The long term goal of this application is to learn how the amounts and release of the endogenous opioid peptides are regulated. This information is critical for an understanding of the role of these peptides in opioid tolerance and dependence and in discovering low to use the endogenous opioid peptides as a new method for the management of pain. The objectives of this proposal are to describe and define the factors that regulate opioid peptide gene expression, biosynthesis and release and to determine whether treatments that may alter opioid peptides and their mRNAs are linked to the function (e.g., analgesia) of the endogenous opioid peptides. In addition to a quantitative Northern blot analysis procedure already in use, methods will be developed or adapted for the quantitation of opioid peptide mRNAs, their processing and localization including a new quantitative solution by hybridization assay, a nuclear run-on transcription assay, a primary transcript protection assay and an in situ hybridization technique. Opioid peptide gene expression and the relative amounts of opioid peptide precursors and posttranslational processing products will be measured by use of radioimmunoassays, size exclusion and high performance liquid chromatographic methods we have developed. The targets for study include the CNS (striatum, hippocampus, hypo- thalamus and pituitary) and the adrenal medulla of rats and hamsters at different postnatal and adult ages, during and after acute and chronic opioid agonist and antagonist treatment and following opioid and nonopioid stressors. These later studies will attempt to link biochemical changes in the levels and the release of the endogenous opioid peptide system to functional effects such as analgesia. Explants of rat adrenal medulla and striatum and a human glioma cell line will be used to examine the co-regulation of opioid peptides and co-localized catecholamine and to define the mechanisms of hormonal and neurogenic regulation of opioid peptide gene expression and biosynthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001457-15
Application #
3206923
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1976-05-01
Project End
1994-04-30
Budget Start
1990-06-01
Budget End
1991-04-30
Support Year
15
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
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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