DIFFERENTIAL ACTIVATION AND DESENSITIZATION OF SENSORY NEURONS BY RESINIFERATOXIN

Recently, with use of rat dorsal root ganglion (DRG) neurons we have b een able to dissociate the binding affinities of vanilloids from their potencies to induce Ca-45 uptake, which suggests the existence of dis tinct classes of the vanilloid receptor (Acs et al., 1996). In the pre sent study, we have demonstrated that the ultrapotent capsaicin analog resiniferatoxin (RTX) desensitized rat DRG neurons to the subsequent induction of Ca-45 uptake by capsaicin and RTX with affinity and coope rativity similar to that found for [H-3]RTX binding, contrasting with a similar to 10-fold weaker potency and lack of cooperativity to induc e Ca-45 uptake. Likewise, the competitive antagonist capsazepine inhib ited RTX-induced desensitization with potency similar to that for inhi bition of specific [H-3]RTX binding, whereas the potency of capsazepin e was similar to 10-fold higher for inhibiting RTX-induced Ca-45 uptak e. Finally, the noncompetitive antagonist ruthenium red inhibited both the RTX-induced desensitization and Ca-45 uptake but showed similar t o 60-fold selectivity for inhibiting RTX-induced desensitization. The RTX-induced desensitization was not associated with loss of specific [ H-3]RTX binding, suggesting lack of gross cell toxicity. In contrast t o RTX, capsaicin caused desensitization with a potency corresponding t o that for Ca-45 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 Ca-45 uptake and d epended on external calcium, Our findings provide further support for the existence of vanilloid receptor subtypes on DRG neurons with disti nct pharmacology and distinct patterns of desensitization.