Circulating microRNA Signatures in Rodent Models of Pain

Abstract

MicroRNAs (miRNAs) remain stable in circulation and have been identified as potential biomarkers for a variety of conditions. We report miRNA changes in blood from multiple rodent models of pain, including spinal nerve ligation and spared nerve injury models of neuropathic pain; a complete Freund's adjuvant (CFA) model of inflammatory pain; and a chemotherapy-induced model of pain using the histone deacetylase inhibitor JNJ-26481585. The effect of celecoxib, a cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug, was investigated in the CFA model as proof of principle for assessing the utility of circulating miRNAs as biomarkers in determining treatment response. Each study resulted in a unique miRNA expression profile. Despite differences in miRNAs identified from various models, computational target prediction and functional enrichment have identified biological pathways common among different models. The Wnt signaling pathway was affected in all models, suggesting a crucial role for this pathway in the pathogenesis of pain. Our studies demonstrate the utility of circulating miRNAs as pain biomarkers and suggest the potential for rigorous forward and reverse translational approaches. Evaluating alterations in miRNA fingerprints under different pain conditions and after administering therapeutic agents may be beneficial in evaluating clinical trial outcomes, predicting treatment response, and developing correlational outcomes between preclinical and human studies.

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

“…Recent studies suggest that miRNAs may have extracellular roles. Circulating miRNAs are present in various body fluids and serve as biomarkers for diseases (Chen et al, 2008; Lehmann et al, 2012; Qureshi et al, 2016). Analysis of cerebrospinal fluid of Alzheimer’s patients revealed an increase of miRNA let-7b (miR-let-7b), which binds toll-like receptor 7 (TLR7) in cortical neurons to induce neurodegeneration (Lehmann et al, 2012).…”

Overview of microRNA Modulation in Analgesic Research

“…Several miRNAs dysregulated by complete Freund's adjuvant (CFA) are restored to baseline levels after celecoxib administration for 7 days in a CFA model of inflammatory pain (Qureshi et al., ). Celecoxib administration reverses the CFA‐induced downregulation of miR‐211, miR‐342‐5p, and miR‐411, suggesting a role for these miRNAs in regulating inflammation (Qureshi et al., ). These findings suggest that reversal of miRNA expression to physiological levels may be important for the therapeutic effect of celecoxib.…”

“…The miRNA expression profiles are altered in several pain-related disorders, including complex regional pain syndrome (CRPS) (Orlova et al, 2011), fibromyalgia (Bjersing, Lundborg, Bokarewa, & Mannerkorpi, 2013), migraine (Andersen, Duroux, & Gazerani, 2016;Tafuri et al, 2015), osteoarthritis (Beyer et al, 2015), and rheumatoid arthritis (Pauley et al, 2008). Circulating miRNA levels are altered by pharmacological treatments (Cheng et al, 2013), including analgesic therapies (Douglas et al, 2015), indicating a potential role for miRNA as a mediator of the response to these drugs.…”

“…For example, the OPRM1 gene, which encodes for MOR, is a predicted target of miR-34a and miR-34c, two miRNAs belonging to the miR-34 family. It has been reported that miR-34a is downregulated in CRPS patients resistant to ketamine therapy (Douglas et al, 2015). In investigating the mechanistic significance of this change, it was found that miR-34a is a negative regulator of corticotropin-releasing hormone receptor 1 (CRHR1).…”

“…Induction of COX2 accounts largely for the high prostanoid production at the site of inflammation (Chen, Yang, & Grosser, 2012). Several miRNAs dysregulated by complete Freund's adjuvant (CFA) are restored to baseline levels after celecoxib administration for 7 days in a CFA model of inflammatory pain (Qureshi et al, 2015). Celecoxib administration reverses the CFA-induced downregulation of miR-211, miR-342-5p, and miR-411, suggesting a role for these miRNAs in regulating inflammation (Qureshi et al, 2015).…”