The vanilloid (capsaicin) receptor: Receptor types and species differences

1. Capsaicin was postulated to exert its pharmacological actions by interacting at a specific recognition site (receptor) expressed predominantly by primary afferent neurons.2. The actual existence of this long-sought “capsaicin-receptor” has recently been demonstrated by the specific binding of ³H]resiniferatoxin (RTX), an ultrapotent capsaicin analog with a unique spectra of actions.3. Since homovanillic acid is the key structural motif shared by capsaicin and RTX, their recognition site appears to be best termed the vanilloid receptor.4. Central (sensory ganglia and spinal cord) vanilloid receptors of the rat bind RTX with high affinity in a cooperative fashion; moreover, they recognize capsaicin with higher affinity than the competitive antagonist, capsazepine. Peripheral (urinary bladder, urethra, airways, colon) vaniiloid receptors, by contrast, bind RTX with lower affinity in a noncooperative manner. An opposite affinity for capsazepine relative to capsaicin appears to distinguish vanilloid receptors in the urinary bladder from those present in the airways or colon. These findings imply heterogeneity in the properties of vanilloid receptors.5. The affinity of ³H]RTX binding in vitro is influenced by reducing agents, suggesting an in vivo modulatory role for endogenous reducing agents in vanilloid receptor functions.6. The size of central vanilloid receptors (270 kDa) as measured by radiation inactivation and the cooperative binding 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 pharmacokinetical differences in tissue equilibration and in plasma binding may form a rational basis to explain the peculiar spectrum of actions of RTX.8. Guinea pig spinal cord and airway membranes bind RTX with lower affinity than rat tissues. The receptor density is, however, higher in the guinea pig in keeping with the marked sensitivity of this species to vanilloid actions.9. The apparently low level of specific ³H]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 ³H]RTX binding sites can be detected; their binding parameters are similar to those determined in guinea pig spinal cord.11. The vanilloid receptor appears to display both intraspecies 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) it belongs to. The ³H]RTX binding assay has, however, the potential of answering these questions. Thus, rapid progress in our knowledge may be anticipated.