It has recently been discovered that glia become progressively more activated upon repeated exposure to morphine, &that this glial activation, in turn, modulates morphine's effects. This discovery was originally made in the context of studying the pain suppressive effects of morphine in spinal cord. The possibility that glia may be fundamentally important in determining the effects of opioids such as morphine is novel &important in its implications. Because of this, we propose to explore whether glia may profoundly alter the effects of repeated morphine in brain, as well. We believe that glia will prove to be powerfully involved in several phenomena currently thought to arise purely as a result of opioid effects on neurons;that is, dependence/withdrawal, reward &aversion. If this were true, it would provide evidence that glia are critically involved, not only in modulating the pain-suppressive effects of opioids, but also in key phenomena associated with human opioid abuse &addiction. Having considered the clinical importance of opioid dependence/withdrawal, reward &aversion &the paucity of knowledge regarding glial involvement in any of these, we have chosen to first determine the range of opioid-related phenomena in which glia &glial products play an important role, before detailed analyses of any single phenomenon. We chose this strategy as it is the right approach for this stage of investigation. The data to be obtained will provide guidance as to which of these phenomena should later be studied in detail, including issues of generality to other opioid &non-opioid drugs beyond morphine.
The aims of the proposal are: (1) To define whether glial activation contributes to the development &/or maintenance of morphine dependence. This will be accomplished by characterizing whether inhibition of glial activation before or after establishment of opioid dependence impacts the expression of morphine withdrawal. Whether glia contribute to CNS side effects associated with dependence-inducing opioid administration will be assessed as well. (2) To characterize changes induced in glia by in vivo morphine dependence/withdrawal. Here, (a) brain regions implicated in the effects of repeated morphine &(b) rapidly isolated microglia will each be examined using immunohistochemical, protein &/or mRNA analyses. (3) To define whether glial activation contributes to morphine reward or aversion. This will be accomplished by characterizing whether inhibition of glial activation disrupts conditioned place preference &/or conditioned place aversion. In these studies, inhibition of glial activation will be accomplished in 2 ways: (a) using 2 blood-brain barrier permeable glial activation inhibitors &(b) blocking the recently discovered non-classical opioid receptor on glia.

Public Health Relevance

It has recently been discovered that glia become progressively more activated upon repeated exposure to morphine &that this glial activation, in turn, decreases the ability of morphine to suppress pain. This proposal extends the exploration of glial regulation of opioid actions, by examining whether glia are powerfully involved in several phenomena currently thought to arise purely as a result of opioid effects on neurons;that is, dependence/withdrawal, reward &aversion. If this proves true, it would provide evidence that glia are critically involved, not only in modulating the pain-suppressive effects of opioids, but also in key phenomena associated with human opioid abuse &addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023132-05
Application #
8215920
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Pilotte, Nancy S
Project Start
2008-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$359,635
Indirect Cost
$119,560
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441-50
Ellis, Amanda; Grace, Peter M; Wieseler, Julie et al. (2016) Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav Immun 58:348-356
Grace, Peter M; Fabisiak, Timothy J; Green-Fulgham, Suzanne M et al. (2016) Prior voluntary wheel running attenuates neuropathic pain. Pain 157:2012-23
Bachtell, Ryan; Hutchinson, Mark R; Wang, Xiaohui et al. (2015) Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4. CNS Neurol Disord Drug Targets 14:692-9
Northcutt, A L; Hutchinson, M R; Wang, X et al. (2015) DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry 20:1525-37
Lewis, Susannah S; Hutchinson, Mark R; Frick, Morin M et al. (2015) Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain. Brain Behav Immun 44:128-36
Grace, Peter M; Maier, Steven F; Watkins, Linda R (2015) Opioid-induced central immune signaling: implications for opioid analgesia. Headache 55:475-89
Grace, Peter M; Strand, Keith A; Maier, Steven F et al. (2014) Suppression of voluntary wheel running in rats is dependent on the site of inflammation: evidence for voluntary running as a measure of hind paw-evoked pain. J Pain 15:121-8
Hutchinson, Mark R; Watkins, Linda R (2014) Why is neuroimmunopharmacology crucial for the future of addiction research? Neuropharmacology 76 Pt B:218-27
Grace, P M; Ramos, K M; Rodgers, K M et al. (2014) Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae. Neuroscience 280:299-317

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