Source Paper
Chronic Morphine Induces Downregulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity
Jianren Mao, Backil Sung, Ru-Rong Ji, Grewo Lim
Journal of Neuroscience • 2002
Source Paper
Jianren Mao, Backil Sung, Ru-Rong Ji, Grewo Lim
Journal of Neuroscience • 2002
Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both morphine tolerance and associated thermal hyperalgesia. Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn. This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes. Morphine-induced GT downregulation reduced the ability to maintain in vivo glutamate homeostasis at the spinal level, because the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in morphine-treated rats with reduced spinal GTs. Moreover, the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia. Consistently, the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia. The effects from regulating spinal GT activity by PDC were at least in part mediated through activation of the NMDA receptor (NMDAR), because the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC. These results indicate that spinal GTs may contribute to the neural mechanisms of morphine tolerance and associated abnormal pain sensitivity by means of regulating regional glutamate homeostasis.
Objective: Examine the role of spinal glutamate transporters in the development of morphine tolerance and associated thermal hyperalgesia through chronic morphine administration
This is a Morphine Tolerance and Thermal Hyperalgesia Assessment protocol using rat as the model organism. The procedure involves 9 procedural steps, 1 equipment items, 6 materials. Extracted from a 2002 paper published in Journal of Neuroscience.
Model and subjects
rat • Not specified • unknown • Not specified • Not specified
Study window
Estimated timing pending
Core workflow
Chronic morphine administration via intrathecal boluses • Chronic morphine administration via continuous infusion • Assess glutamate transporter downregulation
Primary readouts
Key equipment and reagents
Verified items
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Administer morphine through intrathecal boluses in a dose-dependent manner
Note: This is one of two administration routes tested
“Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation”
Administer morphine through continuous infusion in a dose-dependent manner
Note: This is the alternative administration route tested
“Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation”
Examine downregulation of glutamate transporters (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn
Note: Measure in response to morphine treatment
“Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn”
Administer naloxone to determine if opioid receptors mediate glutamate transporter downregulation
Note: Confirms opioid receptor involvement
“This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes”
Assess hyperalgesic response to exogenous glutamate in morphine-treated rats with reduced spinal glutamate transporters
Note: Measure both magnitude and time course of response
“the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in morphine-treated rats with reduced spinal GTs”
Evaluate the temporal relationship between glutamate transporter downregulation and development of morphine tolerance and thermal hyperalgesia
Note: Establish correlation between molecular and behavioral changes
“the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia”
Administer PDC to potentiate the development of morphine tolerance and thermal hyperalgesia
Note: PDC is a glutamate transporter inhibitor
“the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia”
Administer riluzole to reduce the development of morphine tolerance and thermal hyperalgesia
Note: Riluzole is a positive glutamate transporter regulator
“the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia”
Administer MK-801 to determine if NMDA receptor activation mediates PDC-potentiated morphine tolerance and thermal hyperalgesia
Note: MK-801 is a noncompetitive NMDA receptor antagonist
“the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC”
This section explains what the experiment is doing, which readouts matter, what the data artifacts usually look like, and how the analysis should flow from raw capture to reported result.
Examine the role of spinal glutamate transporters in the development of morphine tolerance and associated thermal hyperalgesia through chronic morphine administration
Objective
Examine the role of spinal glutamate transporters in the development of morphine tolerance and associated thermal hyperalgesia through chronic morphine administration
Subjects
From paperrat • Not specified • unknown • Not specified • Not specified
Cohort notes
From paperNot specified
Chronic morphine administration via intrathecal boluses (Not specified)
Chronic morphine administration via continuous infusion (Not specified)
Assess glutamate transporter downregulation (Not specified)
Test naloxone blockade of glutamate transporter changes (Not specified)
Downregulation of spinal glutamate transporters (EAAC1 and GLAST)
From paperNot specified in the provided text
Artifact type
Endpoint measurements summarized by group or timepoint
Comparison focus
Compare endpoint magnitude between groups, timepoints, or both
Development of morphine tolerance
From paperNot specified in the provided text
Artifact type
Endpoint measurements summarized by group or timepoint
Comparison focus
Compare endpoint magnitude between groups, timepoints, or both
Development of thermal hyperalgesia
From paperNot specified in the provided text
Artifact type
Endpoint measurements summarized by group or timepoint
Comparison focus
Compare endpoint magnitude between groups, timepoints, or both
Hyperalgesic response to exogenous glutamate (magnitude and time course)
From paperNot specified in the provided text
Artifact type
Endpoint measurements summarized by group or timepoint
Comparison focus
Compare endpoint magnitude between groups, timepoints, or both
Downregulation of spinal glutamate transporters (EAAC1 and GLAST)
From paperRaw artifact
Per-sample or per-animal endpoint measurements collected during the experiment
Processed artifact
Structured table with cleaned measurements ready for comparison
Final reported form
Summary statistics and between-group or across-timepoint comparisons
Development of morphine tolerance
From paperRaw artifact
Per-sample or per-animal endpoint measurements collected during the experiment
Processed artifact
Structured table with cleaned measurements ready for comparison
Final reported form
Summary statistics and between-group or across-timepoint comparisons
Development of thermal hyperalgesia
From paperRaw artifact
Per-sample or per-animal endpoint measurements collected during the experiment
Processed artifact
Structured table with cleaned measurements ready for comparison
Final reported form
Summary statistics and between-group or across-timepoint comparisons
Hyperalgesic response to exogenous glutamate (magnitude and time course)
From paperRaw artifact
Per-sample or per-animal endpoint measurements collected during the experiment
Processed artifact
Structured table with cleaned measurements ready for comparison
Final reported form
Summary statistics and between-group or across-timepoint comparisons
Acquisition
Collect raw experimental outputs with enough metadata to preserve sample identity, condition, and timing.
Preprocessing / cleaning
Not specified in the provided text
Scoring or quantification
Quantify the primary readouts for this experiment: Downregulation of spinal glutamate transporters (EAAC1 and GLAST); Development of morphine tolerance; Development of thermal hyperalgesia; Hyperalgesic response to exogenous glutamate (magnitude and time course).
Statistical comparison
Statistical method not yet structured for this page.
Reporting output
Report representative outputs alongside summary comparisons for Downregulation of spinal glutamate transporters (EAAC1 and GLAST), Development of morphine tolerance, Development of thermal hyperalgesia, Hyperalgesic response to exogenous glutamate (magnitude and time course).
Source links and direct wording from the methods section for validation and deeper review.
Citation
Jianren Mao et al. (2002). Chronic Morphine Induces Downregulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity. Journal of Neuroscience
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