Title: Spinal cord injury induced hyperalgesia is associated with increased levels of Let-7 family of MicroRNAs.
Background: Spinal cord injury (SCI) results in chronic pain syndromes that are often refractory to treatment with opioids, and may represent mu opioid receptor (MOR) dysfunction. MicroRNAs play a role in gene regulation by binding to target mRNA, causing translational repression or mRNA degradation. Let-7 family microRNAs have been shown to target MOR suggesting they may influence the development of pain states and opioid responsiveness. This study sought to determine temporal changes in Let-7 family miRNA and correlate them to the onset of pain behaviors in a rodent model of post-SCI pain.
Methods and findings: Thermal thresholds (evoked pain) were assessed in rats before and after intramedullary injection of quisqualic acid (n=18) or sham laminectomy (n=18). Three of the Let-7 family miRNA levels were determined (Let-7a, Lets-7c and Let 7g) using RT-PCR and qRT-PCR on spinal cord segments caudal to lesion at 7, 14 and 21 days after injury. Thermal thresholds were significantly reduced compared to baseline in injured animals at day 21 (mean decrease of 1.9 sec; p=0.02; 95% CI=0.41-3.3). Sham animals showed no significant change in thermal thresholds over time (p=0.77; 95% CI=3.2-4.2). SCI led to a trend in increasing Let-7 family miRNA levels over time. Compared to sham animals, miRNA levels studied increased in injured animals at 14 and 21 days, corresponding to the period during which post-injury pain developed.
Conclusions: Our data suggests that increased levels of Let-7 family miRNAs are involved in behavioral responses to SCI. Future work will examine if inhibition of Let-7 family miRNAs alters the behavioral and cellular response to SCI.
Carlene Callahan, Michelle Yanik, Dorothy Dobbins and Kori L Brewer