Astroglial MicroRNA-219-5p in the Ventral Tegmental Area Regulates Nociception in Rats

Abstract

Background The authors previously reported that noncoding microRNA miR-219-5p is down-regulated in the spinal cord in a nociceptive state. The ventral tegmental area also plays critical roles in modulating nociception, although the underlying mechanism remains unknown. The authors hypothesized that miR-219-5p in the ventral tegmental area also may modulate nociception. Methods The authors studied the bidirectional regulatory role of ventral tegmental area miR-219-5p in a rat complete Freund’s adjuvant model of inflammatory nociception by measuring paw withdrawal latencies. Using molecular biology technologies, the authors measured the effects of astroglial coiled-coil and C2 domain containing 1A/nuclear factor κB cascade and dopamine neuron activity on the down-regulation of ventral tegmental area miR-219-5p–induced nociceptive responses. Results MiR-219-5p expression in the ventral tegmental area was reduced in rats with thermal hyperalgesia. Viral overexpression of ventral tegmental area miR-219-5p attenuated complete Freund’s adjuvant–induced nociception from 7 days after complete Freund’s adjuvant injection (paw withdrawal latencies: 6.09 ± 0.83 s vs. 3.96 ± 0.76 s; n = 6/group). Down-regulation of ventral tegmental area miR-219-5p in naïve rats was sufficient to induce thermal hyperalgesia from 7 days after lentivirus injection (paw withdrawal latencies: 7.09 ± 1.54 s vs. 11.75 ± 2.15 s; n = 8/group), which was accompanied by increased glial fibrillary acidic protein (fold change: 2.81 ± 0.38; n = 3/group) and reversed by intraventral tegmental area injection of the astroglial inhibitor fluorocitrate. The nociceptive responses induced by astroglial miR-219-5p down-regulation were inhibited by interfering with astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling. Finally, pharmacologic inhibition of ventral tegmental area dopamine neurons alleviated this hyperalgesia. Conclusions Down-regulation of astroglial miR-219-5p in ventral tegmental area induced nociceptive responses are mediated by astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling and elevated dopamine neuron activity.

Behaviors Related to Psychiatric Disorders and Pain Perception in C57BL/6J Mice During Different Phases of Estrous Cycle

“…Paw withdrawal latencies (PWLs) were measured with the IITC Plantar Analgesia Meter (IITC Life Science Inc., Woodland Hills, CA, United States) in a double-blinded manner as described in our previous studies (Liu et al, 2011(Liu et al, , 2018Zhang H. et al, 2017;Zhang S. et al, 2017). Mice were placed in transparent acrylic enclosures (10 × 10 × 20 cm) on a glass plate in a temperature-controlled and noise-free room.…”

MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5

“…Recently, a strong link between miRNA dysregulation and chronic pain has been established (Descalzi et al, 2015). Manipulation of miRNA expression in pain pathways from primary afferent nociceptors, DRG, spinal cord, and brain associated with pain perception prevents or reverses persistent inflammatory, neuropathic, and cancer pain behavior by post-transcription in cytoplasma (Park et al, 2014;Jiang et al, 2016;Gandla et al, 2017;Zhang et al, 2017). Growing findings suggest that the majority of miRNAs exist in both nucleus and cytoplasma, and some are preferentially enriched in the nucleus (Roberts, 2014;Rasko and Wong, 2017).…”

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

“…Pain is a stressor, causing multiple adaptive changes in the brain [44,45]. A growing body of literature suggests that the mesocorticolimbic DA circuits are implicated in chronic pain [3,6,19,25,46]. Similar stress can induce different firing alterations in these projection-specific VTA DA neurons [47].…”

“…Chronic pain has become an enormous health care issue, affecting [15% of the world population [1,2]. The literature suggests that the mesolimbic reward system plays a critical role in regulating chronic pain [3][4][5][6]. The ventral tegmental area (VTA), a core part of the mesolimbic reward system, contains predominantly dopaminergic (DA) neurons [7].…”