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The Journal of Neuroscience, November 15, 2006, 26(46):12033-12042; doi:10.1523/JNEUROSCI.2530-06.2006

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Cellular/Molecular
Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Jinsong Zeng,¹ Lisa M. Thomson,¹ Sue A. Aicher,² and Gregory W. Terman¹

¹Department of Anesthesiology and the Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, Washington 98195, and ²Neurological Sciences Institute, Oregon Health & Science University, Beaverton, Oregon 97006

Correspondence should be addressed to Dr. Gregory Terman, Department of Anesthesiology, P.O. Box 356540, University of Washington, Seattle, WA 98195-6540. Email: gwt{at}u.washington.edu

Repeated exposure to opiates produces analgesic tolerance, which limits their clinical usefulness. Whole-cell voltage-clamped lamina I cells in spinal slices from opiate-tolerant neonatal rats show an increase in miniature, spontaneous, and primary afferent-evoked EPSCs when compared with lamina I cells from opiate-naive rat spinal slices. This increased excitation can be blocked by the NMDA receptor (NMDAR) antagonist APV, apparently acting at NMDARs on primary afferents. Consistent with these results, electron microscopy demonstrates an increased incidence of NMDARs in substance P-containing spinal dorsal horn primary afferent terminals in opiate-tolerant rats. Moreover, superfusion of spinal slices from opiate-tolerant rats with NMDA produces a reversible increase in miniature EPSC (mEPSC) frequency in contrast to a decrease in mEPSC frequency produced by NMDA in opiate-naive slices. Finally, NMDAR antagonists inhibit the expression of opiate tolerance both in inhibiting EPSCs in spinal slices and in inhibiting behavioral nociceptive responses to heat.

NMDAR antagonists have been reported in many studies to inhibit morphine analgesic tolerance. Our studies suggest that an increase in primary afferent NMDAR expression and activity mediates a hypersensitivity to noxious stimuli and causes the inhibition of opiate efficacy, which defines tolerance.

Key words: voltage clamp; electrophysiology; pain; sensitization; opponent process; in vitro

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Received Dec. 22, 2005; revised Sept. 11, 2006; accepted Oct. 4, 2006.

Correspondence should be addressed to Dr. Gregory Terman, Department of Anesthesiology, P.O. Box 356540, University of Washington, Seattle, WA 98195-6540. Email: gwt{at}u.washington.edu

This article has been cited by other articles:

				L. A. Grande, B. R. O'Donnell, D. R. Fitzgibbon, and G. W. Terman Ultra-Low Dose Ketamine and Memantine Treatment for Pain in an Opioid-Tolerant Oncology Patient Anesth. Analg., October 1, 2008; 107(4): 1380 - 1383. [Abstract] [Full Text] [PDF]

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