title: Increased miR-132-3p expression is associated with chronic neuropathic pain.
abstract: Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: M
authors.initials: M
authors.lastname: Leinders
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Üçeyler
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Pritchard
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lsorkin@ucsd.edu.
authors.forename: L S
authors.initials: LS
authors.lastname: Sorkin
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D002908:Chronic Disease; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009437:Neuralgia / Q000097:blood* / Q000473:pathology / Q000503:physiopathology*; D009841:Oligonucleotides / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; C000604749:MIRN1323 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D012333:RNA, Messenger; D018091:Receptors, AMPA; C477371:locked nucleic acid
keywords: Neuropathic pain; PEAP; SNI; miR-132; neuroimmune; polyneuropathy