Background & Aims

Persistent chronic pain is a characteristic manifestation in patients with sickle cell disease (SCD) with a high prevalence of neuropathic pain. With a growing appreciation for the contribution of microRNAs (miRNA) in a wide range of neuronal functions, this study aimed to investigate the role of miRNA as an epigenetic mechanism in the neuropathogenesis of chronic pain in SCD.

Methods

Negative reinforcement with the conditioned place preference paradigm was employed to determine stimulus-independent ongoing pain in mice. Standard methods were applied to examine mechanical allodynia and thermal hyperalgesia. Exosomes were isolated from serum using volume-excluding polymeric precipitation. The expression of miRNA was determined by real-time RT-PCR and fluorescence in situ hybridization.

Results

In a humanized mouse model of SCD, spontaneous ongoing pain as well as evoked hypersensitivity to mechanical and thermal stimuli were present in mice carrying human sickle hemoglobin, but not in non-sickle control littermates. As compared with non-sickle littermates, the level of let-7 family miRNAs was dramatically increased in sickle cell mice. Prominent elevation of let-7 miRNAs was observed in the spinal cord dorsal horn region of mice with SCD. Spinal administration of LNA-modified antisense oligonucleotides (LNA-anti-let-7) effectively knocked down the expression of supraspinal let-7, attenuated spontaneous pain, mechanical allodynia, and heat hyperalgesia in mice with SCD. We found the pain reversal effect by LNA-anti-let-7 (2 ug/day, i.t., 3 days) lasted for at least 14 days. Moreover, there was a significant upregulation of circulating let-7 miRNAs in sickle cell mice as compared with non-sickle control mice. This finding was in agreement with our observations in the clinic.

Conclusions

These findings suggest the functional participation of let-7 miRNAs in the development of both ongoing spontaneous pain and evoked pain in SCD, which highlighted the possibility of a new intervention target to treat chronic pain in SCD.

References

N/A

Presenting Author

Ying He

Poster Authors

Ying He

PhD

University of Illinois Chicago

Lead Author

E-mail

Topics

  • Genetics