Research
The Pan ZZ lab has made significant impacts and conceptual advances in the following areas:
Epigenetic mechanism for chronic pain development
Chronic pain, like many other chronic neurological diseases, involves maladaptations in gene expression that lead to malfunctions of proteins for pain sensitization, but how these genes were regulated by persistent pain conditions were unknown. We identified histone hypoacetylation on Gad65 gene encoding the presynaptic GABA-synthesizing enzyme GAD65 as the epigenetic mechanism for impaired GABA function, and histone hyperacetylation on Ngf gene encoding the neurotrophin NGF for increased opioid sensitivity. We also show that the DNA methyltransferase Dnmt3a is involved in the development of chronic pain. These studies provide epigenetic mechanisms for chronic pain and increased sensitivity to opioids under pain conditions.
Impact of pain on rewarding effects of opioids
Our recent work focuses on the impact of pain conditions on the rewarding effects and abuse liability of opioids, a long-standing and challenging healthcare issue in pain management and considerably understudied in animal models. Our research provides original molecular and cellular evidence supporting the novel notion that persistent pain increases sensitivity to opioid drugs through epigenetic modulation of shared molecular pathways in gene regulation. This leads to heightened behavioral responses to subsequent pain and opioid stimulation in chronic pain development.
Synaptic plasticity and functions of glutamate receptors
Plasticity of glutamate synapses is a key process in normal brain functions and in disease etiology, but it was unclear how it plays in opioid regulation of reward and emotion. Our research has made important findings on synaptic dynamics of central glutamate synapses, synaptic circuits of glutamate transmission and their modulation by chronic pain and opioids in central amygdala, and molecular adaptation of glutamate AMPA receptors in associative learning of emotion-related stimulation and behavioral responses under chronic pain and long-term opioid conditions.
Brain circuits mediating opposing effects on pain and emotion.
In this latest series of projects with optogenetics and synaptic analyses, we have identified two brain circuits that have opposing functions in modulation of pain and emotion behaviors: activation of the excitatory pathway from the parabrachial nucleus (PBN) that relays peripheral pain signals to the central nucleus of amygdala (CeA) cause behaviors of negative emotion including anxiety, depression and aversion, but does not change pain sensitivity in rats; whereas activation of the excitatory pathway from basolateral amygdala (BLA) that conveys processed corticolimbic signals to CeA opposes these behaviors of negative emotion and inhibits pain. In CeA, pain differentially sensitizes the cell type with glutamate synaptic inputs of the PBN-CeA pathway for negative emotion and different cell type with glutamate synaptic inputs of the BLA-CeA pathway for sensitized pain. These findings identify two functionally distinct cell types in CeA and demonstrate that the pain signal conveyed through the glutamate PBN-CeA pathway is sufficient to drive negative emotion and that the corticolimbic signal via the glutamate BLA-CeA pathway counteracts the negative emotion. These findings suggest a top-down brain mechanism for cognitive control of negative emotion and pain modulation under stressful environmental conditions such as pain.