Similarities and differences in the action of resiniferatoxin and capsaicin on central and peripheral endings of primary sensory neurons

Abstract

We have compared the ability of capsaicin and resiniferatoxin, a natural diterpene present in the latex of plants of the Euphorbia family to excite and desensitize capsaicin-sensitive primary afferents in a variety of models. Both capsaicin and resiniferatoxin inhibited the twitch contractions of the rat isolated vas deferens and prevented, in a concentration-related manner, the effect of a subsequent challenge with 1 μM capsaicin (desensitization). Resiniferatoxin was 1000–10,000 times more potent than capsaicin in both cases. The time course of action of resiniferatoxin was much slower than that of capsaicin, suggesting a slower penetration rate in the tissue. The action of resiniferatoxin was blocked by Ruthenium Red, a proposed antagonist at the cation channel coupled to the capsaicin receptor. Both capsaicin and resiniferatoxin produced a contraction of the rat isolated urinary bladder. Resiniferatoxin was about as potent as capsaicin in this assay although it was 500–1000 times more potent than capsaicin in desensitizing the primary afferents to a subsequent challenge with capsaicin itself. Resiniferatoxin did not affect motility in the isolated vasa deferentia or urinary bladder from capsaicin-pretreated rats. After topical application onto the rat urinary bladder both resiniferatoxin (10 nM) and capsaicin (10μM) increased bladder capacity as assessed in a volume-evoked micturition reflex model in rats without affecting micturition contraction. Intrarterial injection of resiniferatoxin or capsaicin in the ear of anesthetized rabbits evoked a systemic depressor reflex due to activation of para vascular nociceptors, resiniferatoxin being about three times more potent than capsaicin. Superfusion of the ear with capsaicin prevented the excitatory action of resiniferatoxin. Resiniferatoxin produced the simultaneous release of substance P- and calcitonin gene-related peptide-like immunoreactivity from the superfused rat isolated bladder and spinal cord (dorsal half) as well as from the perfused rabbit ear. No release of either peptide-like immunoreactivity was evoked by resiniferatoxin from the urinary bladder or spinal cord of rats pretreated with capsaicin.

These findings are consistent with the idea that resiniferatoxin is a potent capsaicin analog and suggest a common site of action for these two substances (cross-desensitization and blockade by Ruthenium Red). Furthermore, the present findings indicate that the penetration rate of resiniferatoxin in tissues is much slower than that of capsaicin. As a consequence, the estimate of the relative potency of these two agents in exciting primary afferents is strongly influenced in non-equilibrium experimental conditions.