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, and evaluate effects of glutamate transporter inhibitor PDC and positive regulator riluzole on these phenomena
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Administer morphine chronically to rats through either intrathecal boluses or continuous infusion to induce dose-dependent downregulation of glutamate transporters
Note: Two administration routes tested: intrathecal boluses or continuous infusion
“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”
Measure downregulation of glutamate transporters EAAC1 and GLAST in the superficial spinal cord dorsal horn following morphine treatment
Note: Downregulation is mediated through opioid receptors
“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 verify that glutamate transporter downregulation is mediated through opioid receptors
Note: Naloxone should block glutamate transporter changes
“This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes”
Evaluate the ability to maintain in vivo glutamate homeostasis at the spinal level by measuring hyperalgesic response to exogenous glutamate in morphine-treated rats with reduced spinal glutamate transporters
Note: Enhanced hyperalgesic response indicates impaired glutamate homeostasis
“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”
Measure the temporal correlation between spinal glutamate transporter downregulation and the development of morphine tolerance and thermal hyperalgesia
Note: Temporal correlation should be established between all three phenomena
“the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia”
Administer glutamate transporter inhibitor PDC and measure its effects on the development of morphine tolerance and thermal hyperalgesia
Note: PDC should potentiate both morphine tolerance and thermal hyperalgesia development
“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 positive glutamate transporter regulator riluzole and measure its effects on the development of morphine tolerance and thermal hyperalgesia
Note: Riluzole should reduce both morphine tolerance and thermal hyperalgesia development
“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 noncompetitive NMDA receptor antagonist MK-801 to determine if PDC effects are mediated through NMDA receptor activation
Note: MK-801 should block both morphine tolerance and thermal hyperalgesia potentiated by PDC
“the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC”
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