| First Author | Zhang J | Year | 2022 |
| Journal | J Neurosci | Volume | 42 |
| Issue | 48 | Pages | 8918-8935 |
| PubMed ID | 36257688 | Mgi Jnum | J:369674 |
| Mgi Id | MGI:7707910 | Doi | 10.1523/JNEUROSCI.0735-22.2022 |
| Citation | Zhang J, et al. (2022) HDAC2 in Primary Sensory Neurons Constitutively Restrains Chronic Pain by Repressing alpha2delta-1 Expression and Associated NMDA Receptor Activity. J Neurosci 42(48):8918-8935 |
| abstractText | alpha2delta-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained alpha2delta-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of alpha2delta-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), but not HDAC3, at the Cacna2d1 promoter in the DRG. Strikingly, Hdac2 knockdown or conditional knockout in DRG neurons in male and female mice consistently induced long-lasting mechanical pain hypersensitivity, which was readily reversed by blocking NMDA receptors, inhibiting alpha2delta-1 with gabapentin or disrupting the alpha2delta-1-NMDA receptor interaction at the spinal cord level. Hdac2 deletion in DRG neurons increased histone acetylation levels at the Cacna2d1 promoter, upregulated alpha2delta-1 in the DRG, and potentiated alpha2delta-1-dependent NMDA receptor activity at primary afferent central terminals in the spinal dorsal horn. Correspondingly, Hdac2 knockdown-induced pain hypersensitivity was blunted in Cacna2d1 knockout mice. Thus, our findings reveal that HDAC2 functions as a pivotal transcriptional repressor of neuropathic pain via constitutively suppressing alpha2delta-1 expression and ensuing presynaptic NMDA receptor activity in the spinal cord. HDAC2 enrichment levels at the Cacna2d1 promoter in DRG neurons constitute a unique epigenetic mechanism that governs acute-to-chronic pain transition.SIGNIFICANCE STATEMENT Excess alpha2delta-1 proteins produced after nerve injury directly interact with glutamate NMDA receptors to potentiate synaptic NMDA receptor activity in the spinal cord, a prominent mechanism of nerve pain. Because alpha2delta-1 upregulation after nerve injury is long lasting, gabapentinoids relieve pain symptoms only temporarily. Our study demonstrates for the first time the unexpected role of intrinsic HDAC2 activity at the alpha2delta-1 gene promoter in limiting alpha2delta-1 gene transcription, NMDA receptor-dependent synaptic plasticity, and chronic pain development after nerve injury. These findings challenge the prevailing view about the role of general HDAC activity in promoting chronic pain. Restoring the repressive HDAC2 function and/or reducing histone acetylation at the alpha2delta-1 gene promoter in primary sensory neurons could lead to long-lasting relief of nerve pain. |
