Glutamate is a major transmitter in the CNS and can act via the activation of four separate receptor types. (i) ionotropic N-methyl-d-aspartate (NMDA) receptors, (ii) a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, (iii) kainate receptors, and (iv) metabotropic glutamate (mGlu) receptors. Peripheral ionotropic GluR (iGluR) receptors have been suggested to be involved in visceral pain transmission, via activation by endogenous glutamate. This follows from the observation that NMDA receptor antagonists reduce responses to mechanical stimuli in splanchnic and pelvic afferents in rat colon and they decrease the visceromotor response to colorectal distension (173). NMDA receptor antagonists also reduced the response of vagal afferent fibers innervating the rat stomach (174). Similarly, AMPA/kainate receptor antagonists also reduced the response of vagal afferent fibers innervating the rat stomach (174). Actions of glutamate are also mediated via mGlu receptors, some of which are inhibitory G-protein-coupled receptors. Glutamate can inhibit vagal afferent mechanosensitivity, when administered in the presence of kynurenate to block iGluR. This inhibition can be mimicked by selective group II and III mGluR agonists (175). Conversely, group III mGluR antagonists can increase mechanosensitivity to intense stimuli (175). Therefore there appears to be a delicate balancing act in the way in which endogenous or exogenous glutamate can act via mGluR and iGluR to regulate primary afferent mechanosensitivity (175). Whether or not this interplay occurs on spinal afferents as it does in vagal afferents is yet to be determined.
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