Sigma receptor

  The sigma receptors σ₁ and σ₂ are receptors which bind to ligands such as 4-PPBP^[1], SA 4503, and siramesine.^[2]

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Classification

Sigma receptors were once thought to be a type of opioid receptor, because the d stereoisomers of the benzomorphan class of opioid drugs had no effects at μ, κ, and δ receptors, but reduced coughing.

However, pharmacological testing indicated that the sigma receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with these receptors. Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids.

When the σ₁ receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors.

Functions

The functions of these receptors are poorly understood and any endogenous ligands have yet to be identified. Activation of sigma receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be sigma agonists in addition to their major mechanisms of action include cocaine, heroin, PCP, fluvoxamine, methamphetamine and dextromethorphan, however the exact role of sigma receptors is difficult to establish as many sigma agonists also bind to other targets such as the κ-opioid receptor and the NMDA receptor. In animal experiments, sigma antagonists such as rimcazole were able to block convulsions from cocaine overdose. Sigma antagonists are also under investigation for use as antipsychotic medications.

Physiologic effects

Physiologic effects (what happens to the human body) when the sigma receptor is activated include dysphoria (feelings of unease), hypertonia (increased muscle tension), tachycardia (increase in heart rate), tachypnea (increase in rate of breathing), and mydriasis (increase in the size of the pupils, similar to what occurs in conditions of low light).

Recently novel σ–receptor agonists have been able to produce antidepressant effects in mice.^[3]

References

1. ^ Yang S, Bhardwaj A, Cheng J, Alkayed NJ, Hurn PD, Kirsch JR (2007). "Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2". Anesth. Analg. 104 (5): 1179-84, tables of contents. doi:10.1213/01.ane.0000260267.71185.73. PMID 17456670.
2. ^ Skuza G, Rogóz Z (2006). "The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats". J. Physiol. Pharmacol. 57 (2): 217-29. PMID 16845227.
3. ^ Wang J, Mack AL, Coop A, Matsumoto RR (2007). "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". Eur Neuropsychopharmacol 2007 (Mar 19): Epub ahead of print. doi:10.1016/j.euroneuro.2007.02.007. PMID 17376658.