Sigma receptor

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Schematic σ receptor

The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine),[1] SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine,[2] and siramesine.[3]


σ–receptors were once thought to be a type of opioid receptor because the D-stereoisomers of the benzomorphan class of opioid drugs reduced coughing, similar to other opioid derivatives such as dextromethorphan.[clarification needed] However, such drugs had no clinically relevant affinities for μ (mu), κ (kappa), or δ (delta) receptors.

However, pharmacological testing indicated that the σ-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 σ-receptors as biased agonists/antagonists at sigma 1 (versus sigma 2.) 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.


The function of these receptors is poorly understood.[4] Activation of σ–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 σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant berberine. However the exact role of σ–receptors is difficult to establish as many σ–agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ–antagonists such as rimcazole were able to block convulsions from cocaine overdose. σ–antagonists are also under investigation for use as antipsychotic medications.

The abundant neurosteroid steroid hormone DHEA is an agonist at sigma receptors and along with pregnenolone could be endogenous agonist ligands; opposed by sigma antagonistic activity from progesterone.[5] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[6][7]

Physiologic effects[edit]

Physiologic effects when the σ–receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis. Some σ–receptor agonists—such as cocaine, a weak σ–agonist—exert convulsant effects in animals. Behavioral reactions to σ–agonists are rather heterogeneous: some individuals find σ–receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.[citation needed]

Recently selective σ–receptor agonists were shown to produce antidepressant-like effects in mice.[8]






  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. PMC 2596726Freely accessible. PMID 17456670. 
  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. doi:10.1126/science.1166127. PMC 2947205Freely accessible. PMID 19213917. 
  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. PMID 16845227. 
  4. ^ Leonard BE (2004). "Sigma receptors and sigma ligands: background to a pharmacological enigma". Pharmacopsychiatry. 37 Suppl 3: S166–70. doi:10.1055/s-2004-832674. PMID 15547782. 
  5. ^ Maurice T, Su TP. "The pharmacology of sigma-1 receptors". Pharmacol Ther. 124: 195–206. doi:10.1016/j.pharmthera.2009.07.001. PMC 2785038Freely accessible. PMID 19619582. 
  6. ^ Guitart X, Codony X, Monroy X (2004). "Sigma receptors: biology and therapeutic potential". Psychopharmacology. 174 (3): 301–19. doi:10.1007/s00213-004-1920-9. PMID 15197533. 
  7. ^ 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. doi:10.1126/science.1166127. PMC 2947205Freely accessible. PMID 19213917. 
  8. ^ Wang J, Mack AL, Coop A, Matsumoto RR (November 2007). "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". Eur Neuropsychopharmacol. 17 (11): 708–16. doi:10.1016/j.euroneuro.2007.02.007. PMC 4041597Freely accessible. PMID 17376658. 
  9. ^ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. Retrieved 2012-10-22. 
  10. ^ Tsung-Ping, Siu; Maurice, Tangui. [The Pharmacology of Sigma-1 Receptors "The Pharmacology of Sigma-1 Receptors"] Check |url= value (help). Retrieved 8 April 2018. 
  11. ^ Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). "Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)". European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/S0924-977X(96)00042-9. ISSN 0924-977X. PMID 9088882. 
  12. ^ Klepstad P, Maurset A, Moberg ER, Oye I (October 1990). "Evidence of a role for NMDA receptors in pain perception". European Journal of Pharmacology. 187 (3): 513–18. doi:10.1016/0014-2999(90)90379-k. ISSN 0014-2999. PMID 1963598. 
  13. ^ Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V, Ascher JA, Earl NL, Greene PL, Monaghan ET (2000). "A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group". J Clin Psychiatry. 61 (11): 841–50. doi:10.4088/jcp.v61n1106. PMID 11105737. 
  14. ^ Ng F, Hallam K, Lucas N, Berk M (2007). "The role of lamotrigine in the management of bipolar disorder". Neuropsychiatr Dis Treat. 3 (4): 463–74. PMC 2655087Freely accessible. PMID 19300575. 
  15. ^ Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E (Apr 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". Eur J Neurosci. 19: 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047. 
  16. ^ Coppola M, et al. Med Hypotheses. 2012. (2012). "Methoxetamine: from drug of abuse to rapid-acting antidepressant". Med Hypotheses. 79: 504–7. doi:10.1016/j.mehy.2012.07.002. PMID 22819129. 
  17. ^ Zhang CL, Feng ZJ, Liu Y, Ji XH, Peng JY, Zhang XH, Zhen XC, Li BM (2012). "Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action". PLoS ONE. 7 (12): e51910. doi:10.1371/journal.pone.0051910. PMC 3527396Freely accessible. PMID 23284812. 
  18. ^ Kamei, J (Oct–Dec 1996). "Role of opioidergic and serotonergic mechanisms in cough and antitussives". Pulmonary Pharmacology. 9 (5–6): 349–56. doi:10.1006/pulp.1996.0046. PMID 9232674. 
  19. ^ Xu YT, Kaushal N, Shaikh J, Wilson LL, Mésangeau C, McCurdy CR, Matsumoto RR (2010). "A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice". J. Pharmacol. Exp. Ther. 333 (2): 491–500. doi:10.1124/jpet.109.161398. PMC 2872963Freely accessible. PMID 20100904. 

External links[edit]