期刊
NEUROSCIENCE LETTERS
卷 407, 期 1, 页码 64-69出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2006.08.004
关键词
morphine tolerance; glutamate transporters; spinal cord; whole cell voltage clamp
资金
- NIDA NIH HHS [DA14588, T32 DA07278] Funding Source: Medline
Opioid analgesic tolerance is a phenomenon defined as a need for increasingly higher doses of opiates to maintain suitable pain relief following repeated drug exposure. Research suggests that analgesic tolerance may result from heightened NMDA receptor (NMDAR) activity, but little is known regarding the mechanisms by which this elevated NMDAR activity develops. Recent evidence suggests that glutamate transporter downregulation follows repeated opiate exposure and contributes to heightened pain sensitivity. Though glutamate transporter inhibition has been shown to increase activity of spinal cord neurons, it is unknown whether this increase contributes to the heightened NMDAR activity that underlies opiate tolerance. We directly tested this hypothesis by comparing the effects of glutamate transporter inhibition on excitatory post-synaptic currents (EPSCs) in the spinal cord dorsal horn of opiate naive and opiate tolerant rats. We show that non-selective glutamate transporter inhibition increases the rate of spontaneous excitatory post-synaptic currents (sEPSCs) in the opiate naive, but not opiate tolerant slice. This potentiation occurs in the presence of the sodium channel blocker tetrodotoxin (TTX) and is blocked by the NMDAR antagonist D-2-amino-5-phosphonovalerate (APV). The sEPSC rate is elevated at baseline in the opiate tolerant spinal cord slice compared to the opiate naive slice, and glutamate transporter inhibition eliminates this difference. Taken together, we conclude that glutamate transporter inhibition directly contributes to heightened NMDAR activity. Furthermore, we propose that the increased neural activity observed in the opiate tolerant slice is due to a state of glutamate transporter down-regulation and resultant heightened NMDAR activity. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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