Actions of capsaicin on peripheral nociceptors of the neonatal rat spinal cord‐tail in vitro: dependence of extracellular ions and independence of second messengers

Abstract

1 We have tested the hypothesis that capsaicin-induced activation, desensitization and impairment of peripheral nociceptor function is mediated by separate mechanisms. This was investigated by use of an in vitro preparation of the neonatal rat spinal cord with the functionally attached tail in which the cord and tail were separately superfused with physiological solution. Activation of peripheral fibres by noxious (capsaicin, bradykinin, 5-hydroxytryptamine, heat, pinch) and innocuous (light brush) stimuli was assessed by recording the depolarization of a spinal ventral root (L₃-L₅). 2 Brief administration of capsaicin produced dose-related depolarizing responses (EC₅₀ = 280 nm). These responses could be reproduced for many hours following the repeated application of capsaicin at a submaximal concentration. Prolonged application of 0.5–2.0 μm capsaicin induced a selective desensitization to subsequent brief administrations of capsaicin. Prolonged administration at 20–50 μm produced an additional non-selective reduction in responses to all noxious stimuli without changing innocuous brush responses. 3 Removal of extracellular calcium from the tail superfusate did not reduce the response to capsaicin or prevent capsaicin-induced desensitization. However, high concentrations of capsaicin no longer induced a non-specific reduction of responses to other noxious stimuli. The response to a brief administration of capsaicin was unaffected by calcium channel blocking drugs including nifedipine, cadmium or ω-conotoxin. On the other hand high extracellular calcium increased the incidence of the non-selective reduction of responses to all noxious stimuli produced by high concentrations of capsaicin. 4 Replacement of extracellular sodium with choline blocked peripheral nerve conduction but did not prevent the desensitization produced by capsaicin. In addition, high concentrations of capsaicin were less effective in reducing the responsiveness to other noxious stimuli. 5 Neither capsaicin-evoked responses nor capsaicin-induced desensitization were affected by the administration of forskolin, dibutyryl cyclic AMP, nitroprusside, dibutyryl cyclic GMP, β-12,13 phorbol dibutyrate, trifluoperazine, indomethacin, staurosporine or mepacrine, in the tail superfusate. 6 These data suggest that capsaicin-induced activation, desensitization and impairment of peripheral nociceptors may be separable phenomena. Extracellular calcium is not required for capsaicin-induced activation or desensitization but calcium as well as sodium are important for capsaicin-induced impairment of nociceptive responses. Desensitization may occur independently of peripheral fibre activation and cannot be attributed to a central mechanism. Finally neither capsaicin-induced activation nor desensitization require the participation of a second messenger.