Afferent C-fibres release substance P and glutamate.

Capsaicin is currently used as a specific pharmacological tool for investigation of functions of primary afferent C-fibres. Their peripheral terminals play an important role in "neurogenic inflammation," mediated by released substance P and calcitonin gene related peptide, whereas in the mediation of central functions, activation of the N-methyl-D-aspartate (NMDA) receptors has recently been demonstrated. A method for continuous monitoring of glutamate concentration was used to study mechanisms of capsaicin-induced glutamate release from rat spinal cord slices. Both capsaicin and substance P released glutamate from spinal dorsal horns in a concentration-dependent manner (EC50 = 0.53 +/- 0.07 and 0.37 +/- 0.06 microM, respectively). The NMDA antagonist MK-801 (10 microM) had no effect on evoked glutamate release, whereas the tachykinin (NK-1) antagonist CP-99994 (10 microM) reduced responses to both stimuli (p < 0.001). In capsaicin-desensitized rats, evoked glutamate release from dorsal horns was significantly decreased yet not completely abolished. Although the evoked glutamate release from ventral horns was markedly smaller than that from dorsal horns, the normalized responses to capsaicin and to substance P were similar. This might be explained by smaller amounts of mobilizable glutamate in ventral horns. Our findings confirmed the ability of capsaicin to release glutamate mainly from the afferent C-fibres in the spinal cord. The observed effect of exogenous substance P and inhibitory action of the NK-1 antagonist indicate facilitation of capsaicin-induced glutamate release by coreleased substance P.