Opioid actions are mediated primarily by three classic opioid receptors: mu, delta and kappa. Currently, opioid analgesics, mainly mu-opioid receptor (MOR) agonists such as morphine and fentanyl, are still the most effective pain relievers available and are widely used for the treatment of many forms of chronic pain. However, repeated use of opioids causes analgesic tolerance and physical dependence as a result of prolonged stimulation of MOR, which significantly reduces the analgesic effect of MOR agonists and limits their long-term clinical use for chronic pain management. In contrast to the well-characterized MOR actions, the function of delta-opioid receptors (DOR) is much less clear. DOR agonists produce little to weak analgesic effect both in animals and in humans under normal conditions. Recent studies including ours have demonstrated that the weak DOR effect is primarily due to the predominant intracellular localization of non- functional DOR in normal conditions, and more interestingly, the intracellular DOR is trafficked to plasma membrane and becomes functional after several forms of long-term neurochemical stimulation, including chronic morphine exposure. However, the molecular signal and mechanisms mediating the exocytotic DOR trafficking are completely unknown at present. In our preliminary studies exploring the issue recently, we have discovered that nerve growth factor (NGF), a neurotrophin with diverse functions in neuronal growth and differentiation, can trigger and maintain similar DOR trafficking and induce functional DOR in pain-modulating brainstem neurons under normal conditions. This represents a novel NGF function that has not been reported to date. Therefore, this proposal is aimed to identify the molecular mechanisms mediating the NGF- and chronic morphine-induced DOR trafficking and analgesic function, and to determine the synaptic and behavioral interactions of the emergent DOR with MOR in regulation of both central synaptic activity and pain inhibition in the context of chronic morphine. Findings from this project will provide the first evidence for NGF as a critical molecular mediator of membrane trafficking of G-protein-coupled receptors including DOR in central neurons, and will demonstrate the potential for DOR agonists as effective analgesics for chronic pain under chronic opioid conditions with decreased MOR effects. Project Narrative Repeated use of opioid analgesics, the current pain reliever of choice, causes analgesic tolerance and physical dependence, which significantly reduce their analgesic effects and limit their clinical use for adequate control of moderate to severe pain. This research proposal investigates the cellular and molecular mechanisms underlying a new analgesic function of different opioid compounds in brain cells after repeated opioid administration. These studies may provide neuropharmacological evidence for using these opioid compounds as more effective analgesics under an opioid-tolerant and dependent state.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023069-05
Application #
8263781
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Rapaka, Rao
Project Start
2008-07-01
Project End
2013-10-30
Budget Start
2012-05-01
Budget End
2013-10-30
Support Year
5
Fiscal Year
2012
Total Cost
$295,772
Indirect Cost
$103,712
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Cai, You-Qing; Wang, Wei; Hou, Yuan-Yuan et al. (2014) Optogenetic activation of brainstem serotonergic neurons induces persistent pain sensitization. Mol Pain 10:70
Zhang, Zhi; Tao, Wenjuan; Hou, Yuan-Yuan et al. (2014) MeCP2 repression of G9a in regulation of pain and morphine reward. J Neurosci 34:9076-87
Zhang, Zhi; Tao, Wenjuan; Hou, Yuan-Yuan et al. (2014) Persistent pain facilitates response to morphine reward by downregulation of central amygdala GABAergic function. Neuropsychopharmacology 39:2263-71
Zhang, Zhi; Wang, Xinxing; Wang, Wei et al. (2013) Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl- cotransporter and cell-type-specific GABA impairment for activation of descending pain facilitation. Mol Pharmacol 84:511-20
Cai, You-Qing; Wang, Wei; Hou, Yuan-Yuan et al. (2013) Central amygdala GluA1 facilitates associative learning of opioid reward. J Neurosci 33:1577-88
Pan, Zhizhong Z (2012) A life switch in pain. Pain 153:738-9
Pan, Zhizhong Z (2012) Transcriptional control of Gad2. Transcription 3:68-72
Zhang, Zhi; Pan, Zhizhong Z (2012) Signaling cascades for ?-opioid receptor-mediated inhibition of GABA synaptic transmission and behavioral antinociception. Mol Pharmacol 81:375-83
Zhang, Zhi; Cai, You-Qing; Zou, Fang et al. (2011) Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med 17:1448-55
Zhang, Zhi; Pan, Zhizhong Z (2010) Synaptic mechanism for functional synergism between delta- and mu-opioid receptors. J Neurosci 30:4735-45

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