Epigenetic Regulation In Chronic Pain

Chronic pain arising from peripheral inflammation and tissue or nerve injury is a common clinical symptom,debilitating condition that exerts a high social cost in terms of productivity,economic impact and quality of life.Although intensive research on the neurobiological mechanisms of chronic pain has been carried out during previous decades,this disorder is still poorly managed by current drugs such as opioids and non-steroidal anti-inflammatory drugs,suggesting the need for new insight into underlying mechanism(s).Inflammation-,tissue injury-,and/or nerve injury-induced changes in gene expression in sensory neurons of the dorsal root ganglion(DRG),spinal cord dorsal horn,and pain-associated brain regions are thought to participate in chronic pain genesis;however,how these changes occur is still elusive.Given that peripheral and central sensitization under chronic pain conditions share common mechanisms with the neuronal plasticity of memory formation,it is very likely that similar epigenetic mechanisms occur under both conditions.Indeed,accumulating evidence demonstrates that peripheral inflammation and nerve injury drive changes in DNA methylation,histone modifications,and non-coding RNAs in pain-related regions.These changes might be responsible for inflammation/nerve injury-induced alterations of some pain-associated genes in central neurons.Basing on these findings,we propose that epigenetic gene regulation in pain-associated neuronal circuits plays critical roles in chronic pain formation and development.The aim of this project is to characterize the role epigenetic gene regulation in neuronal maladaptation under chronic pain conditions,which will provide potential new therapeutic strategies for chronic pain-induced neurological disorders.The major achievements of the current project include:1)H3 acetylated up-regulation of BDNF by peripheral inflammation induces GluRl phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade,leading to the trafficking of GluAl to pain-modulating neuronal synapses.2)BDNF-TrkB signaling is critical to HDAC inhibitor-induced antinociception,which works by promoting GAD65 accumulation in GABA synaptic terminals.3)H4 acetylated up-regulation of NGF activity by HDAC inhibitors in the NRM promotes the trafficking of?-opioid receptors to pain-modulating neuronal synapses under neuropathic pain conditions,leading to ?-opioid analgesia.4)G9a is a direct transcriptional target of MeCP2 in the regulating cascade of MeCP2-G9a-BDNF in central amygdala regulation of pain and morphine reward.This convergence of regulating mechanisms on common epigenetic regulators may provide a molecular base for understanding functional interactions between pain responses and rewarding effects of opioids through emotion regulations by central amygdala.