We are conducting a coordinated series of biochemical, pharmacological, physiological, and neuroanatomical studies to investigate the functional significance of dynamic peptide processing events in tachykinin and opioid neural systems. Tachykinins are small peptides with potent contractile, secretory and electrical activities. The mammalian tachykinin family includes the widely studied neuropeptide substance P and the more recently described neurokinins A and B. Mature tachykinins are derived by selective processing of preprotachykinin (PPT) molecules expressed from either of two PPT genes. To gain an in depth understanding of the dynamic molecular events underlying PPT systems, we will perform detailed analyses of mature and immature tachykinins, and PPT mRNAs. In addition, we will provide complementary analyses of endogenous opioid peptides and preproenkephalin mRNAs, in order to monitor changes at the molecular level that may accurately reflect functional interrelationships between these major neural systems. Our overall objectives are: 1) to provide biochemical descriptions and chromatographic profiles of different molecular forms of PPT-related peptides in rodent neural tissues, 2) to compare and contrast the extent of terminal amidation of tachykinin peptides in rodent neural tissues, 3) to probe the role of unamidated tachykinin precursor species in the regulation of expression of tachykinin and opioid peptides, 4) to assess the biochemical effects of hormonal, pharmacological, and physiological manipulations on interactive tachykin, opioid, and monoaminergic neural systems, 5) to probe the biochemical and molecular dynamics of interactive tachykinin and opioid systems in anatomical pathways related to pain and analgesia. Overall, the proposed studies will strengthen the molecular foundation for research on functionally interactive tachykinin- and opioid-synthesizing neural systems, and on the molecular mechanisms by which narcotics can influence sensory and affective processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA004128-04A1
Application #
3209304
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1986-07-01
Project End
1993-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Foran, S E; Carr, D B; Lipkowski, A W et al. (2000) A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic. Proc Natl Acad Sci U S A 97:7621-6
Nikulina, E M; Hammer Jr, R P; Miczek, K A et al. (1999) Social defeat stress increases expression of mu-opioid receptor mRNA in rat ventral tegmental area. Neuroreport 10:3015-9
Miczek, K A; Nikulina, E; Kream, R M et al. (1999) Behavioral sensitization to cocaine after a brief social defeat stress: c-fos expression in the PAG. Psychopharmacology (Berl) 141:225-34
Marchand, J E; Cepeda, M S; Carr, D B et al. (1999) Alterations in neuropeptide Y, tyrosine hydroxylase, and Y-receptor subtype distribution following spinal nerve injury to rats. Pain 79:187-200
Nikulina, E M; Marchand, J E; Kream, R M et al. (1998) Behavioral sensitization to cocaine after a brief social stress is accompanied by changes in fos expression in the murine brainstem. Brain Res 810:200-10
Goudas, L C; Carr, D B; Maszczynska, I et al. (1997) Differential effect of central versus parenteral administration of morphine sulfate on regional concentrations of reduced glutathione in rat brain. Pharmacology 54:92-7
Rittenhouse, P A; Markle, R A; Marchand, J E et al. (1996) Streptozotocin-induced diabetes produces a decrease in pituitary substance P content and preprotachykinin mRNA. Neurosci Lett 211:77-80
Rittenhouse, P A; Marchand, J E; Chen, J et al. (1996) Streptozotocin-induced diabetes is associated with altered expression of peptide-encoding mRNAs in rat sensory neurons. Peptides 17:1017-22
Bokesch, P M; Marchand, J E; Connelly, C S et al. (1994) Dextromethorphan inhibits ischemia-induced c-fos expression and delayed neuronal death in hippocampal neurons. Anesthesiology 81:470-7
Kream, R M; Marchand, J E; O'Connor, S T et al. (1994) Expression of substance P and its precursor forms in vagal, tracheal, and lung tissues of the guinea pig. Am J Physiol 267:L807-14

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