A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity

Journal of Neural Transmission

Volumn 120, Issue 9, 2013, Pages 1295-1303

  Frecska, Ede ^a   Szabo, Attila ^a   Winkelman, Michael J ^b   Luna, Luis E ^c   McKenna, Dennis J ^d  

^a UNIVERSITY OF DEBRECEN   (Hungary)

^b ARIZONA STATE UNIVERSITY   (United States)

^c Wasiwaska Research Centre for the Study of Psychointegrator Plants Visionary Art and Consciousness   (Brazil)

^d UNIVERSITY OF MINNESOTA   (United States)

Author keywords

Carcinogenesis; Immunoregulation; Indolethylamine N methyltransferase; N,N dimethyltryptamine; Oxidative stress; Sigma receptors

Indexed keywords

N,N DIMETHYLTRYPTAMINE; SIGMA 1 OPIATE RECEPTOR;

ARTICLE; BIOENERGY; BIOSYNTHESIS; BLOOD BRAIN BARRIER; CARCINOGENESIS; DRUG STORAGE; GENE EXPRESSION; HUMAN; IMMUNITY; IMMUNOREGULATION; NEOPLASM; NERVE CELL; NONHUMAN; PRIORITY JOURNAL; PROTECTION; TISSUE PROTECTION; TISSUE REGENERATION;

ANIMALS; DEATH; HALLUCINOGENS; HEART ARREST; HUMANS; METHYLTRANSFERASES; N,N-DIMETHYLTRYPTAMINE; NEOPLASMS; OXIDATIVE STRESS; RECEPTORS, SEROTONIN; RECEPTORS, SIGMA; REGENERATION; SEROTONIN AGENTS; TISSUE DISTRIBUTION;

EID: 84883466296     PISSN: 03009564     EISSN: 14351463     Source Type: Journal    
DOI: 10.1007/s00702-013-1024-y     Document Type: Article

References (94)

1. Ahern GP (2011) 5-HT and the immune system. Curr Opin Pharmacol 11:29-33. doi: 10.1016/j.coph.2011.02.004
2. Axelrod J (1961) Enzymatic formation of psychotomimetic metabolites from normally occurring compounds. Science 134:343
3. Aydar E, Palmer CP, Djamgoz MB (2004) Sigma receptors and cancer: possible involvement of ion channels. Cancer Res 64:5029-5035
4. Barker SA, Monti JA, Christian ST (1981) N, N-dimethyltryptamine: an endogenous hallucinogen. Int Rev Neurobiol 22:83-110
5. Barker SA, Beaton JM, Christian ST, Monti JA, Morris PE (1982) Comparison of the brain levels of N, N-dimethyltryptamine and alpha, alpha, beta, beta-tetradeutero-N, N-dimethyltryptamine following intraperitoneal injection. The in vivo kinetic isotope effect. Biochem Pharmacol 31:2513-2516
6. Barker SA, McIlhenny EH, Strassman R (2012) A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010. Drug Test Anal 4:617-635. doi: 10.1002/dta.422
7. Beaton JM, Christian ST (1977) Stress induced changes in whole brain indolealkylamine levels in the rat: using gas liquid chromatography-mass spectrometry. Abstr Soc Neurosci 4:1322
8. Bennett JP Jr, Snyder SH (1976) Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors. Mol Pharmacol 12:373-389
9. Bourrie B, Bribes E, Derocq JM, Vidal H, Casellas P (2004) Sigma receptor ligands: applications in inflammation and oncology. Curr Opin Investig Drugs 5:1158-1163
10. Callaway JC (1988) A proposed mechanism for the visions of dream sleep. Med Hypotheses 26:119-124
11. Caraglia M, Marra M, Tagliaferri P, Lamberts SW, Zappavigna S, Misso G, Cavagnini F, Facchini G, Abbruzzese A, Hofland LJ, Vitale G (2009) Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways. Curr Cancer Drug Targets 9:690-704. doi: 10.2174/156800909789056980
12. Christian ST, Harrison R, Quayle E, Pagel J, Monti J (1977) The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. Biochem Med 18:164-183
13. Cloez-Tayarani I, Changeux JP (2007) Nicotine and serotonin in immune regulation and inflammatory processes: a perspective. J Leukoc Biol 81:599-606
14. Cohen I, Vogel WH (1972) Determination and physiological disposition of dimethyltryptamine and diethyltryptamine in rat brain, liver and plasma. Biochem Pharmacol 21:1214-1216
15. Collina S, Gaggeri R, Marra A, Bassi A, Negrinotti S, Negri F, Rossi D (2013) Sigma receptor modulators: a patent review. Expert Opin Ther Pat (epub ahead of print) doi: 10.1517/13543776.2013.769522
16. Cozzi NV, Gopalakrishnan A, Anderson LL, Feih JT, Shulgin AT, Daley PF, Ruoho AE (2009) Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter. J Neural Transm 116:1591-1599. doi: 10.1007/s00702-009-0308-8
17. Cozzi NV, Mavlyutov TA, Thompson MA, Ruoho AE (2011) Indolethylamine-N- methyltransferase expression in primate nervous tissue. Abstr Soc Neurosci 37:840.19
18. Cuevas J, Behensky A, Deng W, Katnik C (2011a) Afobazole modulates neuronal response to ischemia and acidosis via activation of sigma-1 receptors. J Pharmacol Exp Ther 339:152-160. doi: 10.1124/jpet.111.182774
19. Cuevas J, Rodriguez A, Behensky A, Katnik C (2011b) Afobazole modulates microglial function via activation of both sigma-1 and sigma-2 receptors. J Pharmacol Exp Ther 339:161-172. doi: 10.1124/jpet.111.182816
20. Daumann J, Wagner D, Heekeren K, Neukirch A, Thiel CM, Gouzoulis-Mayfrank E (2010) Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis. J Psychopharmacol 24:1515-1524. doi: 10.1177/0269881109103227
21. Deliganis AV, Pierce PA, Peroutka SJ (1991) Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors. Biochem Pharmacol 41:1739-1744
22. Derocq JM, Bourrie B, Segui M, Le Fur G, Casellas P (1995) In vivo inhibition of endotoxin-induced pro-inflammatory cytokines production by the sigma ligand SR-31747. J Pharmacol Exp Ther 272:224-230
23. Dos Santos RG, Valle M, Bouso JC, Nomdedeu JF, Rodriguez-Espinosa J, McIlhenny EH, Barker SA, Barbanoj MJ, Riba J (2011) Autonomic, neuroendocrine, and immunological effects of ayahuasca: a comparative study with d-amphetamine. J Clin Psychopharmacol 31:717-726. doi: 10.1097/JCP.0b013e31823607f6
24. 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 323:934-937. doi: 10.1126/science.1166127
25. Gekker G, Hu S, Sheng WS, Rock RB, Lokensgard JR, Peterson PK (2006) Cocaine-induced HIV-1 expression in microglia involves sigma-1 receptors and transforming growth factor-beta1. Int Immunopharmacol 6:1029-1033
26. Gonzalez-Navajas JM, Lee J, David M, Raz E (2012) Immunomodulatory functions of type I interferons. Nat Rev Immunol 12:125-135. doi: 10.1038/nri3133
27. Griesmaier E, Posod A, Gross M, Neubauer V, Wegleiter K, Hermann M, Urbanek M, Keller M, Kiechl-Kohlendorfer U (2012) Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice. Exp Neurol 237:388-395. doi: 10.1016/j.expneurol.2012.06.030
28. Guzman-Lenis MS, Navarro X, Casas C (2009) Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons. Neuroscience 162:31-38. doi: 10.1016/j.neuroscience.2009.03.067
29. Hall AA, Herrera Y, Ajmo CT Jr, Cuevas J, Pennypacker KR (2009) Sigma receptors suppress multiple aspects of microglial activation. Glia 57:744-754. doi: 10.1002/glia.20802
30. Hayashi T, Su TP (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269-284
31. Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596-610
32. Hollister LE (1977) Some general thoughts about endogenous psychotogens. In: Usdin E, Hamburg DA, Barchas JD (eds) Neuroregulators and psychiatric disorders. Oxford University Press, New York, pp 550-556
33. Jacob MS, Presti DE (2005) Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine. Med Hypotheses 64:930-937
34. Jenner P, Marsden CD, Thanki CM (1980) Behavioural changes induced by N, N-dimethyl-tryptamine in rodents. Br J Pharmacol 69:69-80
35. Karkkainen J, Forsstrom T, Tornaeus J, Wahala K, Kiuru P, Honkanen A, Stenman UH, Turpeinen U, Hesso A (2005) Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues. Scand J Clin Lab Invest 65:189-199
36. Katnik C, Guerrero WR, Pennypacker KR, Herrera Y, Cuevas J (2006) Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. J Pharmacol Exp Ther 319:1355-1365
37. Klouz A, Said DB, Ferchichi H, Kourda N, Ouanes L, Lakhal M, Tillement JP, Morin D (2008) Protection of cellular and mitochondrial functions against liver ischemia by N-benzyl-N′-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), a sigma-1 ligand. Eur J Pharmacol 578:292-299
38. Kopantzev EP, Monastyrskaya GS, Vinogradova TV, Zinovyeva MV, Kostina MB, Filyukova OB, Tonevitsky AG, Sukhikh GT, Sverdlov ED (2008) Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma. Lung Cancer 62:23-34
39. Kourrich S, Su TP, Fujimoto M, Bonci A (2012) The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci 35:762-771. doi: 10.1016/j.tins.2012.09.007
40. Kuhn T (1970) The structure of scientific revolutions. University of Chicago Press, Chicago
41. Larkin SE, Holmes S, Cree IA, Walker T, Basketter V, Bickers B, Harris S, Garbis SD, Townsend PA, Aukim-Hastie C (2012) Identification of markers of prostate cancer progression using candidate gene expression. Br J Cancer 106:157-165. doi: 10.1038/bjc.2011.490
42. Lasfar A, Abushahba W, Balan M, Cohen-Solal KA (2011) Interferon lambda: a new sword in cancer immunotherapy. Clin Dev Immunol 2011:349575. doi: 10.1155/2011/349575
43. Leon-Ponte M, Ahern GP, O'Connell PJ (2007) Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 109:3139-3146
44. Lin RL, Sargeant S, Narasimhachari N (1974) Indolethylamine-N- methyltransferase in developing rabbit lung. Dev Psychobiol 7:475-481
45. Luedtke RR, Perez E, Yang SH, Liu R, Vangveravong S, Tu Z, Mach RH, Simpkins JW (2012) Neuroprotective effects of high affinity sigma 1 receptor selective compounds. Brain Res 1441:17-26. doi: 10.1016/j.brainres.2011.12.047
46. Luna LE (2011) Indigenous and mestizo use of ayahuasca: an overview. In: Dos Santos RG (ed) The ethnopharmacology of ayahuasca. Transworld Research Network, Kerala, pp 1-21
47. Mancuso R, Oliván S, Rando A, Casas C, Osta R, Navarro X (2012) Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics 9:814-826. doi: 10.1007/s13311-012-0140-y
48. Marzullo G, Rosengarten H, Friedhoff AJ (1977) A peptide-like inhibitor of N-methyltransferase in rabbit brain. Life Sci 20:775-783
49. Mavlyutov TA, Epstein ML, Liu P, Verbny YI, Ziskind-Conhaim L, Ruoho AE (2012) Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N, N′-dimethyltryptamine forming enzyme, indole-N-methyl transferase. Neuroscience 206:60-68
50. McEwen CM Jr, Sober AJ (1967) Rabbit serum monoamine oxidase. II. Determinants of substrate specificity. J Biol Chem 242:3068-3078
51. McKenna DJ, Peroutka SJ (1989) Differentiation of 5-hydroxytryptamine2 receptor subtypes using 125I-R-(-)2,5-dimethoxy-4-iodo-phenylisopropylamine and 3H-ketanserin. J Neurosci 9:3482-34890
52. Megalizzi V, Mathieu V, Mijatovic T, Gailly P, Debeir O, De Neve N, Van Damme M, Bontempi G, Haibe-Kains B, Decaestecker C, Kondo Y, Kiss R, Lefranc F (2007) 4-IBP, a sigma1 receptor agonist, decreases the migration of human cancer cells, including glioblastoma cells, in vitro and sensitizes them in vitro and in vivo to cytotoxic insults of proapoptotic and proautophagic drugs. Neoplasia 9:358-369
53. Mueller BH 2nd, Park Y, Daudt DR 3rd, Ma HY, Akopova I, Stankowska DL, Clark AF, Yorio T (2013) Sigma-1 receptor stimulation attenuates calcium influx through activated L-type Voltage Gated Calcium Channels in purified retinal ganglion cells. Exp Eye Res 107:21-31. doi: 10.1016/j.exer.2012.11.002
54. Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007) The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur J Pharmacol 559:132-137
55. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131-181
56. Nuno-Ayala M, Guillen N, Arnal C, Lou-Bonafonte JM, de Martino A, Garcia-de-Jalon JA, Gascon S, Osaba L, Osada J, Navarro MA (2012) Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites. Physiol Genomics 44:702-716. doi: 10.1152/physiolgenomics.00189.2010
57. O'Connell PJ, Wang X, Leon-Ponte M, Griffiths C, Pingle SC, Ahern GP (2006) A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells. Blood 107:1010-1017
58. Pal A, Fontanilla D, Gopalakrishnan A, Chae YK, Markley JL, Ruoho AE (2012) The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol 682:12-20. doi: 10.1016/j.ejphar.2012.01.030
59. Penas C, Pascual-Font A, Mancuso R, Forés J, Casas C, Navarro X (2011) Sigma receptor agonist 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (Pre084) increases GDNF and BiP expression and promotes neuroprotection after root avulsion injury. J Neurotrauma 28:831-840. doi: 10.1089/neu.2010.1674
60. Pierce PA, Peroutka SJ (1990) Antagonist properties of d-LSD at 5-hydroxytryptamine2 receptors. Neuropsychopharmacology 3:503-508
61. Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su TP, Tam SW, Taylor DP (1992) A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13:85-86
62. Reimann W, Schneider F (1993) The serotonin receptor agonist 5-methoxy-N, N-dimethyltryptamine facilitates noradrenaline release from rat spinal cord slices and inhibits monoamine oxidase activity. Gen Pharmacol 24:449-453
63. Ruscher K, Shamloo M, Rickhag M, Ladunga I, Soriano L, Gisselsson L, Toresson H, Ruslim-Litrus L, Oksenberg D, Urfer R, Johansson BB, Nikolich K, Wieloch T (2011) The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain 134:732-746. doi: 10.1093/brain/awq367
64. Ruscher K, Inacio AR, Valind K, Rowshan Ravan A, Kuric E, Wieloch T (2012) Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3- phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke. PLoS One 7:e45118 doi: 10.1371/journal.pone.0045118
65. Sangiah S, Gomez MV, Domino EF (1979) Accumulation of N, N-dimethyltryptamine in rat brain cortical slices. Biol Psychiatry 14:925-936
66. Schetz JA, Perez E, Liu R, Chen S, Lee I, Simpkins JW (2007) A prototypical sigma-1 receptor antagonist protects against brain ischemia. Brain Res 1181:1-9
67. Sitaram BR, Lockett L, Talomsin R, Blackman GL, McLeod WR (1987) In vivo metabolism of 5-methoxy-N, N-dimethyltryptamine and N, N-dimethyltryptamine in the rat. Biochem Pharmacol 36:1509-1512
68. Smith RL, Canton H, Barrett RJ, Sanders-Bush E (1998) Agonist properties of N, N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol Biochem Behav 61:323-330
69. Stahl SM (2008) The sigma enigma: can sigma receptors provide a novel target for disorders of mood and cognition? J Clin Psychiatry 69:1673-1674
70. Strassman RJ (1995) Hallucinogenic drugs in psychiatric research and treatment. Perspectives and prospects. J Nerv Ment Dis 183:127-138
71. Strassman RJ (2001) DMT: the spirit molecule. A doctor's revolutionary research into the biology of near-death and mystical experiences. Park Street Press, Rochester
72. Strassman RJ, Qualls CR, Berg LM (1996) Differential tolerance to biological and subjective effects of four closely spaced doses of N, N-dimethyltryptamine in humans. Biol Psychiatry 39:784-795
73. Su TP, Hayashi T, Vaupel DB (2009) When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor. Sci Signal 2:pe12 doi: 10.1126/scisignal.261pe12
74. Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE (2010) The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31:557-566. doi: 10.1016/j.tips.2010.08.007
75. Szabo A, Osman RM, Bacskai I, Kumar BV, Agod Z, Lanyi A, Gogolak P, Rajnavolgyi E (2012) Temporally designed treatment of melanoma cells by ATRA and polyI: C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5. Melanoma Res 22:351-361. doi: 10.1097/CMR. 0b013e328357076c
76. Szara S (1956) Dimethyltryptamin: its metabolism in man; the relation to its psychotic effect to the serotonin metabolism. Experientia 12:441-442
77. Szara S (1994) Are hallucinogens psychoheuristic? NIDA Res Monogr 146:33-51
78. Tagashira H, Zhang C, Lu YM, Hasegawa H, Kanai H, Han F, Fukunaga K (2013) Stimulation of σ(1)-receptor restores abnormal mitochondrial Ca(2+) mobilization and ATP production following cardiac hypertrophy. Biochim Biophys Acta (epub ahead of print) doi: 10.1016/j.bbagen.2012.12.029
79. Takahashi T, Takahashi K, Ido T, Yanai K, Iwata R, Ishiwata K, Nozoe S (1985) 11C-labeling of indolealkylamine alkaloids and the comparative study of their tissue distributions. Int J Appl Radiat Isot 36:965-969
80. Tchedre KT, Yorio T (2008) Sigma-1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation. Invest Ophthalmol Vis Sci 49:2577-2588
81. Thompson MA, Moon E, Kim UJ, Xu J, Siciliano MJ, Weinshilboum RM (1999) Human indolethylamine N-methyltransferase: cDNA cloning and expression, gene cloning, and chromosomal localization. Genomics 61:285-297
82. Tsai SY, Hayashi T, Harvey BK, Wang Y, Wu WW, Shen RF, Zhang Y, Becker KG, Hoffer BJ, Su TP (2009) Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway. Proc Natl Acad Sci USA 106:22468-72243. doi: 10.1073/pnas.0909089106
83. Tsai SY, Rothman RK, Su TP (2012) Insights into the sigma-1 receptor chaperone's cellular functions: a microarray report. Synapse 66:42-51. doi: 10.1002/syn.20984
84. Tuerxun T, Numakawa T, Adachi N, Kumamaru E, Kitazawa H, Kudo M, Kunugi H (2010) SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neurosci Lett 469:303-308. doi: 10.1016/j.neulet.2009.12.013
85. Vagnerova K, Hurn PD, Bhardwaj A, Kirsch JR (2006) Sigma-1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. Anesth Analg 103:430-434
86. Vitale AA, Pomilio AB, Cañellas CO, Vitale MG, Putz EM, Ciprian-Ollivier J (2011) In vivo long-term kinetics of radiolabeled N, N-dimethyltryptamine and tryptamine. J Nucl Med 52:970-977. doi: 10.2967/jnumed.110.083246
87. Wallach JV (2009) Endogenous hallucinogens as ligands of the trace amine receptors: a possible role in sensory perception. Med Hypotheses 72:91-94. doi: 10.1016/j.mehy.2008.07.052
88. Warren JM, Dham-Nayyar P, Alexander J (2012) Recreational use of naturally occurring dimethyltryptamine - contributing to psychosis? Aust N Z J Psychiatry (epub ahead of print) doi: 10.1177/0004867412462749
89. Watcharanurak K, Nishikawa M, Takahashi Y, Takakura Y (2012) Controlling the kinetics of interferon transgene expression for improved gene therapy. J Drug Target 20:764-769. doi: 10.3109/1061186X.2012.716848
90. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, Kainz C, Lahodny J, Denison U, Muller-Holzner E, Marth C (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 82:1138-1144
91. Yanai K, Ido T, Ishiwata K, Hatazawa J, Takahashi T, Iwata R, Matsuzawa T (1986) In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N, N-[11C]dimethyltryptamine. Eur J Nucl Med 12:141-146
92. 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 104:1179-1184
93. Yang ZJ, Carter EL, Torbey MT, Martin LJ, Koehler RC (2010) Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. Exp Neurol 221:166-174. doi: 10.1016/j.expneurol.2009.10.019
94. Zhang Y, Shi Y, Qiao L, Sun Y, Ding W, Zhang H, Li N, Chen D (2012) Sigma-1 receptor agonists provide neuroprotection against gp120 via a change in bcl-2 expression in mouse neuronal cultures. Brain Res 1431:13-22. doi: 10.1016/j.brainres.2011.10.053