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
peripheral nerve injury regulated regional GT uptake activity and
glutamate homeostasis. Chronic constriction nerve injury (CCI) in rats significantly reduced spinal GT uptake activity ((3)H-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, 30mug) 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, 200mug) further reduced spinal GT uptake activity and increased extracellular
glutamate concentration in CCI rats. GT uptake activity was also attenuated when AA (10 or 100nM) was directly added into spinal samples of naïve 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.