Opioid administration, not only results in immediate effects at the neurotransmitter or ion channel levels, but also produces neuronal plasticity mediated by changes in gene expression. The overall objectives of this research are to quantitate and localize the alterations in receptor, neurotransmitter, neuromodulator, and signal transduction gene expression and biosynthesis that occur in opioid tolerant and dependent systems. By use of solution hybridization, ligand binding assays, radioimmunoassays, in situ hybridization and immunocytochemical techniques, the mRNA and/or peptide levels for NMDA, opioid receptors, nitric oxide synthase (NOS), proenkephalin, prodynorphin, c-fos, and tyrosine hydroxylase will be examined in selected CNS areas that are associated with opioid analgesia, tolerance and dependence. The strategy to be employed will use facile solution hybridization, RIA and binding assays to identify CNS areas where opioid induced changes occur. Then a systematic analysis employing additional techniques will be used to localize the changes and to identify additional discriminative markers. These studies will be conducted in animals made tolerant and/or dependent with mu, kappa or delta opioids. The specificity of the opioid induced effects will be enhanced by the use of paradigms in which animals are also co-administered agents (an NMDA antagonist, a NOS inhibitor or an antisense oligonucleotide) that attenuate opioid tolerance and dependence. Excitatory amino acid antagonists (NMDA and non-NMDA), NOS inhibitors, neuronal specific calcium channel blockers and antisense oligos will be evaluated in vivo for their ability to attenuate and/or reverse opioid tolerance. In addition to providing new insights into the biochemical and molecular events that underly opioid tolerance and dependence these studies are designed to discover new, prototypic drug that may be of value as adjuncts in the management of pain and in the treatment of opioid abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001457-23
Application #
2683800
Study Section
Special Emphasis Panel (SRCD (03))
Program Officer
Lin, Geraline
Project Start
1976-05-01
Project End
1999-03-31
Budget Start
1998-04-20
Budget End
1999-03-31
Support Year
23
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Xu, Jin; Xu, Ming; Brown, Taylor et al. (2013) Stabilization of the ?-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action. J Biol Chem 288:21211-27
Schierberl, Kathryn; Hao, Jin; Tropea, Thomas F et al. (2011) Cav1.2 L-type Ca²? channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels. J Neurosci 31:13562-75
Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole et al. (2011) Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation. Synapse 65:643-51
Hunter, Deirtra A; Barr, Gordon A; Shivers, Kai-Yvonne et al. (2011) Interactions of estradiol and NSAIDS on carrageenan-induced hyperalgesia. Brain Res 1382:181-8
Gregus, Ann M; Tropea, Thomas F; Wang, Yanran et al. (2010) Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference. Neurosci Lett 468:186-9
Weyerbacher, Amanda R; Xu, Qinghao; Tamasdan, Cristina et al. (2010) N-Methyl-D-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain 148:237-46
Gregus, A M; Inra, C N; Giordano 3rd, T P et al. (2010) Spinal mediators that may contribute selectively to antinociceptive tolerance but not other effects of morphine as revealed by deletion of GluR5. Neuroscience 169:475-87
Bogulavsky, Johanna J; Gregus, Ann M; Kim, Paul T-H et al. (2009) Deletion of the glutamate receptor 5 subunit of kainate receptors affects the development of morphine tolerance. J Pharmacol Exp Ther 328:579-87
Garraway, Sandra M; Xu, Qinghao; Inturrisi, Charles E (2009) siRNA-mediated knockdown of the NR1 subunit gene of the NMDA receptor attenuates formalin-induced pain behaviors in adult rats. J Pain 10:380-90
Klein, Gad; Rossi, Grace C; Waxman, Amanda R et al. (2009) The contribution of MOR-1 exons 1-4 to morphine and heroin analgesia and dependence. Neurosci Lett 457:115-9

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