期刊
PAIN
卷 131, 期 1-2, 页码 121-131出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2006.12.020
关键词
glutamate transporter; neuropathic pain; nerve injury; phospholipase A2; arachidonic acid; glutamate uptake; microdialysis; high pressure liquid chromatography; gas chromatography
资金
- NIDA NIH HHS [R01 DA008835-09, R01 DA008835-10, R01 DA008835] Funding Source: Medline
- NINDS NIH HHS [R01 NS042661, R01 NS042661-03, R01 NS045681, R01 NS42661, R01 NS045681-04, R01 NS042661-04, R01 NS045681-03, R01 NS45681] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS042661, R01NS045681] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA008835] Funding Source: NIH RePORTER
Spinal glutamate transporters (GT) have been implicated in the mechanisms of neuropathic pain; however, how spinal GT uptake activity is regulated remains unclear. Here we show that alteration of spinal arachidonic acid (AA) turnover after periplieral nerve injury regulated regional GT uptake activity and glutamate homeostasis. Chronic constriction nerve injury (CCI) in rats sianificantly reduced spinal GT uptake activity (H-3-glutamate uptake) with an associated increase in extracellular AA and glutamate concentration from spinal microdialysates on postoperative day 8. AACOCF3 (a cytosolic phospholipase A2 inhibitor, 30 mu g) given intrathecally twice a day for postoperative day 1-7 reversed this CCI-induced spinal AA production, prevented the reduced spinal GT uptake activity and increased extracellular glutamate concentration. Conversely, alteration of spinal AA metabolism by diclofenac (a cyclooxygenase 1/2 inhibitor, 200 mu g) further reduced spinal GT uptake activity and increased extracellular glutamate concentration in CCI rats. GT uptake activity was also attenuated when AA (10 or 100 nM) was directly added into spinal samples of naive rats in an in vitro 3 H-glutamate uptake assay, indicating a direct inhibitory effect of AA on GT uptake activity. Consistent with these findings, AACOCF3 reduced the development of both thermal hyperalgesia and mechanical allodynia, whereas diclofenac exacerbated thermal hyperalgesia, in CCI rats. Thus, spinal AA turnover may serve as a regulator in CCI-induced changes in regional GT uptake activity, glutamate homeostasis, and neuropathic pain behaviors. These data suggest that regulating spinal AA turnover may be a useful approach to improving the clinical management of neuropathic pain. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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