The goal of this research project is to understand neural and molecular mechanisms of thermal hyperalgesia associated with narcotic tolerance. Recent investigations have indicated that thermal hyperalgesia develops in association with the development of narcotic tolerance and that excitatory amino acid (EAA) receptor activation and subsequent intracellular second messenger systems may play a critically important role in central nervous system mechanisms of thermal hyperalgesia associated with narcotic tolerance. Thus, multidisciplinary approaches including behavioral, pharmacological, autoradiographic, and immunocytochemical methods will be used to accomplish 3 specific aims: (l) To clarify the time course and dose-response relationships of morphine treatment as well as the role of the opiate kappa receptor in the development of thermal hyperalgesia associated with narcotic tolerance; (2) To determine the role of EAA receptors (both ionotropic and metabotropic EAA receptors) and their relationships in the development and expression of the thermal hyperalgesia; and (3) To determine the role of EAA receptor mediated changes in intracellular protein kinase C and nitric oxide and their relationships in the development and expression of the thermal hyperalgesia. This proposed work will provide novel and important information on neural and molecular mechanisms of hyperalgesia that may be common to thermal hyperalgesia associated with the development of narcotic tolerance in particular and with neurogenic and inflammatory etiologies in general. Because of the intimate relationship between narcotic tolerance and associated thermal hyperalgesia as well as potential interrelations between hyperalgesia induced by narcotic treatment and nerve (tissue) injury or inflammation, the results of this work may help to improve clinical utility of narcotic analgesics in treatment of chronic pain states. In addition, the results from assessment of the roles of EAA receptors, protein kinase C, and nitric oxide will provide insights into the neurobiology of narcotic tolerance which could result in additional clinical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008835-03
Application #
2377391
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1995-04-01
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Shen, Shiqian; Lim, Grewo; You, Zerong et al. (2017) Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci 20:1213-1216
Yang, Liling; Wang, Shuxing; Sung, Backil et al. (2008) Morphine induces ubiquitin-proteasome activity and glutamate transporter degradation. J Biol Chem 283:21703-13
Sung, Backil; Wang, Shuxing; Zhou, Bei et al. (2007) Altered spinal arachidonic acid turnover after peripheral nerve injury regulates regional glutamate concentration and neuropathic pain behaviors in rats. Pain 131:121-31
Wang, Shuxing; Lim, Grewo; Mao, Ji et al. (2007) Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats. Pain 131:96-105
Wang, Shuxing; Lim, Grewo; Yang, Liling et al. (2006) Downregulation of spinal glutamate transporter EAAC1 following nerve injury is regulated by central glucocorticoid receptors in rats. Pain 120:78-85
Lim, Jeongae; Lim, Grewo; Sung, Backil et al. (2006) Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats. Brain Res 1123:80-8
Lim, Grewo; Wang, Shuxing; Mao, Jianren (2005) Central glucocorticoid receptors modulate the expression of spinal cannabinoid receptors induced by chronic morphine exposure. Brain Res 1059:20-7
Lim, Grewo; Wang, Shuxing; Zeng, Qing et al. (2005) Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor. J Neurosci 25:11145-54
Mao, Jianren (2005) Glutamate transporter: an unexpected target for some antibiotics. Mol Pain 1:5
Lim, Grewo; Wang, Shuxing; Zeng, Qing et al. (2005) Evidence for a long-term influence on morphine tolerance after previous morphine exposure: role of neuronal glucocorticoid receptors. Pain 114:81-92

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