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File:Sigma opioid receptor.png
Schematic σ receptor

The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP,[1] SA 4503, Ditolylguanidine, Dimethyltryptamine[2] and siramesine.[3]

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.

Function

The function of these receptors are poorly understood[4] though an endogenous ligand, dimethyltryptamine, was found to interact with sigma-1.[5][6] 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 include cocaine, diacetylmorphine, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant berberine. 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 when the sigma receptor is activated include hypertonia, tachycardia, tachypnea, and mydriasis. Some sigma receptor agonists--such as cocaine, a weak sigma agonist--exert convulsant effects in animals. Behavioral reactions to sigma agonists are rather heterogeneous: some individuals find sigma receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.

Recently selective σ–receptor agonists were shown to produce antidepressant effects in mice.[7]

Ligands

Agonists

Antagonists

  • Rimcazole
  • BD-1047: selective σ1 antagonist, N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine, CAS# 138356-20-4
  • BMY-14802: (4-Fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol, CAS# 105565-55-7

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.
  2. Fontanilla D, Johannessen M, Hajipour A, Cozzi N, Jackson M, Ruoho A (2009). The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator. Science 323 (5916): 934-937.
  3. 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.
  4. Leonard BE (2004). Sigma receptors and sigma ligands: background to a pharmacological enigma. Pharmacopsychiatry 37 Suppl 3: S166–70.
  5. Guitart X, Codony X, Monroy X (2004). Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl.) 174 (3): 301–19.
  6. Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE (2009). The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323 (5916): 934–7.
  7. 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.

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