Opioid dependence is a chronic and relapsing disease and characterized by compulsive drug seeking and use. Opioid dependence results in excessive degrees of physical dependence (withdrawal syndrome). Although psychological dependence on opioids is an important feature of dependence/abuse, physical dependence itself (withdrawal syndrome) is a major cause of compulsive drug-taking behavior and short term relapse. Unfortunately, the mechanism of opioid in the pathological changes in opioid dependence is not yet understood in detail. Recent studies show that chronic morphine induces release of proinflammatory cytokines (e.g. TNF?). Oxidative stress may participate in the process of dependence /withdrawal of heroin. However, very few studies have addressed the precise mechanisms by which these glial elements contribute to CNS neuronal TNFR, calcium and ROS response in opioid withdrawal. The role of the PAG in the expression of opioid withdrawal has been suggested by studies, but we know little of the detailed molecular mechanisms. Here, we hypothesize that glial activation resulting in the release of proinflammatory cytokines, and that neurons activated by cytokine receptor induce mitochondrial ROS and pCREB (a key protein in drug abuse behavior) in the development of morphine withdrawal.
Specific Aim 1, To test whether glial TLR4 activation induces release of cytokine in morphine withdrawal.
Specific Aim 2, To test whether activation of cytokine receptor induces mitochondrial ROS in morphine withdrawal in the PAG.
Specific Aim 3, To test whether mitochondrial ROS in the PAG is involved in MW through the pCREB. The proposal will use assays of pharmacology, molecular biology, immunohistochemistry, cell type-targeting gene transfection, and imaging density analysis to complete the novel hypothesis. The results of these studies will provide important insights into the pathogenesis of opioid abuse, and may provide preclinical evidence for a novel therapy of opioid dependence.
Opioid dependence places a large burden on the nation's health care systems and the economy. This proposal will investigate the activation of glia to neurons in the opioid dependence, and will provide significant insights as to the discrete neurobiological mechanisms. Identification of these mechanisms may be useful for developing new therapeutic strategies to treat or prevent drug abuse and addiction.
|Kanda, H; Kanao, M; Liu, S et al. (2016) HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a. Gene Ther 23:340-8|
|Kanda, Hirotsugu; Liu, Shue; Iida, Takafumi et al. (2016) Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats. Anesth Analg 122:264-72|
|Gunda, Sampath; Kanmanthareddy, Arun; Atkins, Donita et al. (2015) Role of yoga as an adjunctive therapy in patients with neurocardiogenic syncope: a pilot study. J Interv Card Electrophysiol 43:105-10|
|Guedon, Jean-Marc G; Wu, Shaogen; Zheng, Xuexing et al. (2015) Current gene therapy using viral vectors for chronic pain. Mol Pain 11:27|
|Kanao, Megumi; Kanda, Hirotsugu; Huang, Wan et al. (2015) Gene Transfer of Glutamic Acid Decarboxylase 67 by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 Combined with ddC in Rats. Anesth Analg 120:1394-404|
|Zheng, Wenwen; Huang, Wan; Liu, Shue et al. (2014) IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats. Mol Pain 10:49|
|Zheng, Wenwen; Huang, Wan; Liu, Shue et al. (2014) Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats. Anesth Analg 119:693-701|