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Sigma receptors
Sigma receptors were first postulated in 1976 by Martin and coworkers based on the actions of SKF 10,047 (N -allylnormetazocine) and related benzomorphans [1]. The name sigma is derived from the first letter 'S'in SKF 10,047, which is now known to be a nonselective ligand that binds to multiple receptor proteins. Consequently, sigma receptors were once thought to be an opioid receptor subtype, and then later, the phencyclidine (PCP) binding site on the NMDA receptor [2]. Today, sigma receptors are recognized as unique proteins with a distinct anatomical distribution, drug selectivity pattern and molecular biological profile from other mammalian proteins [2].
Sigma receptors are found in the brain and many peripheral organs that serve as targets for psychostimulant drugs, including the heart and lung [2]. In the brain, significant levels of sigma receptors are found in motor, limbic and endocrine regions [3-5]. These receptors have also been reported on monoaminergic and glutamatergic neurons, where they can modulate the synthesis and release of classical neurotransmitters, as well as cellular activity [4,6-10].
Many drugs of abuse interact with sigma receptors, including cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), some opioids and PCP, at concentrations that are achievable in the body [2,11-15]. In addition, many typical neuroleptics, antihistamines, antidepressant drugs, dissociative anesthetics and neuroactive steroids have been shown to have significant affinity for sigma receptors [15-17].
Consistent with the different classes of synthetic ligands that bind to sigma receptors, diverse compounds appear to serve as endogenous ligands at these receptors. Three types of studies support the existence of endogenous sigma ligands. First, screening of known endogenous ligands using receptor-binding assays reveals select neuroactive steroids (e.g., progesterone) and trace amines (e.g., N,N-dimethyltryptamine) as naturally occurring candidates [18,19]. Both classes of compounds have been shown to produce some functional effects in addition to binding, further supporting a potential role as endogenous ligands for sigma receptors [18-20]. Second, fractionation studies in a number of laboratories have uncovered tissue extracts that displace binding to sigma receptors. Although the structures of the active constituents in the fractions remain undetermined, some of them are believed to be peptides, since their binding could be obliterated by trypsin digestion or proteolysis [21,22]. Other extract fractions were not affected by pronase digestion [23], suggesting that the...