Resiniferatoxin, a potent capsaicin‐like stimulator of peripheral nociceptors in the neonatal rat tail in vitro

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Abstract
1 A spinal ventral root response was measured following the activation of peripheral fibres by noxious (heat at 48°C, capsaicin, bradykinin) and innocuous (brush) stimuli in a preparation of the neonatal rat spinal cord-tail maintained in vitro. 2 Following superfusion of the tail with 0.1–1.0 nm of the potent irritant, resiniferatoxin (RTX), brief, irregular depolarization and a selective loss of capsaicin sensitivity was produced. RTX 10–100 nm evoked a tonic response, initiated transient irregular depolarizations and densitization to further applications of RTX and capsaicin but not to other stimuli. Following RTX 1 μm a prolonged loss of sensitivity to all noxious stimuli was produced. 3 When a selective densitization to capsaicin was produced by a long application of capsaicin, RTX was also ineffective. 4 Superfusion of the tail with 4β-phorbol, 12, 13-dibutyrate (PDBu), a protein kinase C activator, stimulated capsaicin-sensitive peripheral fibres. Prolonged administration of PDBu attenuated or abolished further responses to PDBu and bradykinin but responses to RTX and capsaicin were unchanged. The protein kinase C inhibitor staurosporine (50–200 nm), attenuated the effects of PDBu and bradykinin but not those of RTX or capsaicin. 5 The present data suggest that neither RTX nor capsaicin act on peripheral nociceptors via a phorbol ester-like stimulation of protein kinase C. Rather, RTX acts on nociceptors by a similar mechanism to capsaicin. These effects may be the basis for the irritant properties of RTX and may further relate to the antinociceptive actions observed in vivo. RTX is therefore a potent new tool with which to investigate the properties of nociceptive neurones and provides a prototype for further development of antinociceptive agents.