The human infant is often exposed to opiate drugs over extended periods of time, either due to drug abuse of the mother or because of medical conditions. Two serious clinical problems are the development of tolerance to the medical use of opiates for analgesia and dependence to both prescribed and abused opiates. Little is known of the mechanisms that mediate either withdrawal or tolerance in the infant in large part because appropriate animal models have only recently been developed. Although many of the biological mediators of opiate withdrawal in the infant are similar to those of the adult, we have recently discovered that NMDA glutamate antagonists, which are effective antidotes for withdrawal and tolerance to opiates in the adult, are fully ineffective in the infant rat and may indeed exacerbate both withdrawal and tolerance in the young. In contrast, our preliminary data show that both an AMPA glutamate receptor blocker and a metabotropic glutamate receptor (mGluR) agonist completely prevent the expression of morphine withdrawal. We hypothesize specific developmental mechanisms that could explain these data including developmental differences in glutamate receptor subtypes and subunits and alterations in the ability of opiates to up- and downregulate glutamate receptors. The experiments described in this application provide detailed descriptions of the effects of NMDA, AMPA and mGlu receptor antagonists and mGluR Group H agonists on precipitated withdrawal and tolerance to the analgesic effects of morphine both in vivo, measured behaviorally or by c-fos expression, and measured electrophysiologically in the isolated spinal cord preparation. The latter preparation allows us to focus experiments in subsequent aims on the spinal cord and to describe both the normal maturation of glutamate receptors and the ability of morphine to up- or downregulate those receptors. In the final aim, we study mice with genetic disruptions of the normal expression of specific glutamate receptors to determine if the changes in withdrawal and tolerance in the infant mice follow the predictions based on the hypotheses put forth and the pharmacological and biochemical data from the prior aims. The results of these experiments will provide substantial information about mechanisms by which glutamate receptor function is different in the infant than the adult and provide direction for the development of pharmacological tools that are uniquely effective in the human infant.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006600-13
Application #
6719033
Study Section
Special Emphasis Panel (ZRG1-IFCN-5 (05))
Program Officer
Thadani, Pushpa
Project Start
1989-09-30
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
13
Fiscal Year
2004
Total Cost
$237,167
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Barr, Gordon A; McPhie-Lalmansingh, Anika; Perez, Jessica et al. (2011) Changing mechanisms of opiate tolerance and withdrawal during early development: animal models of the human experience. ILAR J 52:329-41
McPhie, Anika A; Barr, Gordon A (2009) Regional Fos expression induced by morphine withdrawal in the 7-day-old rat. Dev Psychobiol 51:544-52
Butkevich, Irina P; Barr, Gordon A; Vershinina, Elena A (2007) Sex differences in formalin-induced pain in prenatally stressed infant rats. Eur J Pain 11:888-94
Butkevich, I P; Barr, G A; Vershinina, E A (2007) [Sex-dependent differences in parameters of a long-term pain caused by inflammatory focus in prenatally stressed newborn rats] Zh Evol Biokhim Fiziol 43:54-9
Butkevich, Irina P; Barr, Gordon A; Mikhailenko, Victor A et al. (2006) Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infant rats. Neurosci Lett 403:222-6
Zhu, Hongbo; Barr, Gordon A (2003) Ontogeny of NMDA receptor-mediated morphine tolerance in the postnatal rat. Pain 104:437-47
Jones, Kathy L; Zhu, Hongbo; Jenab, Shirzad et al. (2002) Attenuation of acute morphine withdrawal in the neonatal rat by the competitive NMDA receptor antagonist LY235959. Neuropsychopharmacology 26:301-10
Jones, K L; Barr, G A (2001) Injections of an opioid antagonist into the locus coeruleus and periaqueductal gray but not the amygdala precipitates morphine withdrawal in the 7-day-old rat. Synapse 39:139-51
Zhu, H; Barr, G A (2001) Opiate withdrawal during development: are NMDA receptors indispensable? Trends Pharmacol Sci 22:404-8
Zhu, H; Barr, G A (2001) Inhibition of morphine withdrawal by the NMDA receptor antagonist MK-801 in rat is age-dependent. Synapse 40:282-93

Showing the most recent 10 out of 23 publications