Elsevier

Pharmacology & Therapeutics

Volume 180, December 2017, Pages 1-15
Pharmacology & Therapeutics

Associate editor: P. Holzer
MicroRNA and chronic pain: From mechanisms to therapeutic potential

https://doi.org/10.1016/j.pharmthera.2017.06.001Get rights and content

Abstract

Chronic pain is a major public health issue with an incidence of 20–25% worldwide that can take different forms like neuropathic, cancer-related or inflammatory pain. Chronic pain often limits patients in their daily activities leading to despair. Thus, the goal of treatments is to relieve pain sufficiently to enable patients to go back to a normal life. Unfortunately, few patients with chronic pain obtain complete relief from the analgesics that are currently available. It is thus of prime importance to get a better understanding of chronic pain mechanisms to design new therapeutic strategies and pain-killers. In this sense, the study of microRNA (miRNAs) in chronic pain conditions could lead to a breakthrough in pain management. miRNAs have emerged as master regulators of gene expression in the nervous system where they contribute to neuronal network plasticity. The involvement of miRNAs in the maladaptive plasticity mechanisms of chronic pain is now well documented. Here, we review studies conducted in different animal models and in patients that screened chronic pain-related miRNAs and their targets. Clinical studies suggest that miRNAs expression could reflect the high variability among pain patients that could help to categorize patients and finally lead to personalized therapies. We also point out the different strategies investigated to design miRNA-based analgesics. Finally, we highlight the current miRNA-based clinical trials to hypothesize their potential as therapeutic tool for chronic pain.

Introduction

Chronic pain is a major clinic issue with an incidence of 20–25% worldwide; in Europe it affects 19% of the adult population, seriously reducing the quality of their social and working lives (Breivik, Collett, Ventafridda, Cohen, & Gallacher, 2006). In the United States of America, more than 100 million people are affected by chronic pain with an annual cost of more than $600 billion (Gereau et al., 2014). Chronic pain disorders are difficult to treat due to their diversity (Kress et al., 2013). Spontaneous pain results from the stimulation of a primary nociceptive afferent that makes synapse in the dorsal horn of the spinal cord, and from here, pain information travels to supra-spinal areas (prefrontal cortex, cingulate, and parietal cortex) via thalamus for further processing. The establishment of chronic pain can arise from long-term sensitization at any level of this pathway (Ligon, Moloney, & Greenwood-Van Meerveld, 2016). The most common features of chronic pain are allodynia and hyperalgesia. Allodynia is a central pain sensitization state where a stimulus that does not usually provoke pain is inducing a pain response. Hyperalgesia results also from pain sensitization and can be defined as an increased sensitivity to painful stimuli resulting in an exaggerated pain sensation. One of the mechanisms involving peripheral and/or central sensitization is the altered regulation of gene expression. Initial studies of gene expression regulation date back to late 80s (for review see Hökfelt, Zhang, & Wiesenfeld-Hallin, 1994). More recently, regulation of gene expression has been shown to occur in nearly all models of pain, and affect a broad array of targets all along pain pathways. For instance, in the chronic pain model of spinal nerve ligation (SNL), consisting in a tight ligation of L5 and L6 spinal nerves, leading to mechanical allodynia and heat hyperalgesia, it was first described that inhibitory γ-aminobutyric acid receptor A (GABAA) is down-regulated in neurons of the Dorsal Root Ganglia (DRG) (Fukuoka et al., 1998). In the spinal cord of animals with peripheral nerve injury it has been shown that the up-regulation of interleukin-6 (IL-6) mRNA (Arruda, Colburn, Rickman, Rutkowski, & DeLeo, 1998) and neurokinin-1 receptor in the dorsal horn was correlated with thermal hypersensitivity (Taylor & McCarson, 2004). Besides, in the supra-spinal areas, it has been shown that downregulation of dopaminergic D1 and D2 receptors occurs in the anterior cingulate cortex in a rat model of neuropathic pain (Ortega-Legaspi et al., 2011) and the upregulation of interleukin-1β (IL-1β) in the prefrontal cortex of rats with spared nerve injury (SNI) (Apkarian et al., 2006). Thus, it is clear that altered gene expression in the pain pathways is one of the mechanisms of chronic pain. The next step is to understand how genes are dys-regulated in chronic pain conditions and to eventually find a way to normalize gene expression and thus relief pain.

Gene expression can be modulated by different regulators acting at both the transcriptional and the translational level. In this review, we will consider the regulation exerted by a class of regulators receiving more and more interest in the field of pain, the microRNAs (miRNAs).

MicroRNAs are small non-coding RNAs that regulate gene expression by translational inhibition or mRNA degradation (Bartel, 2009). They are highly conserved in closely related animals and many are also conserved among animal lineages (Ambros, 2003, Aravin et al., 2003, Lagos-Quintana et al., 2003, Lim et al., 2003), which facilitates the correlation of miRNA studies between species. Like other small RNAs such as small interfering RNAs (siRNAs) or Piwi-interacting RNAs (piRNAs), miRNAs have important roles in gene regulation and RNA silencing, however miRNAs differ from other small RNAs in their biogenesis (Bartel, 2009).

In 2007, the pioneer study by Bai and collaborators suggested the implication of miRNAs in the development and/or maintenance of inflammatory pain (Bai, Ambalavanar, Wei, & Dessem, 2007). Hence, they showed that upon inflammatory pain initiation by complete Freund's adjuvant (CFA) injection in the masseter muscle multiple miRNAs were down-regulated in the trigeminal ganglion. Then, many others miRNAs have been described as regulators of pain in most, if not all, pain models such as sciatic nerve ligation (Kusuda et al., 2011), diabetic neuropathy (Chattopadhyay et al., 2012, Gong et al., 2015) or chronic constriction injury (Brandenburger et al., 2012, Genda et al., 2013).

In this review, we focus on the regulatory mechanisms of miRNAs in chronic pain highlighting their potential as therapeutic targets and diagnosis tools.

Section snippets

miRNAs biogenesis

Half of miRNA-coding genes reside in the intergenic space and are regulated by their own promoters (Corcoran et al., 2009, Lagos-Quintana et al., 2001), around 40% of miRNA genes are situated in introns (Rodriguez et al., 2004, Smalheiser, 2008) and the final 10% are located in exon terminals. As a consequence, the expression of half of the miRNA genes depends on the regulation of their host gene, so they may be involved in the control of genetic networks related to the expected function of the

miRNAs are involved in chronic pain mechanisms

Chronic pain is characterized by persistent nociceptive hypersensitivity (Woolf & Mannion, 1999); its development and maintenance involves changes in neuronal function and gene expression. Since microRNAs have a critical function in gene regulation, the study of their roles in chronic pain mechanisms in various animal models has developed gradually during the last decade.

A solid proof of miRNA involvement in pain mechanisms came in 2010 from Zhao and collaborators. They showed the importance of

Relevance of miRNA-based mechanisms in the clinics

Pioneer clinical studies showed that it is possible to purify and reliably quantify miRNAs from minute amounts of biological fluids or biopsies and to use miRNA expression as a biomarker for various diseases. Indeed, a signature of cancer was identified by miRNA profiling from biopsies of prostate and breast cancer patients (Mattie et al., 2006). While biopsies offer a reliable source of biomarkers, their invasive nature can limit their use in the clinics. The easy access to biological fluids

Future perspectives of miRNA treatments

Targeting miRNAs in the context of chronic pain looks promising but since miRNA action relies on their altered expression, either an up- or a down-regulation in pain conditions, we need drugs that can either decrease or increase specific miRNAs.

Final remarks

As a conclusion, animal model studies demonstrated that (i) miRNAs are key elements of chronic pain mechanisms and (ii) miRNAs are a relevant therapeutic target since pain relief is significant without appreciable toxicity. Screening of patients' samples suggests that the pain mechanisms involving miRNAs identified in animal models are also present in human pathology.

Before treating chronic pain patients with miRNA-based drugs, researchers now have to solve three issues: (i) confirm with larger

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This project was supported by Rôle des micro ARNs dans les mécanisme de douleur d’origine cancéreuse, Association pour la Recherche sur le Cancer (SFI20111203977), Institut National du Cancer (PLBIO15-300) and European Commission FP7/2013-2017 under agreement 602133.

References (180)

  • Q. Chen et al.

    Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery

    Journal of Controlled Release

    (2010)
  • S.R. Douglas et al.

    Analgesic response to intravenous ketamine is linked to a circulating microRNA signature in female patients with complex regional pain syndrome

    The Journal of Pain: Official Journal of the American Pain Society

    (2015)
  • T. Fukuoka et al.

    Change in mRNAs for neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model

    Pain

    (1998)
  • R.W. Gereau et al.

    A pain research agenda for the 21st century

    The Journal of Pain

    (2014)
  • Q. Gong et al.

    Altered microRNAs expression profiling in mice with diabetic neuropathic pain

    Biochemical and Biophysical Research Communications

    (2015)
  • J.C. Griepenburg et al.

    Caged oligonucleotides for bidirectional photomodulation of let-7 miRNA in zebrafish embryos

    Bioorganic & Medicinal Chemistry

    (2013)
  • A. Grimson et al.

    MicroRNA targeting specificity in mammals: Determinants beyond seed pairing

    Molecular Cell

    (2007)
  • T. Hökfelt et al.

    Messenger plasticity in primary sensory neurons following axotomy and its functional implications

    Trends in Neurosciences

    (1994)
  • O. Issler et al.

    MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

    Neuron

    (2014)
  • A. Khvorova et al.

    Functional siRNAs and miRNAs exhibit strand bias

    Cell

    (2003)
  • A.A. Koshkin et al.

    LNA (locked nucleic acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition

    Tetrahedron

    (1998)
  • K.L. Kynast et al.

    Modulation of central nervous system-specific microRNA-124a alters the inflammatory response in the formalin test in mice

    Pain

    (2013)
  • A. Latremoliere et al.

    Central sensitization: A generator of pain hypersensitivity by central neural plasticity

    The Journal of Pain

    (2009)
  • B.P. Lewis et al.

    Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

    Cell

    (2005)
  • T. Li et al.

    Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans

    Clinica Chimica Acta

    (2011)
  • N.K. Liu et al.

    Altered microRNA expression following traumatic spinal cord injury

    Experimental Neurology

    (2009)
  • J.J. Lucas et al.

    Molecular mechanisms of pain: Serotonin1A receptor agonists trigger transactivation by c-fos of the prodynorphin gene in spinal cord neurons

    Neuron

    (1993)
  • M.T. Manners et al.

    MicroRNAs downregulated in neuropathic pain regulate MeCP2 and BDNF related to pain sensitivity

    FEBS Open Bio

    (2015)
  • E.A. Matthews et al.

    Effects of ethosuximide, a T-type Ca(2 +) channel blocker, on dorsal horn neuronal responses in rats

    European Journal of Pharmacology

    (2001)
  • N.M. Agalave et al.

    Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain

    Molecular Medicine

    (2014)
  • M. Agostini et al.

    miR-34: From bench to bedside

    Oncotarget

    (2014)
  • A. Aksoy-Aksel et al.

    MicroRNAs and synaptic plasticity—a mutual relationship

    Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

    (2014)
  • C. Altier et al.

    Differential role of N-type calcium channel splice isoforms in pain

    The Journal of Neuroscience

    (2007)
  • L. Alvarez-Erviti et al.

    Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes

    Nature Biotechnology

    (2011)
  • R.E. Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nature Genetics

    (1999)
  • H.H. Andersen et al.

    Serum microRNA signatures in migraineurs during attacks and in pain-free periods

    Molecular Neurobiology

    (2016)
  • A.V. Apkarian et al.

    Expression of IL-1beta in supraspinal brain regions in rats with neuropathic pain

    Neuroscience Letters

    (2006)
  • G. Bai et al.

    Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain

    Molecular Pain

    (2007)
  • K.K. Bali et al.

    Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain

    EMBO Molecular Medicine

    (2013)
  • M.H. Bao et al.

    Protective effects of let-7a and let-7b on oxidized low-density lipoprotein induced endothelial cell injuries

    PLoS One

    (2014)
  • S. Baskerville et al.

    Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes

    RNA

    (2005)
  • J.L. Bjersing et al.

    Profile of circulating microRNAs in fibromyalgia and their relation to symptom severity: An exploratory study

    Rheumatology International

    (2015)
  • J.L. Bjersing et al.

    Profile of cerebrospinal microRNAs in fibromyalgia

    PLoS One

    (2013)
  • R.A. Boon et al.

    Intercellular transport of microRNAs

    Arteriosclerosis, Thrombosis, and Vascular Biology

    (2013)
  • E. Bourinet et al.

    Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception

    The EMBO Journal

    (2005)
  • X. Cai et al.

    Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs

    RNA

    (2004)
  • G. Cerda-Olmedo et al.

    Identification of a microRNA signature for the diagnosis of fibromyalgia

    PLoS One

    (2015)
  • M. Chattopadhyay et al.

    Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy

    Molecular Pain

    (2012)
  • X. Chen

    A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development

    Science

    (2004)
  • G. Chen et al.

    Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice

    Brain: A Journal of Neurology

    (2014)
  • Cited by (91)

    • miRNA contributes to neuropathic pains

      2023, International Journal of Biological Macromolecules
    • Inhibition of microRNA-19a-3p alleviates the neuropathic pain (NP) in rats after chronic constriction injury (CCI) via targeting KLF7

      2023, Transplant Immunology
      Citation Excerpt :

      However, the inhibition of KLF7 could reverse the effect by miR-19a-3p downregulation (Fig. 6D-E). Previous researches reported that miRNAs and mRNAs are associated with the modulation and occurrence of NP [20,21]. For instance, miR-23a was revealed to mediate NP in sciatic nerve injury in mice via targeting CXCR4/NLRP3 [7].

    View all citing articles on Scopus
    View full text