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The Journal of Neurophysiology Vol. 84 No. 6 December 2000, pp. 2998-3009
Copyright ©2000 by the American Physiological Society
Department of Anatomy and Neurosciences and Marine Biomedical Institute, The University of Texas Medical Branch, Galveston, Texas 77555-1069
Neugebauer, Volker,
Ping-Sun Chen, and
William D. Willis.
Groups II and III Metabotropic Glutamate Receptors Differentially
Modulate Brief and Prolonged Nociception in Primate STT Cells. J. Neurophysiol. 84: 2998-3009, 2000. The heterogeneous family of G-protein-coupled
metabotropic glutamate receptors (mGluRs) provides excitatory and
inhibitory controls of synaptic transmission and neuronal excitability
in the nervous system. Eight mGluR subtypes have been cloned and are
classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group
II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the
ability to inhibit cAMP formation. The present study examined the roles
of groups II and III mGluRs in the processing of brief nociceptive
information and capsaicin-induced central sensitization of primate
spinothalamic tract (STT) cells in vivo. In 11 anesthetized male
monkeys (Macaca fascicularis), extracellular recordings were
made from 21 STT cells in the lumbar dorsal horn. Responses to brief
(15 s) cutaneous stimuli of innocuous (brush), marginally and
distinctly noxious (press and pinch, respectively) intensity were
recorded before, during, and after the infusion of group II and group
III mGluR agonists into the dorsal horn by microdialysis. Different
concentrations were applied for at least 20 min each (at 5 µl/min) to
obtain cumulative concentration-response relationships. Values in this
paper refer to the drug concentrations in the microdialysis fibers;
actual concentrations in the tissue are about three orders of magnitude
lower. The agonists were also applied at 10-25 min after intradermal
capsaicin injection. The group II agonists
(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1, 1 µM-10 mM,
n = 6) and
(
)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268; 1 µM-10 mM, n = 6) had no significant effects on the responses to brief cutaneous mechanical stimuli (brush, press, pinch)
or on ongoing background activity. In contrast, the group III agonist
L(+)-2-amino-4-phosphonobutyric acid (LAP4, 0.1 µM-10 mM,
n = 6) inhibited the responses to cutaneous mechanical
stimuli in a concentration-dependent manner, having a stronger effect on brush responses than on responses to press and pinch. LAP4 did not
change background discharges significantly. Intradermal injections of
capsaicin increased ongoing background activity and sensitized the STT
cells to cutaneous mechanical stimuli (ongoing activity > brush > press > pinch). When given as posttreatment, the
group II agonists LCCG1 (100 µM, n = 5) and LY379268
(100 µM, n = 6) and the group III agonist LAP4 (100 µM, n = 6) reversed the capsaicin-induced
sensitization. After washout of the agonists, the central sensitization
resumed. Our data suggest that, while activation of both group II and
group III mGluRs can reverse capsaicin-induced central sensitization,
it is the actions of group II mGluRs in particular that undergo
significant functional changes during central sensitization because
they modulate responses of sensitized STT cells but have no effect
under control conditions.
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