Histone methyltransferase G9a diminishes expression of cannabinoid CB₁ receptors in primary sensory neurons in neuropathic pain.

ABSTRACT: Type 1 cannabinoid receptors (CB₁Rs) are expressed in the dorsal root ganglion (DRG) and contribute to the analgesic effect of cannabinoids. However, the epigenetic mechanism regulating the expression of CB₁Rs in neuropathic pain is unknown. G9a (encoded by the Ehmt2 gene), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined G9a's role in regulating CB₁R expression in the DRG and in CB₁R-mediated analgesic effects in an animal model of neuropathic pain. We show that nerve injury profoundly reduced mRNA levels of CB₁Rs but increased the expression of CB₂ receptors in the rat DRG. ChIP results indicated increased enrichment of histone 3 at lysine 9 dimethylation, a G9a-catalyzed repressive histone mark, at the promoter regions of the CB₁R genes. G9a inhibition in nerve-injured rats not only up-regulated the CB₁R expression level in the DRG but also potentiated the analgesic effect of a CB₁R agonist on nerve injury-induced pain hypersensitivity. Furthermore, in mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce CB₁R expression in the DRG and to decrease the analgesic effect of the CB₁R agonist. Moreover, nerve injury diminished the inhibitory effect of the CB₁R agonist on synaptic glutamate release from primary afferent nerves to spinal cord dorsal horn neurons in WT mice but not in mice lacking Ehmt2 in DRG neurons. Our findings reveal that nerve injury diminishes the analgesic effect of CB₁R agonists through G9a-mediated CB₁R down-regulation in primary sensory neurons.

SUBMITTER: Luo Y 

PROVIDER: S-EPMC7076223 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature