Role of metabotropic glutamate receptor subtype mGluR1 in brief nociception and central sensitization of primate STT cells

G-protein coupled metabotropic glutamate receptors (mGluRs) are important m odulators of synaptic transmission in the mammalian CNS and have been impli cated in various forms of neuroplasticity and nervous system disorders. Inc reasing evidence also suggests an involvement of mGluRs in nociception and pain behavior although the contribution of individual mGluR subtypes is not yet clear. Subtypes mGluR1 and mGluR5 are classified as group I mGluRs and share the ability to stimulate phosphoinositide hydrolysis and activate pr otein kinase C. The present study examined the role of group I mGluRs in no ciceptive processing and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 10 anesthetized male monkeys ( Macaca fascicularis) extracellular recordings were made from 20 STT cells i n the lumbar dorsal hem. Responses to brief (15 s) cutaneous stimuli of inn ocuous (BRUSH) and barely and substantially noxious (PRESS and PINCH, respe ctively) intensity were recorded before, during, and after the infusion of group I mGluR agonists and antagonists into the dorsal horn by microdialysi s. Cumulative concentration-response relationships were obtained by applyin g different concentrations for at least 20 min each (at 5 mu l/min). The ac tual concentrations reached in the tissue are 2-3 orders of magnitude lower than those in the microdialysis fibers (values in this paper refer to the latter). The group I antagonists were also applied at 10-25 min after capsa icin injection. S-DHPG, a group I agonist at both mGluR 1 and mGluR5, poten tiated the responses to innocuous and noxious stimuli (BRUSH > PRESS > PINC H) at low concentrations (10-100 mu M; n = 5) but had inhibitory effects at higher concentrations (1-10 mM; n = 5). The mGluR5 agonist CHPG (1 mu M-10 0 mM; n = 5) did not potentiate but inhibited all responses (10-100 mM; n = 5). AIDA (1 mu M-100 mM)1 a mGluR1-selective antagonist, dose-dependently depressed the responses to PINCH and PRESS but nor to BRUSH (n = 6). The gr oup I (mGluR1 > mGluR5) antagonist CPCCOEt (1 mu M-100 mM) had similar effe cts (il = 6). Intradermal injections of capsaicin sensitized the STT cells to cutaneous mechanical stimuli. The enhancement of the responses by capsai cin resembled the potentiation by the group I mGluR agonist S-DHPG (BRUSH > PRESS > PINCH). CPCCOEt (1 mM) reversed the capsaicin-induced sensitizatio n when given as posttreatment (n = 5). After washout of CPCCOEt, the sensit ization resumed. Similarly, AIDA (1 mM; n = 7) reversed the capsaicin-induc ed sensitization and also blocked the potentiation by S-DHPG (n = 5). These data suggest that the mGluR1 subtype is activated endogenously during brie f high-intensity cutaneous stimuli (PRESS, PINCH) and is critically involve d in capsaicin-induced central sensitization.