Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB light-touch mechanoreceptors. These light-touch-sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch-sensitive neuronal type recruited during mechanical allodynia.
Ϫ/Ϫ mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3 Ϫ/Ϫ mutant mice and perhaps also in human PD.
The transcription factor Pitx3 plays an important role in the development of midbrain to promote the growth and differentiation of dopamine neurons. The present study has demonstrated that overexpression of Pitx3 in SH-SY5Y cells and primary ventral mesencephalic (VM) cultures significantly increased the mRNA levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and remarkably elevated the protein levels of these two neurotrophic factors. Our data provide the first evidence that pitx3-expressing cells are able to upregulate the expression of BDNF and GDNF. Therefore, Pitx3 might be a good target for the treatment of Parkinson's disease.
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