Abstract
Sigma (σ) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of σ receptors, termed σ1 and σ2. Of these two subtypes, the σ1 receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for σ1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates σ1 receptors. Certain neurosteroids are known to interact with σ1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, σ1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of σ1 receptors, focussing on σ1 ligand neuropharmacology and the role of σ1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of σ1 ligands.
Highlights
Sigma () receptors were first described as a subclass of opioid receptors [102] to account for the psychotomimetic actions of (±)-SKF-10,047 (N-allylnormetazocine) and other racemic benzomorphans
Sigma1 receptors have been thoroughly studied in an attempt to elucidate their possible neuropharmacological applications, mainly in learning and memory processes, depression and anxiety, schizophrenia, analgesia and some effects of certain drugs of abuse
Due to the complex pathogenesis of schizophrenia and the differential effects of 1 antagonists and 1 agonists, treatment based exclusively on 1 ligands would probably be complex
Summary
Sigma () receptors were first described as a subclass of opioid receptors [102] to account for the psychotomimetic actions of (±)-SKF-10,047 (N-allylnormetazocine) and other racemic benzomorphans This early confusion was due to the complex pharmacology of this racemic compound; later studies showed that (–)-SKF-10,047 binds to and opioids, whereas the (+)-isomer lacks affinity for opioid receptors but binds to PCP (phencyclidine) binding sites with low affinity, and to a different site with high affinity, which currently retains the designation of [reviewed in 112 and 214 amongst others]. In this review we describe some aspects of the general biology of 1 receptors, but focus on 1 ligand neuropharmacology and the role of 1 receptors in behavioral animal studies, which have contributed greatly to the understanding of the possible neuropharmacological properties of 1 receptors.
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