A recent study uncovered the role the enzyme JMJD3 plays in regulating dopamine (DA) production in the brain, and how this process connects to chronic inflammatory pain.
The study published in Acta Neuropathologica Communications focused on midbrain dopamine (mDA) neurons, which play crucial roles in motor control, cognition, emotion, and pain regulation. Dopamine production in these neurons depends heavily on the enzyme tyrosine hydroxylase (TH), whose expression is controlled by transcription factors including NURR1. The researchers looked into the role of epigenetic factors in this process.
They identified JMJD3, a histone demethylase, as a pivotal regulator of DA biosynthesis in mDA neurons. By removing repressive histone marks (H3K27me3), JMJD3 enables the activation of genes essential for dopamine production, including Th and Nurr1.
The researchers examined mice with a conditional knockout of JMJD3 in their dopamine neurons and noted that they exhibited reduced levels of dopamine in key brain regions, such as the midbrain and striatum. Pharmacological inhibition of JMJD3 with the compound GSK-J4 produced similar effects. These changes did not affect motor function but led to prolonged sensitivity to inflammatory pain stimuli, regardless of age or sex, they noted.
The connection between dopamine and pain modulation is well-documented, but this study is the first to link JMJD3 deficiency with exaggerated chronic inflammatory pain. The researchers observed that mice lacking JMJD3 failed to recover from pain induced by inflammation as quickly as normal mice.
The findings highlight a broader epigenetic mechanism underlying dopamine regulation. By removing H3K27me3 marks, JMJD3 directly influences the transcription of genes critical for dopamine biosynthesis. The study also raised questions about potential compensatory roles of other histone demethylases, such as UTX, and their interactions with JMJD3 in maintaining dopamine levels.
The research opens new avenues for addressing chronic pain and dopamine-related disorders such as Parkinson’s disease. Given that chronic pain is a common non-motor symptom among patients with Parkinson’s, targeting JMJD3 or related pathways could offer dual benefits for managing pain and motor symptoms, the authors wrote.
The authors declared no conflicts of interest with this research.
