeminal ganglion (TG) in the head or the dorsal root ganglion (DRG) along the spinal cord. Approximately half of the neurons in these tissues are nociceptors. The nociceptor cell body (also known as the soma) contains organelles and the nucleus. Projecting away from the cell body is an axon with two branches. One end project back to the spinal cord and synapses with interneurons which in turn relay pain signals to the brain. The opposing branch innervates the skin and detects noxious stimuli (e.g. heat, cold, mechanical stimuli, inflammatory cues, etc.). The axon is encased by Schwann cells which are shed as they penetrate the keratinocyte layer. In the skin, the axon forms complex branched networks and contacts numerous cell types including fibroblasts and keratinocytes. A growing body of evidence suggests that these cells also contribute to nociceptive behaviours (Moehring, Halder, Seal, & Stucky, 2018). Thus, axons play a critical role in both detection of noxious cues and as mediators of signal propagation through action potentials from the periphery to the central nervous system (CNS).

Figure 1 –

Figure 1 –

Nociceptor anatomy. Potential damaging stimuli are sensed by nerve endings in the skin that can detect inflammatory mediators (e.g. NGF, IL-6). Nociceptor axons are coated with Schwann cells which support its structure and conductance. The nociceptor cell body is situated in the trigeminal ganglion or dorsal root ganglion (DRG). Signals received in the skin are relayed by axons back to the dorsal horn of the spinal cord. Information is then forwarded to the central nervous system for further processing via ascending fibres along the spinal cord.

Table 1:

Classification of nociceptors

Type Activated by Fiber type Myelination Diameter (μm) Conduction velocity (m/sec) Pain characteristic
Mechanical Intense mechanical stimulus Myelinated 1–5 5–40 Fast, sharp, pricking pain.
Thermal Intense thermal (hot or cold) stimulus
Polymodal Intense mechanical or thermal stimulus; specific chemicals C Unmyelinated 0.2–1.5 0.5–2 Burning, aching, sore pain.

Beyond their roles in information relay from the periphery, nociceptors have emerged as key players in persistent pain (Barragan-Iglesias et al., 2018; Bogen, Alessandri-Haber, Chu, Gear, & Levine, 2012; Ferrari, Bogen, Chu, & Levine, 2013a; Ferrari, Bogen, & Levine, 2013; Inceoglu et al., 2015; Khoutorsky et al., 2016; Melemedjian et al., 2010; Moy et al., 2017; J. T. Xu et al., 2014). Generally, they are electrically silent and transmit all or none action potentials when stimulated (Dubin & Patapoutian, 2010). Injury changes the neurochemical and electrophysiological phenotypes of these neurons leading to persistent hyperexcitability that lasts for days or even weeks. These phenotypic changes outlive the healing process and contribute to abnormally increased sensitivity to noxious stimuli (referred to as hyperalgesia). Long-term changes in the electrophysiological activity of nociceptors, called plasticity, is thought to be a major driver of spontaneous pain (Khoutorsky & Price, 2018). What mediates the persistence of these signals? A potential mechanism that evokes the idea of synaptic plasticity is to control neurotransmitter release at the synapse between the nociceptor and the spinal cord in the dorsal horn (Todd, 2010). While this is an intuitive short-term solution, longer-term changes require sustained responses that appear to be driven largely by translation of mRNA (Alvarez, 2001; Alvarez, Giuditta, & Koenig, 2000; Khoutorsky et al., 2015; Price & Geranton, 2009). New insights into mRNA function within nociceptors suggests a plethora of mechanisms that contribute to nociceptor plasticity.

Location, location, location

In neurons, translation can occur in the cell body, dendrites, or axons (Bramham & Wells, 2007; Brittis, Lu, & Flanagan, 2002). The latter two cases are examples of “local translation” (Medioni, Mowry, & Besse, 2012). De novo translation of newly transcribed transcripts in the cell body would require approximately 250 hours based on a transit distance of one meter (Buxbaum, Yoon, Singer, & Park, 2015). Neurons in the peripheral nervous system have the longest axons in the body. As a solution to generate new proteins, these neurons rely heavily on translation of pre-existing localized mRNA. The mechanism of local protein synthesis enables on-demand synthesis of polypeptides near or at the site where they are required and provides a means to rapidly modulate cellular phenotypes. The requirements for local translation include ribosomes, mRNA targets, and regulatory factors to ensure that the ribosomes are poised to translate the correct targets at the appropriate point in time. A variety of stimuli trigger local protein synthesis. For example, learning and memory promote translation of immediate early genes in dendrites (Jimenez-Diaz et al., 2008; Steward, Farris, Pirbhoy, Darnell, & Driesche, 2014; Steward & Levy, 1982). How these mechanisms contribute to pain is unclear. A growing body of evidence indicates that ribosomes present in axons catalyse protein synthesis which raises the question of how local translation is regulated in nociceptors and which mRNAs are the relevant targets (Barragan-Iglesias et al., 2018; Kar, Lee, & Twiss, 2018).

Anatomy of an mRNA

Regulatory information present in mRNA enables meticulous control. These controls can occur at the level of splicing, editing, translation, stability, and subcellular localization. In aggregate, they determine the amount, timing, and site of protein synthesis. What then dictates polarity in the distribution of mRNAs in the cytoplasm? Part of the answer can be found within the mRNA itself. mRNA is resplendent with regulatory information (Figure 2A). Virtually every portion of the mRNA is subject to reversible or irreversible modifications. For example, the presence of an m7G cap protects the mRNA from 5’ to 3’ exonucleolytic decay (Yanagiya et al., 2012). The cap also plays a central role in translation via the cytoplasmic cap-binding complex (referred to as eIF4F) consisting of the cap-binding protein (eIF4E), a DEAD-box RNA helicase (eIF4A), and a scaffold (eIF4G) (Gingras, Raught, & Sonenberg, 1999; Matsuo et al., 1997; Sonenberg, Morgan, Merrick, & Shatkin, 1978). One way eIF4F stimulates translation is through recruitment of the small ribosomal subunit. Removal of the cap by cytoplasmic decapping enzymes (e.g. dcp2) renders the 5’ end susceptible to exonucleases. Recently described cytoplasmic recapping enzymes may allow specific transcripts to resist decay (Otsuka, Kedersha, & Schoenberg, 2009). Immediately following the cap is the 5’ untranslated region (UTR). The 5’ UTR is a critical source of regulatory information encoded by sequences and structures. Examples include internal ribosomal entry sequences (IRES) that promote translation through direct binding to translation factors and/or ribosomes (Hellen & Sarnow, 2001). Upstream open reading frames (uORFs) have emerged as a major regulatory mechanism to downregulate the main open reading frame but also appear to have the potential to generate functional peptides or N-terminal extensions (Hellen & Sarnow, 2001; Starck et al., 2016; Y. Xu et al., 2019). In rare cases, such as during environmental stress, uORFs can enhance translation of the main reading frame (Hinnebusch, Ivanov, & Sonenberg, 2016). Secondary structures present in the 5’ UTR can also influence translation through an increased dependence on helicases such as eIF4A (Feoktistova, Tuvshintogs, Do, & Fraser, 2013; Garcia-Garcia, Frieda, Feoktistova, Fraser, & Block, 2015).

Figure 2 –

Figure 2 –

(A) Anatomy of an mRNA. mRNAs are typically capped (black ball). Immediately afterwards is a 5’ untranslated region (UTR) rendered here with a secondary structure that can modulate translation efficiency or mediate bypass of general translation factors. The coding sequences (CDS) contain the primary sequence of the polypeptide that results from translation. This is followed by a 3’ UTR rich in regulatory elements decoded by trans-acting RNAs (e.g. miRNAs) and RNA-binding proteins (RBPs). Most mRNA have a poly(A) tail at the 3’ end. (B) Regulation of cap-dependent translation initiation. The eIF4F complex containing eIF4A, eIF4E, and eIF4G recruits eIF3 and ribosomes to scan the mRNA for a suitable start codon. This process is controlled by MAPK kinases such as ERK that act via MNK to phosphorylate eIF4E. A second pathway controls eIF4E activity through mTORC1 which phosphorylates 4EBPs preventing their association and sequestration of eIF4E. Additionally, the association of eIF4G and the poly(A) binding protein (PAB) stimulates the efficiency of translation initiation. (C) An overview of eIF2α-dependent translation. Upstream kinases control the activity of eIF2. Phosphorylation of the α subunit inhibits the guanine nucleotide exchange factor eIF2B, resulting in bulk translational inhibition.

The coding region has emerged as a major player in mRNA stability (Hanson & Coller, 2018; Presnyak et al., 2015). In somatic cells, the distribution of optimal codons is directly proportional to mRNA stability which in turn is linked to protein output. The situation appears to be more complex in neurons where codon optimality is not directly linked to stability (Burow et al., 2018). This could provide a mechanism to amplify the regulatory effects of trans-acting factors over mRNA decay specifically in neurons. The coding region is controlled by additional pathways including RNA editing by ADAR enzymes that convert adenosine to inosine (Bass, 2002). Subsequent decoding by the ribosome results in recoding of inosine as guanine. Exceptionally efficient editing of the ionotropic AMPA glutamate receptor 2 in the brain renders the channels Ca2+-impermeable and is required for certain forms of learning and memory (Sommer, Kohler, Sprengel, & Seeburg, 1991). AMPA receptors play critical roles in spinal nociceptive transmission suggestive of a potential link between RNA editing and pain (Larsson & Broman, 2008; Tao, 2012).

The 3’ UTR is a key repository for regulatory information in the form of cis-acting elements. The 3’ UTR can contain elements that enhance or reduce RNA stability, translation, or localization. A prototypical example are miRNA binding elements. The 3’ ends of mRNA are also dynamic. Through a process conceptually similar to alternative splicing (though mechanistically distinct), alternative polyadenylation (APA) allows for rapid modulation of 3’ UTR length (Masamha et al., 2014; Mayr & Bartel, 2009). APA is critical to the survival of motor neurons and likely has major implications for which transcripts are destined to be translated locally (Gray et al., 2018).

Immediately following the 3’ UTR is the poly(A) tail. The number of adenosines in the poly(A) tail is subject to modulation through deadenylation and polyadenylation. Both processes can be controlled by cytoplasmic enzymes whose specificity appears to be dictated by recruitment through RNA-binding protein partners (Goldstrohm & Wickens, 2008). Loss of the poly(A) tail stimulates decapping and subsequent decay (Chen & Shyu, 2011). Additional modifications to the 3’ end include uridylation and guanylation (Lim et al., 2014; Lim et al., 2018). These newly discovered modifications have opposing effects on stability and may serve unexplored functions in sensory neurons. Knowledge of the corresponding polymerases provides the basis to probe their biological functions.

Cap-dependent translation

Nascent protein synthesis can be modulated in an activity-dependent fashion. One signalling cascade that links translation to extracellular factors is mTORC1 (Figure 2B). mTORC1 phosphorylates 4E-binding proteins (4EBPs) resulting in their sequestration and an increase in free eIF4E. eIF4E binds to the mRNA cap and nucleates the assembly of the eIF4F complex. Inhibition of mTORC1 with rapamycin (and related compounds) attenuates mechanical hypersensitivity in many models of inflammatory-, cancer-, and injury-induced pain (Geranton et al., 2009; Jimenez-Diaz et al., 2008; Price et al., 2007). eIF4E is also controlled by MAP kinase-interacting kinases (MNKs) which phosphorylate eIF4E and may enhance translation of a subset of transcripts (Altman et al., 2013; Gelinas et al., 2007; Konicek et al., 2011; Megat et al., 2019; Moy et al., 2017; Panja et al., 2009; Robichaud et al., 2018; Ueda et al., 2010).

Two inflammatory mediators, nerve growth factor (NGF) and interleukin 6 (IL6) rapidly induce nascent protein synthesis in nociceptors (Melemedjian et al., 2010). They also increase phosphorylation of mTORC1, eIF4E, eIF4G, and 4EBP1. Blocking either mTORC1 or MNK1 (e.g. by Cercosporamide treatment) attenuates mechanical hypersensitivity resulting from injection of NGF or IL-6 (Melemedjian et al., 2010; Moy et al., 2017). Similarly, inhibition of the eIF4F assembly with a small molecule (4EGI1) that impairs binding of eIF4E to eIF4G reduces pain amplification behaviour. As all the compounds in these experiments were injected into the paw, these data suggest that local translation in afferent fibers is required for the pain amplification behaviour. This raises the question – what are the relevant targets of mTOR required for the maintenance of pain?

A major hindrance to translational profiling of tissues is cellular heterogeneity. One approach to overcome this problem is the use of translating ribosome affinity purification (TRAP) (Heiman et al., 2008). TRAP was recently applied to understand translational responses of sensory neurons in animals with neuropathic pain elected by a chemotherapeutic (Paclitaxel) (Megat et al., 2019). In this study, an epitope tagged ribosomal subunit (l10a) was expressed exclusively in nociceptors. Sequencing of ribosome-bound transcripts revealed that components of the mTOR pathway are preferential targets of translation. Similar to the IL6 and NGF model, chemotherapy-induced nociceptor plasticity is driven by sustained eIF4E phosphorylation. The pain-associated behavioural effects of paclitaxel were reversed upon injection of the MNK inhibitor, eFT508. This suggests that pharmacological disruption of cap-dependent translation may provide a means to reverse neuropathic pain states. Consistent with this notion, elimination of the sole phosphorylation site on eIF4E results in profound deficits in pain behavioural responses to inflammatory mediators (Moy et al., 2017). Two key questions remain. First, what is the relevant target of eIF4E driven translation? And second, does the target need to be translated locally or in the soma?

In addition to 4EBPs, mTORC1 targets p70S6K1 and p70S6K2 (S6K1/2). The role of S6K1/2 in pain does not appear to be as prominent as 4EBPs (Melemedjian et al., 2013). Deletion of S6K1/2 in mice does not impact thermal sensitivity but increases sensitivity to mechanical stimuli. A possible explanation for the sensitivity is increased Erk phosphorylation. Thus, animals with genetic loss of S6K1/2 appear to have hyperactive eIF4E phosphorylation which may obscure the role of S6Ks.

Sequence specific RNA-binding proteins

RNA-binding proteins (RBPs) collaborate to control mRNA function. Several RBPs have been associated with various pain conditions (Table 2; for in depth review see (de la Pena & Campbell, 2018)). Some of these RBPs have well characterized roles in activity-dependent mRNA trafficking in the CNS. For instance, Fragile X mental retardation protein (FMRP) binds and regulates the translation of plasticity-relevant transcripts in the synapse (Darnell & Klann, 2013). Loss of FMRP leads to Fragile X syndrome, a neurodevelopmental disorder characterized by autistic behaviour, cognitive impairment, and learning disabilities. Mice with genetic deletion of the FMRP gene exhibit altered nociceptive sensitization (Price et al., 2007). Additionally, mTOR inhibition fails to block inflammation-associated pain in these mice suggestive of major defects in plasticity. Mechanical hypersensitivity caused by IL-6 is also abrogated in FMRP-deficient animals. Why does loss of FMRP compromise pain sensitization? As FMRP promotes translation elongation (Darnell et al., 2011), one possibility is that the rate of protein synthesis in fibres is carefully regulated to ensure proper timing of protein synthesis following a noxious challenge.

Table 2:

RBPs implicated in pain

RBP Pain condition Relevant findings Reference
Fragile X mental retardation protein (FMRP) Inflammation and neuropathic pain Mice with genetic deletion of the FMR gene showed decreased nociceptive response. (Price et al., 2007)
HuD or ELAV Like RNA Binding Protein 4 (Elavl4) Antiretroviral toxic neuropathy An ASO against HuD reverted pain hypersensitivity in mice. (Sanna, Peroni, Quattrone, Ghelardini, & Galeotti, 2015)
HuR or ELAV Like RNA Binding Protein 1 (Elavl1) Multiple Sclerosis related neuropathic pain Spinal HuR silencing alleviated hypernociceptive behaviour in mice. (Sanna, Quattrone, & Galeotti, 2017)
eukaryotic translation initiation factor 4E (eIF4E) Inflammation and neuropathic pain Phosphorylation of eIF4E, at serine 209, is a key factor in nociceptor sensitization and the development of chronic pain. (Moy et al., 2017)
Cytoplasmic polyadenylation element binding protein (CPEB) Inflammation and neuropathic pain Blocking CPEB reduced hyperalgesia and mechanical allodynia. (Bogen et al.,2012; Iida et al., 2016)
Poly(A)-binding protein (PABP) Inflammation and injury Local delivery of a PABP SPOT-ON blocked mechanical hyperalgesia induced by pro-inflammatory cytokines, capsaicin, or incision. (Barragan-Iglesias et al.,2018)

The Hu family of RBPs enhances the stability of transcripts by binding to adenylate-uridylate-rich elements (AU-rich elements) in the 3′ UTR (Antic, Lu, & Keene, 1999). Depletion of some members of the Hu family (HuR and HuD) attenuates neuropathic pain in mice, suggesting that these RBPs facilitate pain, likely at the level of RNA stability. A major unresolved question is the identity of the relevant targets and mechanisms of action responsible for attenuation of pain.

CPEBs are RNA-binding proteins that modulate poly(A) tail length. They bind AU-rich sequences found in the 3’UTR and can activate or repress polyadenylation as a direct result of post-translational modifications (Hodgman, Tay, Mendez, & Richter, 2001). Protein partners can also influence their binding specificity (Campbell, Bhimsaria, et al., 2012; Campbell, Menichelli, et al., 2012; Menichelli, Wu, Campbell, Wickens, & Williamson, 2013; J. Wu, Campbell, Menichelli, Wickens, & Williamson, 2013). Knockdown of CPEB through intrathecal injection of a CPEB ASO blocks nociception and mechanical hyperalgesia (Bogen et al., 2012). Deletion of CPEB3 results in thermal hypersensitivity (Fong, Lin, Wu, Chen, & Huang, 2016). Alpha calmodulin-dependent protein kinase II (αCaMKII) has been suggested as the downstream target of CPEB (Ferrari, Bogen, & Levine, 2013). The next logical question becomes: is αCaMKII the sole relevant target?

Poly(A)-binding proteins (PABPs) regulate mRNA stability, translation initiation, mRNA localization, mRNA export, nonsense mediated decay, and miRNA mediated translational repression (Gorgoni & Gray, 2004). The association of PABP with mRNA is linked to the length of the poly(A) tail and its translation (Gorgoni & Gray, 2004; Smith, Blee, & Gray, 2014). We have demonstrated that stabilized RNAs that mimic the poly(A) tail function as a competitive inhibitor of PABP, attenuate translation at initiation, and block mechanical hypersensitivity triggered by various inflammatory cues (Barragan-Iglesias et al., 2018). This inhibitor, termed specificity-derived competitive inhibitor oligonucleotides or SPOT-ON, is compact, taken up by neurons, and well-tolerated in vivo. The simplicity of its design is enabled by advances in unbiased assessment of RNA-protein interactions (Campbell, Valley, & Wickens, 2014; Campbell & Wickens, 2015; Zhou et al., 2018). The robust anti-hyperalgesic behavioural effects of the poly(A) decoy suggest that SPOT-ONs can be used to elucidate mechanisms underlying chronic pain and provide a new strategy for the identification of targets relevant to pain.

The poly(A) tail

Noxious stimuli can trigger long-term changes in nociceptor sensitivity. Intriguingly, certain forms of peripheral plasticity are blocked by peripheral administration of cordycepin, an inhibitor of polyadenylation (Ferrari, Araldi, & Levine, 2015; Ferrari, Bogen, Chu, & Levine, 2013b). Importantly, transcriptional inhibitors can prevent the initial onset of pain but fail to reverse hyposensitivity (Ferrari, Bogen, Reichling, & Levine, 2015). Taken together with the above-mentioned role of CPEB and PABP, these findings suggest that the poly(A) tail is important for the persistence of pain hypersensitivity. Advances in high throughput sequencing of poly(A) tails may provide a means to identify transcripts that undergo regulated polyadenylation, in axons and cell bodies, during the development of nociceptive sensitization (Lim et al., 2014).

eIF2α and the integrated stress response

Eukaryotic initiation factor 2 (eIF2) is an integral player in cellular stress response and nociception (Figure 2C) (Khoutorsky et al., 2016; Sidrauski, McGeachy, Ingolia, & Walter, 2015). Phosphorylation of the α subunit attenuates nascent translation specifically at the step of initiation (Holcik & Sonenberg, 2005). The net effect of eIF2α phosphorylation is inhibition of a second translation factor called eIF2B that mediates formation of the ribosomal pre-initiation complex. eIF2α resides at the heart of a regulatory network called the integrated stress response (ISR). Four upstream kinases control eIF2α phosphorylation. These include the viral sensor PKR (double-stranded RNA-dependent protein kinase); an ER stress responsive kinase called PERK (PKR-like ER kinase); a nutrient sensor GCN2 (general control non–derepressible-2); and the heme sensor HRI (heme-regulated inhibitor). Phosphorylation of eIF2α is increased in a model of chronic inflammatory pain (Khoutorsky et al., 2016). Heterozygous mice defective in eIF2α phosphorylation display enhanced thermal sensitivity. Intriguingly, these mice have no deficits with respect to mechanical perception but have reduced sensitivity to inflammatory pain. eIF2α phosphorylation has also been linked to neuropathic pain (Barragan-Iglesias et al., 2019). Methyl glyoxal, a reactive glycolytic metabolite associated with painful diabetic neuropathy, robustly increases eIF2α phosphorylation through PERK. The small molecule ISRIB is a robust initiator of PERK signalling that can reverse the effects of eIF2α phosphorylation and restore translational homeostasis through direct association with eIF2B (Tsai et al., 2018). Intriguingly, pain observed both in animals treated with streptozotocin, a chemical used for the destruction of insulin-producing cells that induces type I diabetes, and in animals given methyl glyoxal was reversed by ISRIB. Collectively, these experiments highlight the critical role of eIF2α phosphorylation in pain. Future efforts will require understanding the relevant regulatory targets. While eIF2α phosphorylation is generally inhibitory, translation of specific mRNAs with uORFs is increased. Alternatively, mRNAs with decreased reliance on cap-dependent translation are likely less impacted by eIF2α phosphorylation. Genome-wide assays of translation will be crucial to identify the relevant target(s) moving forward.

RNA therapeutics directed against mRNA

miRNAs/siRNAs

MicroRNAs (miRNAs) are a class of small non-coding RNAs that destabilize mRNA and elicit translational repression. Compromised miRNA biogenesis via deletion of Dicer results in profound deficits in pain behavioural responses in an inflammatory pain model (J. Zhao et al., 2010). miRNAs have emerged as important players in post-transcriptional control of neuronal plasticity (Z. Hu & Li, 2017). miRNA modulation has also emerged as a new source of possible pain therapeutics (Table 3) (Dai et al., 2018; Lopez-Gonzalez, Landry, & Favereaux, 2017). For example, knockdown of miRNA 155 has anti-hyperalgesic effects in a neuropathic pain model (Liu, Zhu, Sun, & Xie, 2015). Specific miRNAs may possess deviant roles as mediators of intercellular messengers via binding to extracellular receptors (Park et al., 2014). Addition of the let-7b miRNA to DRG neurons results in inward action potentials. Injection of a let-7b mimic is sufficient to induce pain hypersensitivity. Conversely, administration of a let-7b inhibitor blocks pain associated behaviours in an inflammatory pain model. While it is unclear if micromolar concentrations of secreted let-7b can be attained in vivo, the sequence specificity of the interaction implies that this small RNA moonlights as a secreted pro-nociceptive mediator.

Table 3:

miRNAs associated with pain conditions in both preclinical and clinical studies.

miRNA Expression change Pain condition/model Subjects Reference
miR-30c-5p Up Neuropathic pain Human and mouse (Tramullas et al., 2018)
miR-146a Up Diabetic neuropathy Human (Ciccacci et al., 2014)
Rat (Yousefzadeh, Alipour, & Soufi, 2015)
miR-126 Down Neuropathic pain Human (Orlova et al., 2011)
Mouse (Manners, Tian, Zhou, & Ajit, 2015)
miR-155 Down Inflammation and pain Human (Yao et al., 2011)
Up Mouse (Poh, Yeo, & Ong, 2011)
let-7 family Down Neuropathic pain Human (Orlova et al., 2011)
Up Neuropathic pain Rat, Mouse (Brandenburger et al.,2012; Park et al., 2014)
miR-200c Up Intervertebral disc degeneration Human (B. Zhao, Yu, Li, Guo, & He, 2014)
Spinal cord trauma Mouse (D. S. Yu et al., 2014)
miR-223 Down Fibromyalgia Human (Bjersing, Lundborg, Bokarewa, & Mannerkorpi, 2013)
Up Inflammation and pain Mouse (Poh et al., 2011)
miR-195 Down Fibromyalgia Human (Bjersing et al., 2013)
Up Neuropathic pain Rats (Shi et al., 2013)

Unlike miRNAs that base pair imperfectly to target mRNAs, siRNAs are typically exogenous dsRNAs that trigger cleavage of their targets and subsequent decrease in target protein levels. Early uses of siRNAs for pain include knockdown of the P2X3 ATP receptor resulting in a reduction in neuropathic pain (Dorn et al., 2004). A hindrance in this study is the need for large amounts of siRNA. Subsequent experiments have made use of improved delivery methods that increase knockdown efficiencies (e.g. polyethyleneimine/RNA complexes) by ~40% and require less RNA (Tan, Yang, Shih, Lan, & Cheng, 2005). siRNAs delivered as complexes directed against NR2B result in decreased spontaneous pain in an inflammatory model. More recently, knockdown of matrix metalloproteases (MMPs) has been shown to suppress mechanical sensitivity in a nerve injury model. Numerous advances in the area of siRNAs that modify preclinical models of pain are provided in Table 4. Perhaps the most exciting aspect of the preclinical uses of siRNAs is the recent FDA approval of Onpattro, an siRNA directed against transthyretin (TTR), a transport protein in the cerebrospinal fluid that shuttles the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol (Solomon et al., 2019). Mutations in TTR can cause hereditary transthyretin-mediated amyloidosis (hATTR) in peripheral nerves resulting in nerve injury and neuropathic pain. With the successful demonstration of this type of pharmacology in humans, hopefully, Onpattro is a harbinger of improved treatment strategies for chronic pain in humans.

Table 4:

siRNA involved in various pain conditions

Molecular target Pain condition Knockdown efficiency Reference
P2X purinoceptor 3 (P2X3) Neuropathic pain 40% in DRG (Dorn et al., 2004)
NMDA receptor, NR2B subunit Inflammatory pain 70–80% in SC (Tan et al., 2005)
Bone cancer pain ~50% in rACC (Y. Xu, G. Wang, et al., 2016)
NMDA receptor, NR1 subunit Inflammatory pain 60–75% in SC (Garraway, Xu, & Inturrisi, 2007)
Tyrosine kinase receptor B (TrkB) Inflammatory pain 70% in medulla (Guo et al., 2006)
Prostaglandin E2 receptor 4 (PGE2 EP4) Inflammatory pain 69% in DRG (Lin et al., 2006)
Transient receptor potential cation channel subfamily V member 1 (TrpV1) Inflammatory and neuropathic pain 75% in DRG (Christoph et al., 2008; Christoph et al., 2006)
~20% in DRG (Kasama et al., 2007)
Matrix metalloproteinase (MMP) −2 and −9 Neuropathic pain 50% in DRG and SC (Kawasaki et al., 2008)
Inwardly rectifying potassium (Kir) 4.1 channel Neuropathic pain 40% in trigeminal ganglion (Vit, Ohara, Bhargava, Kelley, & Jasmin, 2008)
Acid-sensing ion channel (ASIC-3) Inflammatory pain 50–90% in DRG (Deval et al., 2008)
platelet-derived growth factor (PDGF) Bone cancer pain 60–80% SC (Y. Xu, J. Liu, et al., 2016)
interferon regulatory factor 5 (IRF5) Neuropathic pain 50–60% microglia (Terashima et al., 2018)
caspase-6 (CASP6) Inflammatory pain 30–40% DRG (Berta et al., 2014)
Toll-like receptor 4 (TLR4) Neuropathic pain
Bone cancer pain
~50% in SC
~60% in SC
(F. X. Wu et al.,2010)
(Pan et al., 2015)
YAP/TAZ Neuropathic pain ~50 – 60% in SC (N. Xu et al.,2016)
C-X-C chemokine receptor type 4 Inflammatory and neuropathic pain ~50% in DRG (Yang et al., 2017)
(CXCR-4) Bone cancer pain ~50% in SC (X. M. Hu et al.,2017)
C-C chemokine receptor 2 (CCR2) Inflammatory pain ~50% in DRG (Begin-Lavallee et al., 2016)
chemokine CXC motif ligand 12 (CXCL12) Chemotherapy-induced peripheral neuropathy ~50% in SC (Li et al., 2017; T. Xu et al., 2017)
Phosphodiesterase 4 (PDE4) B Neuropathic pain ~40% in SC (Ji et al., 2016)
FK506 binding protein 51 (FKBP51) Neuropathic pain ~80% in DRG (H. M. Yu, Wang, & Sun, 2017)
NF-κB p65 Chemotherapy-induced peripheral neuropathy ~50% in DRG (J. Wang et al.,2017)
NaV1.6 Inflammatory and neuropathic pain ~50–70% in DRG (Xie, Strong, Ye, Mao, & Zhang, 2013; Xie, Strong, & Zhang, 2015)
growth-associated protein 43 (GAP43) Neuropathic pain ~50% in DRG and SN (Xie, Strong, & Zhang, 2017)
Raf-1 Opioid-induced hyperalgesia ~80% in SC (Tumati et al., 2008; Tumati et al.,2010)
Interferon regulatory factor-5 (IRF5) Neuropathic pain ~60% in SC (Masuda et al.,2014)
CCR1 and CCR5 Neuropathic pain ~50% in SN (Kiguchi, Maeda, Kobayashi, Fukazawa, & Kishioka, 2010)
TNF Receptor Associated Factor 6 (TRAF6) Neuropathic pain ~40% in cultured astrocytes (Lu et al., 2014)
Pannexin-1 Neuropathic pain ~40% in DRG (Zhang, Laumet, Chen, Hittelman, & Pan, 2015)
T-cell death-associated gene 8 (TDAG8) Bone cancer pain ~40% in SC (Hang et al., 2012)
Sensory neuron-specific receptors (SNSRs) Inflammatory pain ~30% in DRG (Ndong et al., 2009)
Brain-derived neurotrophic factor (BDNF) Bone cancer pain ~60% in SC (L. N. Wang et al., 2012)
GTP cyclohydrolase I (GCH1) Neuropathic pain ~50% in DRG (S. J. Kim et al., 2009)

Antisense oligonucleotides (ASOs)

ASOs are exogenous single stranded nucleic acids that bind to mRNAs and modulate protein synthesis and RNA processing through a variety of mechanisms. Typically, ASOs suppress RNA stability through Watson-Crick base pairing to target mRNAs and subsequent cleavage by RNase H. Currently, there are ongoing clinical trials for the therapeutic use of ASOs in the nervous system for treatment of ALS (NCT02623699) and Huntington’s disease (NCT02519036). Additionally, an ASO therapy targeted to the nervous system, nusinersen, has been approved by the FDA for treatment of spinal muscular atrophy (Finkel et al., 2017; Rigo et al., 2014). ASOs delivered systemically or centrally can target transcripts in the spinal cord and DRG (Mohan et al., 2018). Remarkably, an ASO directed against the sodium channel Nav1.7 resulted in decreased mechanical sensitivity that persists for four weeks in rats. Additional studies have focused on p38, p65, CREB, and P2X receptors (Table 5). A limitation of ASOs are the modest effects on mRNA abundance ca. 50%. However, their ease of use and established safety and efficacy in humans suggests that mRNA destabilization is a viable and increasingly common strategy to attenuate pain.

Table 5:

ASOs used in preclinical models of pain

Molecular target Pain condition Knockdown efficiency Reference
Nav 1.8 Neuropathic pain ~40% in SN (Gold et al., 2003)
~40% in DRG (Lai et al., 2002)
Inflammatory and neuropathic pain ~50% in DRG (Porreca et al., 1999)
Inflammatory pain ~30% in DRG (Y. Q. Yu, Zhao, Guan, &Chen, 2011)
Visceral pain ~50% in DRG (Yoshimura et al., 2001)
cAMP response element binding protein (CREB) Neuropathic pain ~50% in SC (Gu et al., 2013)
~80% in SC (Ma, Hatzis, & Eisenach, 2003)
~50% in SC (Y. Y. Wang et al., 2006)
P2X3 receptor Inflammatory and neuropathic pain ~30% in DRG (Honore et al., 2002)
~30% in SC (Barclay et al., 2002)
metabotropic glutamate receptor 1 (mGluFM) Neuropathic pain ~50% in SC (Fundytus et al., 2001)
Inflammation pain ~50% in SC (Fundytus, Osborne, Henry, Coderre, & Dray, 2002)
p38α MAP kinase isoform Neuropathic and postoperative pain ~50% in SC (Luo et al., 2018)
p38β MAP kinase isoform Bone cancer pain ~50% in SC (Dong, Xiang, Ye, & Tian, 2014)
p65 subunit of NF-κB Neuropathic pain ~30% in SC (T. Sun et al., 2006)
Nav1.7 Inflammatory pain ~50% in DRG (Mohan et al., 2018)
TRPV1 Neuropathic pain ~80% in DRG,
~50% in SC
(Christoph et al., 2007)
HuR Multiple sclerosis associated pain ~30% in SC (Sanna et al., 2017)
Epac1 Inflammatory pain ~40% in DRG (H. Wang et al., 2013)
extracellular signal-regulated protein kinase 5 (ERK5) Neuropathic pain ~60% in SC (J. L Sun et al., 2013)
ERK Neuropathic pain ~70% in SC (Song et al., 2005)
beta-arrestin Neuropathic pain ~60% in cultured cells (Przewlocka et al., 2002)
Neurotrophin-3 Neuropathic pain ~45% in SC (White, 2000)
acid-sensing ion channels (ASICs) Inflammatory pain ~60% in SC (Duan et al., 2007)
NMDA-R1, NMDA-R2C, and NMDA-R2D Inflammatory pain 20–40% in SC (Yukhananov, Guan, & Crosby, 2002)
T-subtype calcium channels (Cav3.2, and Cav3.3) Neuropathic pain ~70% in SC (Duan et al., 2007)
glial fibrillary acidic protein (GFAP) Neuropathic pain ~60% in DRG
~30% in SC
(D. S. Kim et al., 2009)

Conclusion

Despite the clear genetic and pharmacologic evidence that post-transcriptional and translational controls permeate nociceptor function, in many cases it remains unclear which mRNAs must be properly repressed or activated to engender sustained excitability. Advances in high-throughput approaches to profiling nascent translation coupled to RNA directed interventions may provide a synergistic means to address this problem. Comprehensive identification of translational efficiencies across a range of pain states at different time points are a promising avenue to address this problem (Megat et al., 2019; Sonali Uttam, 2018). The identification of targets and new mechanisms afford remarkable advances in our understanding of pain molecular biology and hopefully improved strategies for blocking the plasticity that facilitates chronic pain. Therapeutics that act peripherally have tremendous clinical potential as they differ fundamentally from opiates that act on pain processing and have profound impacts on the reward centres of the brain. This work has highlighted a variety of approaches to disrupt nociceptive pain signalling by simply shooting the proverbial messenger (or otherwise disrupting its function). The major challenge moving forward is to define the most effective and safe target in humans.

Funding Information

This work was supported in part by an NIH grant R01NS100788.

Footnotes

No conflicts of interest

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