Abrupt abstinence or withdrawal from opiate drugs causes a series of severe adverse symptoms, which keep drug-dependent individuals craving continued opiates. One of the core of withdrawal symptoms is an increase in pain sensitivity (pain sensitization or hyperalgesia). This pain sensitization is due to synaptic plasticity, particularly in the spinal cord and primary afferents. Recent evidence suggests that mechanisms underlying synaptic plasticity in the hippocampus may also occur in the spinal cord. Although acute exposure to opiates may induce hyperalgesia, chronic or repeated administration of the drug facilitate the magnitude and duration of opiate-induced hyperalgesia, and may expand the anatomical sites at which hyperalgesia is induced. Persistence of chronic opiate-induced hyperalgesia is consistent with cellular mechanisms of opiate dependence that only develop after repeated exposure to the drug. It has been demonstrated that AMPA glutamate receptor trafficking within the spinal cord is involved in the development of pain sensitivity. Similarly, hippocampal glutamatergic systems are thought to be involved in opiate-induced neuronal and behavioral plasticity. We propose to document the parallel changes in AMPA receptor expression occurring in opiate dependence and pain sensitivity at three different levels: 1) hippocampus, 2) spinal cord and 3) primary afferent neurons. The proposed experiments will test the hypothesis that acute withdrawal from repeated morphine administration results in sensory sensitization by altering synaptic expression and composition of AMPA receptors and that this neuroplasticity in AMPA receptors is similar to that underlying chronic inflammatory pain.
In Specific Aim 1 we will characterize the sensory sensitization that develops in a model of morphine withdrawal and compare it to the sensitization that develops in a model of chronic inflammatory pain.
In Specific Aim 2 we will analyze the dynamic changes in expression and composition of AMPA receptor subunits (GluR1/2/3) in morphine withdrawal-associated sensitization and compare them to those occurring in chronic inflammatory pain.
In Specific Aim 3 we will characterize the neuroplasticity in AMPA receptor synapses underlying morphine withdrawal-associated sensory sensitization and compare it to the AMPA receptor neuroplasticity underlying chronic inflammatory pain.
In Specific Aim 4 we will demonstrate that treatment with AMPA antagonists relieves both morphine withdrawal-associated sensory sensitization as well as that associated with chronic inflammatory pain. These studies are significant because they will elucidate key glutamatergic maladaptive changes that opiate addicts and inflammatory pain patients have in common. Overall, these studies will provide insight into the neuroplasticity that may lead to novel approaches for pharmacotherapeutic intervention for pain treatment in opiate addicts.

Public Health Relevance

The experiments proposed in this application will address the question of how drug-induced alterations in the hippocampus, spinal cord and primary afferents contribute to enhanced sensory sensitivity in opiate addicts. These results will enhance our understanding of the synaptic molecular and membrane mechanisms underlying this adverse effect of drug dependence and will help us to improve pain management in opiate addicts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA027460-04S1
Application #
8657525
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (50))
Program Officer
Sorensen, Roger
Project Start
2010-05-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$7,020
Indirect Cost
$520
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Massaly, Nicolas; Morón, Jose A; Al-Hasani, Ream (2016) A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System. Front Neurosci 10:480
Fakira, Amanda K; Massaly, Nicolas; Cohensedgh, Omid et al. (2016) Morphine-Associated Contextual Cues Induce Structural Plasticity in Hippocampal CA1 Pyramidal Neurons. Neuropsychopharmacology 41:2668-78
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Beaudry, H; Gendron, L; Morón, J A (2015) Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain. Eur J Neurosci 41:901--7
Szteyn, Kalina; Rowan, Matthew P; Gomez, Ruben et al. (2015) A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons. Pain 156:2364-72
Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda et al. (2015) Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors. J Neurosci 35:12217-31
Gallo, Eduardo F; Salling, Michael C; Feng, Bo et al. (2015) Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology 40:1609-18
Hipólito, Lucia; Fakira, Amanda K; Cabañero, David et al. (2015) In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model. Pain 156:849-58
Stockton Jr, Steven D; Gomes, Ivone; Liu, Tong et al. (2015) Morphine Regulated Synaptic Networks Revealed by Integrated Proteomics and Network Analysis. Mol Cell Proteomics 14:2564-76
Fakira, Amanda K; Portugal, George S; Carusillo, Brianna et al. (2014) Increased small conductance calcium-activated potassium type 2 channel-mediated negative feedback on N-methyl-D-aspartate receptors impairs synaptic plasticity following context-dependent sensitization to morphine. Biol Psychiatry 75:105-14

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