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