Glutamate-induced excitation and sensitization of nociceptors in rat glabrous skin

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Abstract
Novel in vitro skin-nerve preparation using the glabrous skin from the rat hindpaw. In the first series of experiments, recordings were obtained from 141 fibers that responded to a strong mechanical search stimulus. Based on their conduction velocity they were classified as C (27%), Aδ (28%) and Aβ (45%) fibers. The C and Aδ fibers typically exhibited sustained firing during suprathreshold mechanical stimuli whereas both rapidly (66%) and slowly (34%) adapting responses were obtained from Aβ fibers. Noxious heat excited 46% of the C fibers but only 12% of the Aδ units. In another series of experiments application of an ascending series of glutamate concentrations (10, 100, 300, and 1000 μM) to Aδ (n=14) and C (n=19) nociceptors resulted in a significant excitation of 43% (6/14) Aδ fibers and 68% (13/19) C fibers. At these concentrations, there was no excitation of Aβ units (n=13). Superfusion of the receptive fields of either mechanoheat-sensitive A (AMH, n=10) or C fibers (CMH, n=12) for 2 min with 300 μM glutamate resulted in sensitization of 90% (9/10) AMH and 92% (11/12) CMH fibers to subsequent thermal stimulation. This was evidenced by a significant (1) decrease in thermal threshold for activation, (2) increase in discharge rate, and (3) increase in peak instantaneous frequencies during the second heat trial. Glutamate-induced sensitization to heat occurred in the absence of either a glutamate-induced excitation or an initial heat response. Exposure of Aδ or C fibers to glutamate did not result in a decrease in von Frey thresholds. These data provide a physiological basis for the nociceptive behaviors that arise following intraplantar injection of glutamate or glutamate agonists. Furthermore, demonstration of glutamate-induced excitation and heat sensitization of nociceptors indicates that local or topical administration of glutamate receptor antagonists may have therapeutic potential for the treatment of pain....