N-Methyl-D-aspartate receptor antagonist MK-801 attenuates morphine tolerance and associated glial fibrillary acid protein up-regulation: a proteomic approach.
BACKGROUND
It is well known that long-term morphine administration results in tolerance, which limits the clinical use of this drug in pain management.


METHODS
Male Wistar rats were randomly assigned to receive one of four different infusions: morphine [15 microg/h, intrathecal (i.t.)], saline, MK-801 (5 microg/h, i.t.) plus morphine (15 microg/h, i.t.), or MK-801 (5 microg/h, i.t.) alone.


RESULTS
Morphine infusion induced a maximal antinociceptive effect on day 1 and tolerance on day 3, and the maximal anti-receptive tolerance was observed on day 5. Co-infusing MK-801 with morphine attenuated morphine's anti-receptive tolerance. Two-dimensional gel electrophoretic analysis of spinal proteins revealed that eight protein spots were up-regulated in morphine-tolerant rats, and that they were significantly inhibited by MK-801 co-infusion. Among the up-regulated proteins, glial fibrillary acid protein (GFAP), a glial-specific maker, was identified by mass spectrometry. This finding was also confirmed by Western blot analysis.


CONCLUSIONS
Using proteomic analysis, we identified eight GFAP protein spots that were up-regulated in the dorsal horn of morphine-tolerant rat spinal cords. This up-regulation was partly inhibited by N-methyl-D-aspartate receptor antagonist MK-801 co-infusion, which suggests that GFAP protein can be considered to be a pathogenesis marker of morphine tolerance.
Wen
Z-H
ZH
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
Wu
G-J
GJ
Hsu
L-C
LC
Chen
W-F
WF
Chen
J-Y
JY
Shui
H-A
HA
Chou
A-K
AK
Wong
C-S
CS
D000818:Animals; D015153:Blotting, Western; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004361:Drug Tolerance; D015180:Electrophoresis, Gel, Two-Dimensional; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects* / Q000235:genetics; D008297:Male; D013058:Mass Spectrometry; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D012965:Sodium Chloride; D016291:Dizocilpine Maleate; D009020:Morphine