Opioids are the most effective treatment for pain. Unfortunately, their efficacy decreases with repeated administration because of the development of tolerance. The broad long-term objective of this research is to understand the underlying neural mechanisms for tolerance so more effective pain treatments can be developed. Many previous studies have examined opioid tolerance. However, these studies show over 30 different mechanisms for tolerance, and it is unlikely that all of these putative mechanisms are directly involved. The proposed studies will focus on tolerance in the ventrolateral periaqueductal gray (PAG) in an attempt to identify causal mechanisms for tolerance. PAG neurons are particularly well suited for studying opioid tolerance because microinjection of morphine into the PAG produces antinociception and repeated microinjections produce tolerance. In addition, the neuronal circuitry and intracellular signaling cascades through which opioids produce antinociception have been described. The proposed studies will take advantage of both intracellular and behavioral measures of tolerance in an attempt to understand the neurochemical basis of tolerance in these neurons. Tolerance could be caused by a change anywhere along the signaling pathway from opioid receptors to feedback circuits.
The aims of this project will examine all of the steps along this pathway.
Aim 1 will identify the specific PAG neurons that contribute to opioid tolerance.
Aim 2 will determine whether receptor internalization contributes to the development of tolerance.
Aim 3 will identify the intracellular molecules that contribute to the development of tolerance.
And Aim 4 will determine whether feedback to the PAG is necessary for the development of tolerance. A unique feature of this project is that whole cell recordings will be used to link neuronal changes to behavioral measures of tolerance. For example, the intracellular signaling cascades believed to contribute to tolerance will be systematically disrupted to determine the contribution of each step in this signaling cascade to opioid tolerance measured behaviorally. The combined use of in vivo and in vitro techniques provides a powerful approach to understanding the link between molecular changes and behavioral consequences. In the long term, such knowledge will contribute to the development of therapies that improve pain treatment by preventing tolerance to opioids.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA015498-01A1
Application #
6613655
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Lin, Yu
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$272,140
Indirect Cost
Name
Washington State University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Campion, Kyle N; Saville, Kimber A; Morgan, Michael M (2016) Relative contribution of the dorsal raphe nucleus and ventrolateral periaqueductal gray to morphine antinociception and tolerance in the rat. Eur J Neurosci 44:2667-2672
Tryon, Valerie L; Mizumori, Sheri J Y; Morgan, Michael M (2016) Analysis of morphine-induced changes in the activity of periaqueductal gray neurons in the intact rat. Neuroscience 335:1-8
Bobeck, Erin N; Ingram, Susan L; Hermes, Sam M et al. (2016) Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance. Behav Brain Res 298:17-24
Morgan, Michael M; Reid, Rachel A; Saville, Kimber A (2014) Functionally selective signaling for morphine and fentanyl antinociception and tolerance mediated by the rat periaqueductal gray. PLoS One 9:e114269
Bobeck, Erin N; Chen, QiLiang; Morgan, Michael M et al. (2014) Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance. Neuropsychopharmacology 39:2142-52
Bobeck, Erin N; Haseman, Rachel A; Hong, Dana et al. (2012) Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat. J Pain 13:799-807
Morgan, Michael M; Christie, MacDonald J (2011) Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol 164:1322-34
Gunn, Amanda; Bobeck, Erin N; Weber, Ceri et al. (2011) The influence of non-nociceptive factors on hot-plate latency in rats. J Pain 12:222-7
Macey, T A; Ingram, S L; Bobeck, E N et al. (2010) Opioid receptor internalization contributes to dermorphin-mediated antinociception. Neuroscience 168:543-50
Fyfe, Leon W; Cleary, Daniel R; Macey, Tara A et al. (2010) Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons. J Pharmacol Exp Ther 335:674-80

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