The discovery of sigma binding sites has prompted investigation into the functional role of these sites. Binding studies have revealed that sigma sites exhibit a unique pharmacological profile, and have provided evidence favoring the existence of a multiplicity of sigma binding sites in central nervous system. However, the findings that chemicals having diverse structures and therapeutic applications are all potent sigma agents, and that sigma binding sites are present in peripheral tissues, have raised concerns about the physiological and pharmacological relevances of this site. Furthermore, an endogenous ligand for the sigma binding site has not yet been identified. Finally, there is a lack of data regarding the functional coupling of sigma binding sites, although recent studies have provided some clues as to a possible signalling mechanism (Karbon et al., 1990). Besides raising questions about the relevance of sigma sites, the paucity of information on their functional properties has made it difficult to distinguish sigma agonists from and antagonists. While haloperidol is assumed to be a sigma antagonist, the finding that prolonged administration of this neuroleptic decreases the number of sigma sites would seem to argue in favor of it being an agonist for this site. Regardless of the precise nature of the sigma binding site, studies have suggested that it may represent the site of action for a number of important drugs. For example, haloperidol, a butyrophenone antipsychotic, exhibits high affinity for sigma binding sites, and several psychotomimetics, including PCP and (+)-benzomorphans, also bind this site.(ABSTRACT TRUNCATED AT 250 WORDS)