Inhibition of the ubiquitin-proteasome activity prevents glutamate transporter degradation and morphine tolerance.
Glutamate transporters play a crucial role in physiological glutamate homeostasis and neurotoxicity. Recently, we have shown that downregulation of glutamate transporters after chronic morphine exposure contributed to the development of morphine tolerance. In the present study, we examined whether regulation of the glutamate transporter expression with the proposed proteasome inhibitor MG-132 would contribute to the development of tolerance to repeated intrathecal (twice daily x 7 days) morphine administration in rats. The results showed that MG-132 (5 nmol) given intrathecally blocked morphine-induced glutamate transporter downregulation and the decrease in glutamate uptake activity within the spinal cord dorsal horn. Co-administration of morphine (15 nmol) with MG-132 (vehicle=1<2.5<5=10 nmol) also dose-dependently prevented the development of morphine tolerance in rats. These findings suggest that prevention of spinal glutamate transporter downregulation may regulate the glutamatergic function that has been implicated in the development of morphine tolerance. The possible relationship between MG-132-mediated regulation of glutamate transporters, ubiquitin-proteasome system, and the cellular mechanisms of morphine tolerance is discussed in light of these findings.
Yang
Liling
L
MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, WACC 324, 15 Parkman Street, Boston, MA 02114, USA.
Wang
Shuxing
S
Lim
Grewo
G
Sung
Backil
B
Zeng
Qing
Q
Mao
Jianren
J
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D007278:Injections, Spinal; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism*
D000701:Analgesics, Opioid; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D009020:Morphine; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde