Research PaperIncreased miR-132-3p expression is associated with chronic neuropathic pain
Introduction
Neuropathic pain is characteristically severe and persistent and may greatly impair health related quality of life by additionally inducing anxiety, depression, and cognitive impairment (Breivik et al., 2006). There is ample evidence for a potential role of the immune system and particularly of pro- and anti-inflammatory mediators in the pathophysiology of neuropathic pain (Kuner, 2010, McMahon and Malcangio, 2009). Peripheral neuropathies of the same etiology can either be painful or painless (Üçeyler et al., 2007). The mechanism for this discrepancy is unknown.
In recent years, non-coding RNAs have been studied in normal cellular functioning as well as in pathological processes (Huttenhofer and Schattner, 2006, Mattick, 2004). Micro-RNAs (miRNAs) are a family of non-coding RNAs that post-transcriptionally regulate gene expression by inhibiting mRNA translation or inhibiting mRNA and protein degradation (Mattick, 2004). Various diseases, including neuropathic pain disorders, appear to possess unique miRNA expression signatures. Recent reports on modulation of miRNA function in both neuronal and immune processes predict the therapeutic potential of manipulating miRNAs in diseases affecting the immune system and the brain (O'Connor et al., 2012, Soreq and Wolf, 2011). miRNAs that communicate between the nervous and immune system have been termed “neurimmiRs” and primarily target transcription factors or other regulatory genes, which enable simultaneous cross-communication between neural and immune compartments (Soreq and Wolf, 2011). Thus, miRNAs possibly control cellular pathways in multiple systems and act as “master-switches” (Soreq and Wolf, 2011).
Aberrant expression of several miRNAs has been reported throughout many peripheral and central nervous system loci associated with pain perception (Aldrich et al., 2009, Bai et al., 2007, Imai et al., 2011, Kusuda et al., 2011, von Schack et al., 2011). First reports describing characteristic miRNA expression profiles in blood or cerebrospinal fluid of patients with distinct pain conditions are starting to emerge (Andersen et al., 2016, Beyer et al., 2015, Bjersing et al., 2013, Orlova et al., 2011), however evidence linking specific miRNA expression profiles to specific pain disorders is still insufficient.
miR-132 is abundantly expressed in the brain and is emerging as a regulator of cognition, neuronal plasticity, and memory. It can regulate synapse structure and function (Bredy et al., 2011, Miller et al., 2012, Schratt, 2009, Soreq and Wolf, 2011). Hippocampal miR-132 mediates stress-induced cognitive deficits through suppression of acetylcholinesterase (Haramati et al., 2011) and miR-132 has recently been implicated in neuropathic pain after chronic constriction injury (CCI) (Arai et al., 2013). Similarly, spinal cord miR-132 is now proposed as a mediator of neuropathic pain following spared nerve injury (SNI) (Zhang et al., 2015). However, direct links between pain and miR-132 expression levels in human and/or animal models of neuropathic pain still remain elusive.
The current studies evaluated blood and sural nerve miR-132-3p, a splice variant of miR-132, expression in patients suffering from chronic neuropathic pain accompanying peripheral neuropathy and analyzed the role of miR-132-3p in pain behavior in an animal model of neuropathic pain.
Section snippets
Patient assessment and diagnostic classification
Patients with neuropathies of different etiologies were recruited at the Department of Neurology, University of Würzburg between 2014 and 2015, where they underwent diagnostic work-up, including sural nerve biopsy. The study was approved by the Würzburg Medical Faculty Ethics Committee and written informed consent was obtained from every study participant before recruitment. The diagnosis of neuropathy was based on characteristic symptoms and signs in the neurological examination and typical
Basic description of the patient cohort
We included 81 patients with neuropathies of different etiology. The study cohort had a median age of 66 years (range 33–84 years) and consisted of 55 men (median age: 66 years, range 33–84 years) and 26 women (median age: 67 years, range 47–84 years). Clinical characteristics of the cohort and diagnostic subgroups are summarized in Table 1. In 23/81 (28%) patients an inflammatory neuropathy was diagnosed (CIDP, vasculitic neuropathy, PIAN, paraproteinemic neuropathy), while in 24/81 patients (30%)
Discussion
miRNAs have a vital role in post-transcriptional regulation, are widely expressed throughout the brain, are regulated by neuronal activity and some, including miR-132 are thought to be necessary for neuronal plasticity required for memory consolidation and pathological pain (Elramah et al., 2014, Soreq and Wolf, 2011). For example, overexpression of hippocampal miR-132 increased local excitatory postsynaptic currents and impaired learning and memory processes (Edbauer et al., 2010), and
Conclusion
Taken together these findings imply that aberrant neural miR-132-3p expression is associated with human neuropathic pain, and that in animals targeted antagonism of miR-132-3p results in dose-dependent reversal of pain behavior while miR-132-3p mimicry results in a dose-dependent induction of pain behavior allowing us to designate miR-132-3p as a pro-nociceptive miRNA in our study. Importantly, alterations in miRNA levels may be indicative of their functional involvement in pain
Conflicts of interest
The authors have no conflicts of interest.
Acknowledgement
The authors would like to thank Joanne Steinauer for assistance with the confocal microscope, Dr. Gary Firestein for the use of his RT-PCR and Tony Yaksh for helpful discussions. This work was supported by NIH NINDS 067459 (LSS) and BaCaTeC® (No. 20; 2013-2) (ML, CS, LSS). NÜ and CS received funding by the European Union's Seventh Framework Programme (“ncRNAPain”, grant agreement number 602133). This work is part of the doctoral thesis of ML.
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2022, International ImmunopharmacologyCitation Excerpt :In a rat model of spared nerve injury (SNI), the miR-132-3p expression is upregulated in the spinal cord and DRGs. Application of miR-132-3p could induce mechanical hypersensitivity, whereas the intrathecal injection of miR-132-3p antagonist relieves SNI-induced neuropathic pain [27]. In addition, a clinical study has also highlighted that miR-132-3p, miR-98-5p, miR-let-7d-5p are upregulated in patients with neuropathic pain [28].