Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome

Douglas, Sabrina R.; Shenoda, Botros; Qureshi, Rehman; Saçan, Ahmet; Alexander, Guillermo M.; Perreault, Marielle J.; Barrett, James E.; Aradillas-Lopez, Enrique; Schwartzman, Robert J.; Ajit, Seena K.

doi:10.1016/j.jpain.2015.05.008

Cited by 37 publications

(39 citation statements)

References 61 publications

(8 reference statements)

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“…However, it is possible that some of the miRNAs evaluated in our initial screen that showed less than 30% inhibition of reporter activity could also be important regulators of UGT1A regulation. A recent report (published after our screening studies were completed) showed a small but statistically significant decrease (by 20%) in UGT1A −3’UTR luciferase reporter activity in HEK293 cells transfected with a miR-548d-5p precursor, but no effect on a reporter containing the cytochrome P450 3A4 3’UTR [35]. A review of our initial library screening data showed that miR-548d-5p, decreased UGT1A-3’UTR luciferase reporter activity by 28% (i.e.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach

Papageorgiou

Court

2017

Biochemical Pharmacology

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Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 1A expression by microRNAs (miRNAs) may be an important mechanism underlying interindividual variability in drug glucuronidation. Furthermore, the UGT1A 3’-UTR shared by all UGT1A enzymes is polymorphic, containing three linked SNPs (rs10929303, rs1042640, and rs8330) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT1A expression through binding to the reference and/or common variant UGT1A 3’-UTR. Luciferase reporter plasmids containing either the reference or variant UGT1A 3’-UTR were screened against a 2,048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Four novel miRNAs (miR-103b, miR-141–3p, miR-200a-3p, and miR-376b-3p) were identified that repressed both reference and variant UGT1A 3’-UTR, while two other miRNAs selectively repressed the reference (miR-1286) or variant (miR-21–3p) 3’-UTR. Deletion and mutagenesis studies confirmed the binding site location for each miRNA. rs8330 disrupted miR-1286 binding to the reference UGT1A 3’-UTR, while rs10929303 enhanced miR-21–3p binding to the variant 3’-UTR. Transfection of miR-21–3p, miR-103b, miR-141–3p, miR-200a-3p, and miR-376b-3p mimics into LS180 human intestinal cells showed repression of UGT1A1 and UGT1A6 mediated glucuronidation and mRNA without affecting UGT2B7 activity or mRNA. Furthermore, transfection of miR-21–3p, miR-141–3p, and miR-200a-3p into primary human hepatocytes, repressed UGT1A1 activity and mRNA without affecting CYP3A activity. Finally, miR-21–3p and miR-200a-3p expression were negatively correlated with UGT1A6 activity and mRNA in human liver samples. Thus, UGT1A is regulated by multiple miRNAs with some showing allele-dependent effects.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach

Papageorgiou

Court

2017

Biochemical Pharmacology

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“…However, approximately a third of patients fail to respond to ketamine treatment [ 5 ]. Our data have shown that poor responders to ketamine therapy had lower body mass index (BMI) relative to responders [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Hsa-miR-34a mediated repression of corticotrophin releasing hormone receptor 1 regulates pro-opiomelanocortin expression in patients with complex regional pain syndrome

2016

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BackgroundKetamine provides relief for a subset of patients with complex regional pain syndrome (CRPS). The poor responders had a lower body mass index (BMI) relative to responders. Regulation of proopiomelanocortin (POMC) expression is crucial in normal body weight homeostasis. The main objectives of this study were to investigate the mechanisms underlying lower BMI characterizing CRPS patients responding poorly to intravenous ketamine therapy and identify potential biomarkers for predicting response.MethodsWe investigated POMC transcript levels in blood from CRPS patients grouped as responders and poor responders to ketamine therapy. Plasma levels of β-endorphin, ACTH and α-MSH were measured by ELISA. We previously identified differential expression of small noncoding microRNA hsa-miR-34a in blood between responders and poor responders. We investigated whether a 11-fold downregulation of hsa-miR-34a in poor responders relative to responders is contributing to the differences in POMC levels by targeting POMC regulator CRHR1. Binding of miR-34a to CRHR1 was assessed using reporter assay; changes in mRNA and protein levels of CRHR1 were used to determine the regulation of CRHR1 by miR-34a. RNA from blood of CRPS and control subjects were used for quantitative PCR for CRHR1.ResultsThough ketamine treatment did not alter POMC expression, poor responders had higher levels of POMC mRNA than responders, both before and after treatment. Corticotropin-releasing hormone (CRH) is a key regulator of POMC expression and the biological effects are mediated through its receptor corticotrophin releasing hormone receptor 1 (CRHR1). We show that hsa-miR-34a is a negative regulator of CRHR1; overexpression of hsa-miR-34a in Jurkat cells resulted in reduction of CRH-mediated POMC expression. Poor responders had higher expression of CRHR1 transcripts than responders, indicating a regulatory role for miR-34a. In addition, we found positive correlations between the pretreatment levels of miR-34a to BMI and response to ketamine therapy.ConclusionsOur findings indicate a mechanism by which hsa-miR-34a can regulate the CRH/CRHR1/POMC axis and may influence BMI. Studies in larger patient cohorts are required to confirm the biomarker utility of circulating hsa-miR-34a levels in predicting treatment response to ketamine therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0820-1) contains supplementary material, which is available to authorized users.

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

Section: Modulation Of Mirnas In Pain and Analgesiamentioning

confidence: 99%

“…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., ). 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).…”

Section: Modulation Of Mirnas In Pain and Analgesiamentioning

confidence: 99%

“…In a recent proof‐of principle study, intravenous ketamine treatment altered circulating miRNA levels in blood from patients with CRPS and induced the differential expression of 14 miRNAs, in good and poor responders, before and after ketamine treatment, indicating the miRNA profile may predict treatment response (Douglas et al., ). The different expression levels of the 14 miRNAs between the good and poor responders indicate that ketamine elicits different responses in these two groups.…”

Section: Modulation Of Mirnas In Pain and Analgesiamentioning

confidence: 99%

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Overview of microRNA Modulation in Analgesic Research

2017

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MicroRNA(miRNA)-mediated gene regulation underlies cellular processes, playing an important role in homeostasis and diseases. The expression and function of miRNAs are altered by various pharmacological agents, with differences in the endogenous levels of miRNAs influencing drug efficacy and toxicity. Thus, miRNA levels could be a biomarker for predicting treatment response, efficacy, and safety. In addition, elucidating the mechanistic significance of miRNA alterations can aid in the identification of therapeutic targets and patient selection, and guide personalized therapy. Discussed in this overview are the properties of miRNA, their modulation, and the ways to measure them. The effects of different classes of analgesics, including opioid and non-opioid, are described as examples of drug-induced modifications of miRNA, with a discussion on how measurement of miRNA levels in patients receiving analgesic therapy can assist in maximizing effectiveness while minimizing the untoward responses to this drug class. © 2017 by John Wiley & Sons, Inc.

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Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome

Cited by 37 publications

References 61 publications

Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach

Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach

Hsa-miR-34a mediated repression of corticotrophin releasing hormone receptor 1 regulates pro-opiomelanocortin expression in patients with complex regional pain syndrome

Overview of microRNA Modulation in Analgesic Research

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