THE VANILLOID (CAPSAICIN) RECEPTOR - RECEPTOR TYPES AND SPECIES-DIFFERENCES

1. Capsaicin was postulated to exert its pharmacological actions by in teracting at a specific recognition site (receptor) expressed predomin antly by primary afferent neurons. 2. The actual existence of this lon g-sought ''capsaicin-receptor'' has recently been demonstrated by the specific binding of [H-3]resiniferatoxin (RTX), an ultrapotent capsaic in analog with a unique spectra of actions. 3. Since homovanillic acid is the key structural motif shared by capsaicin and RTX, their recogn ition site appears to be best termed the vanilloid receptor. 4. Centra l (sensory ganglia and spinal cord) vanilloid receptors of the rat bin d RTX with high affinity in a cooperative fashion; moreover, they reco gnize capsaicin with higher affinity than the competitive antagonist, capsazepine. Peripheral (urinary bladder, urethra, airways, colon) van iiloid receptors, by contrast, bind RTX with lower affinity in a nonco operative manner. An opposite affinity for capsazepine relative to cap saicin appears to distinguish vanilloid receptors in the urinary bladd er from those present in the airways or colon. These findings imply he terogeneity in the properties of vanilloid receptors. 5. The affinity of [H-3]RTX binding in vitro is influenced by reducing agents, suggest ing an in vivo modulatory role for endogenous reducing agents in vanil loid receptor functions. 6. The size of central vanilloid receptors (2 70 kDa) as measured by radiation inactivation and the cooperative bind ing both suggest a receptor cluster with cooperating subunits. 7. RTX binds to vanilloid receptors with orders of magnitude higher affinity than capsaicin; its ability to induce cooperative binding is also more pronounced. These differences in receptor binding along with the phar macokinetical differences in tissue equilibration and in plasma bindin g may form a rational basis to explain the peculiar spectrum of action s of RTX. 8. Guinea pig spinal cord and airway membranes bind RTX with lower affinity than rat tissues. The receptor density is, however, hi gher in the guinea pig in keeping with the marked sensitivity of this species to vanilloid actions. 9. The apparently low level of specific [H-3]RTX binding sites in the hamster and rabbit is in accord with the resistance of these species to vanilloid actions. 10. In post-mortem human spinal cord specific [H-3]RTX binding sites can be detected; the ir binding parameters are similar to those determined in guinea pig sp inal cord. 11. The vanilloid receptor appears to display both intraspe cies heterogeneity and marked interspecies differences. 12. As yet, it is not known whether the vanilloid receptor is operated by endogenous ligands. It is not known either which receptor superfamily (if any) i t belongs to. The [H-3]RTX binding assay has, however, the potential o f answering these questions. Thus, rapid progress in our knowledge may be anticipated.