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Volume 17, Number 14, Issue of July 15, 1997 pp. 5622-5628
Copyright ©1997 Society for Neuroscience

Differential Activation and Desensitization of Sensory Neurons by Resiniferatoxin

Received Feb. 7, 1997; revised April 29, 1997; accepted May 6, 1997.

Geza Acs, Tamas Biro, Peter Acs, Shayan Modarres, and Peter M. Blumberg

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

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 ⁴⁵Ca uptake, which suggests the existence of distinct classes of the vanilloid receptor (). In the present study, we have demonstrated that the ultrapotent capsaicin analog resiniferatoxin (RTX) desensitized rat DRG neurons to the subsequent induction of ⁴⁵Ca uptake by capsaicin and RTX with affinity and cooperativity similar to that found for [³H]RTX binding, contrasting with a ~10-fold weaker potency and lack of cooperativity to induce ⁴⁵Ca uptake. Likewise, the competitive antagonist capsazepine inhibited RTX-induced desensitization with potency similar to that for inhibition of specific [³H]RTX binding, whereas the potency of capsazepine was ~10-fold higher for inhibiting RTX-induced ⁴⁵Ca uptake. Finally, the noncompetitive antagonist ruthenium red inhibited both the RTX-induced desensitization and ⁴⁵Ca uptake but showed ~60-fold selectivity for inhibiting RTX-induced desensitization. The RTX-induced desensitization was not associated with loss of specific [³H]RTX binding, suggesting lack of gross cell toxicity. In contrast to RTX, capsaicin caused desensitization with a potency corresponding to that for ⁴⁵Ca 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 ⁴⁵Ca 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.

Key words: dorsal root ganglion neurons; capsaicin; resiniferatoxin; desensitization; [³H]RTX binding; ⁴⁵Ca uptake; capsazepine; ruthenium red; pain; rat

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