Differential Activation and Desensitization of Sensory Neurons by Resiniferatoxin

Abstract

Recently, with use of rat dorsal root ganglion (DRG) neurons we have been able to dissociate the binding affinities of vanilloids from their potencies to induce 45 Ca uptake, which suggests the existence of distinct classes of the vanilloid receptor (Acs et al., 1996). In the present study, we have demonstrated that the ultrapotent capsaicin analog resiniferatoxin (RTX) desensitized rat DRG neurons to the subsequent induction of 45 Ca uptake by capsaicin and RTX with affinity and cooperativity similar to that found for [3 H]RTX binding, contrasting with a ϳ10-fold weaker potency and lack of cooperativity to induce 45 Ca uptake. Likewise, the competitive antagonist capsazepine inhibited RTXinduced desensitization with potency similar to that for inhibition of specific [ 3 H]RTX binding, whereas the potency of capsazepine was ϳ10-fold higher for inhibiting RTX-induced 45 Ca uptake. Finally, the noncompetitive antagonist ruthenium red inhibited both the RTX-induced desensitization and 45 Ca uptake but showed ϳ60-fold selectivity for inhibiting RTXinduced desensitization. The RTX-induced desensitization was not associated with loss of specific [3 H]RTX binding, suggesting lack of gross cell toxicity. In contrast to RTX, capsaicin caused desensitization with a potency corresponding to that for 45 Ca uptake and did so in a noncooperative manner. Unlike the RTX-induced desensitization, the desensitization by capsaicin was blocked by ruthenium red only at doses that blocked 45 Ca uptake and depended on external calcium. Our findings provide further support for the existence of vanilloid receptor subtypes on DRG neurons with distinct pharmacology and distinct patterns of desensitization.

Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances

“…Nevertheless, the concentration of 12-(S)-HPETE required to activate i cap was similar to those found to activate other channels (12,14). Although the activation of i cap by 12-(S)-HPETE in isolated membrane patches was weak, it is possible that different subtypes of capsaicin receptors could have different sensitivities to capsaicin and 12-(S)-HPETE, as suggested by others (37). The slow activation of the channel by 12-(S)-HPETE also contrasts with the rapid activation by capsaicin.…”

Intravesical Capsaicin Versus Resiniferatoxin In Patients With Detrusor Hyperreflexia: A Prospective Randomized Study

“…24 Nothing in this commentary is at variance with concepts involving resiniferatoxin and capsaicin actions on different C-fiber subsets 25 or vanilloid receptor subtypes. 26 Rather it emphasizes the fact that ethanol concentrations should be restricted to the necessary minimum when this agent is given as an intravesical vehicle. Capsaicin (1 mM.)…”

Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice

“…TRPV1 desensitization is a complex process that seems to be mediated by calcineurin activation (Docherty et al, 1996) and by calmodulin binding (Numazaki et al, 2003). Different ligands, such as capsaicin, resiniferatoxin, and protons, produce TRPV1 desensitization with different profiles, including extracellular Ca 2 þ -dependence and degree of efficacy (Acs et al, 1997;Mohapatra et al, 2003;Numazaki et al, 2003). Moreover, a recent study has shown that only the TRPV1 antagonist capsazepine, but not the TRPV1 channel blocker ruthenium red, inhibit capsaicin-induced desensitization to its nociceptive effect in vivo (Sakurada et al, 2003).…”