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Volume 17, Number 21,
Issue of November 1, 1997
pp. 8129-8136
Copyright ©1997 Society for Neuroscience
Neurokinin 1 Receptor Internalization in Spinal Cord Slices
Induced by Dorsal Root Stimulation Is Mediated by NMDA Receptors
Received April 2, 1997; revised Aug. 8, 1997; accepted Aug. 12, 1997.
Juan Carlos G. Marvizón1,
Vicente Martínez1,
Eileen F. Grady3,
Nigel W. Bunnett3, 4, and
Emeran A. Mayer1, 2
1 CURE: Digestive Diseases Research Center,
Neuroenteric Disease Program, Department of Medicine, and
2 Department of Physiology, University of California, Los
Angeles, California 90073, and 3 Departments of Surgery and
4 Physiology, University of California, San Francisco,
California 94143
The excitability of spinal neurons that transmit pain is modulated
by glutamate and substance P (SP). Glutamate is an excitatory neurotransmitter in the dorsal horn, and its effects are enhanced by SP
acting on neurokinin 1 receptors (NK1Rs). We assessed activation of
NK1Rs by studying their internalization in spinal cord slices. NK1Rs
were localized in sections from the slices by using
immunohistochemistry combined with fluorescence and confocal
microscopy. Incubating the slices with SP induced internalization in
most NK1R-positive neurons in laminae I, IIo, and X
and in half of NK1R-positive neurons in laminae III-V. SP-induced
internalization was abolished by the specific NK1R antagonist L-703,606
(1 µM). Stimulating the dorsal root with long-duration
(0.4 msec) pulses evoked EPSPs in dorsal horn neurons with latencies
consistent with the conduction speed of A - and C-fibers.
High-frequency (100 Hz) stimulation of the dorsal root with these
pulses induced NK1R internalization in neurons in laminae
I-IIo of the stimulated side of the slice but not in the
contralateral side or in other laminae. Stimulation at lower
frequencies (1 and 10 Hz) failed to elicit significant internalization,
suggesting that the release of SP is frequency-dependent. Internalization produced by the 100 Hz tetanus was mimicked by NMDA and
blocked by an NMDA antagonist, 2-amino-5-phosphonopentanoic acid, but
not by the AMPA and kainate antagonist CNQX. The NK1R antagonist
L-703,606 abolished the internalization produced by 100 Hz stimulation
or NMDA. Therefore, the release of SP in the dorsal horn appears to be
controlled by NMDA receptors.
Key words:
C-fibers;
central sensitization;
dorsal horn;
glutamate
receptor;
internalization;
LTP;
NK1 receptor;
NMDA receptor;
slices;
substance P
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