The association between spinal cord trauma-sensitive miRNAs and pain sensitivity, and their regulation by morphine

Abstract

Increased pain sensitivity is a common sequela to spinal cord injury (SCI). Moreover, drugs like morphine, though critical for pain management, elicit pro-inflammatory effects that exacerbate chronic pain symptoms. Previous reports showed that SCI results in the induction and suppression of several microRNAs (miRNAs), both at the site of injury, as well as in segments of the spinal cord distal to the injury site. We hypothesized that morphine would modulate the expression of these miRNAs, and that expression of these SCI-sensitive miRNAs may predict adaptation of distal nociceptive circuitry following SCI. To determine whether morphine treatment further dysregulates SCI-sensitive miRNAs, their expression was examined by qRT-PCR in sham controls and in response to vehicle and morphine treatment following contusion in rats, at either 2 or 15 days post-SCI. Our data indicated that expression of miR1, miR124, and miR129-2 at the injury site predicted the nociceptive response mediated by spinal regions distal to the lesion site, suggesting a molecular mechanism for the interaction of SCI with adaptation of functionally intact distal sensorimotor circuitry. Moreover, the SCI-induced miRNA, miR21 was induced by subsequent morphine administration, representing an alternate, and hitherto unidentified, maladaptive response to morphine exposure. Contrary to predictions, mRNA for the pro-inflammatory interleukin-6 receptor (IL6R), an identified target of SCI-sensitive miRNAs, was also induced following SCI, indicating dissociation between miRNA and target gene expression. Moreover, IL6R mRNA expression was inversely correlated with locomotor function suggesting that inflammation is a predictor of decreased spinal cord function. Collectively, our data indicate that miR21 and other SCI-sensitive miRNAs may constitute therapeutic targets, not only for improving functional recovery following SCI, but also for attenuating the effects of SCI on pain sensitivity.

MicroRNA‑381/Hes1 is a potential therapeutic target for spinal cord injury

“…miRNA may be a novel target for therapeutic intervention that promotes post-SCI nerve repair and regeneration (6). miRNA in SCI remains to be intensively studied, and the mechanisms of action and interaction of miRNAs are important directions of future study (20). This research will aid our understanding of the regulatory role of post-SCI miRNA, and accelerate the development of miRNA regulation-based SCI therapeutic measures (6).…”

Integrated analysis of microRNA and mRNA expression profiles in the rat spinal cord under inflammatory pain conditions

“…Extracellular matrix molecules have been implicated in a wide variety of biological processes, including cell differentiation, migration and neurite outgrowth (Lander et al ., ). The other two genes targeted by miR‐124‐3p and miR‐149‐3p, interleukin‐6 receptor (IL‐6R) and ceramide synthase 2 (CERS2), were previously experimentally identified to be involved in the development of inflammatory and neuropathic hyperalgesia (Kobayashi et al ., ; Murakami et al ., ; Strickland et al ., ).…”

“…In addition, administration of a miR‐124 mimic could decrease nociceptive behavior in rats, which was accompanied by the downregulated expression of MeCP2. IL‐6R may play a role in remodeling inflammation‐driven pain neuro‐circuitry following spinal cord injury (SCI) (Strickland et al ., ). Murakami et al .…”

The Role of microRNA Markers in the Diagnosis, Treatment, and Outcome Prediction of Spinal Cord Injury

“…Importantly, investigators often achieve functional recovery in experiments on miRNAs in SCIs (7, 15, 16, 25, 29, 30, 35, 38, 47, 51, 72, 74, 75, 77, 78). Recent evidence shows miRNAs may be helpful for repairing hind limb functionality in murine SCI (55).…”

“…Therefore, careful consideration should be given to optimal pain treatment of patients with SCI, as 1 mode in particular leads to decreased motor recovery and increased chronic pain (30). In their study of morphine delivery and SCI, Strickland et al noticed that acute administration of morphine correlated to these effects, potentially via the expression of miRNA, including miR-21 and 146 (30). The miR-21 and 146 expressions were elevated by morphine.…”