Sigma Ligands Research Articles

1,4-Dibenzylpiperazines possess anticocaine activity

N,N-Dibenzylpiperazines have high affinity for sigma receptors, and we aimed to increase their anticocaine activity by introducing substituents known to enhance such activity in other sigma ligands. Ligands with high affinity for sigma-1 receptors resulted, but their activity in attenuating cocaine-induced convulsions did not correlate with sigma-1 binding affinity, and may be more closely related to their sigma-2 binding affinities.

Metabolism of N,N-Dipropyl-2-[4-Methoxy-3-(2-Phenyl-Ethoxy)-Phenyl]-Ethyl-Amine-Monohydrochloride (NE-100), A Novel Sigma Ligand: Contribution of Cytochrome P450 Forms Involved in the Formation of Individual Metabolites in Human Liver and Small Intestine

In the present study, human cytochrome P450 (CYP) forms involved in producing the primary metabolites of NE-100 were identified. Major metabolites of NE-100 in human liver microsomes (HLM) were N-depropylation of NE-100 (NE-098), p-hydroxylation of phenyl group of NE-100 (NE-152), m-hydroxylation of phenyl group of NE-100 (NE-163) and O-demethylation of NE-100 (NE-125). Judging from the correlation and inhibition studies, NE-125 and NE-152+163mix formations were predominantly mediated by CYP2D6 and NE-098 formation was mediated by multiple CYP forms at a low NE-100 concentration (0.1 microM) in the HLM. According to relative activity factor (RAF) approaches, all these reactions were predominantly catalyzed by CYP2D6 at a substrate concentration assuming a plasma level of NE-100 (K(m)>>S) in case of the human liver. Depending on the increase in NE-100 concentrations, the rate of contribution for NE-098 and NE-152+163mix formations increased in CYP3A4, although the predominant contribution of CYP2D6 for NE-125 formation did not change. In human intestinal microsomes (HIM), NE-100 was mainly metabolized to NE-098 and NE-152+163mix by CYP3A4. The intrinsic clearance for their formations in HIM was 3.2 and 14.9 times less than those in HLM, respectively, and no formation of NE-125 was observed in HIM. These results strongly suggest that CYP2D6 is the predominant form for NE-100 metabolism in the human liver in in vivo conditions (K(m)>>S) and the liver plays a more important role than does the small intestine in the first pass metabolism.

Transcriptomic classification of antitumor agents: application to the analysis of the antitumoral effect of SR31747A.

SR31747A is a sigma ligand that exhibits a potent antitumoral activity on various human tumor cell lines both in vitro and in vivo. To understand its mode of action, we used DNA microarray technology combined with a new bioinformatic approach to identify genes that are modulated by SR31747A in different human breast or prostate cancer cell lines. The SR31747A transcriptional signature was also compared with that of seven different representative anticancer drugs commonly used in the clinic. To this aim, we performed a two-dimensional hierarchical clustering analysis of drugs and genes which showed that 1) standard molecules with similar mechanism of action clustered together and 2) SR31747A does not belong to any previously characterized class of standard anticancer drugs. Moreover, we showed that 3) SR31747A mainly exerted its antiproliferative effect by inhibiting the expression of genes playing a key role in DNA replication and cell cycle progression. Finally, contrasting with other drugs, we obtained evidence that 4) SR31747A strongly inhibited the expression of three key enzymes of the nucleotide synthesis pathway (i.e., dihydrofolate reductase, thymidylate synthase, and thymidine kinase) with the latter shown both at the mRNA and protein levels. These results, obtained through a novel molecular approach to characterize and compare anticancer agents, showed that SR31747A exhibits an original mechanism of action, very likely through unexpected targets whose modulations may account for its antitumoral effect.

The selective sigma ligand MS-377 attenuates the blockade by phencyclidine of NMDA-induced intracellular calcium.

The role of MS-377, a novel selective sigma1 ligand currently being developed for the treatment of schizophrenia, in modulating the activities of phencyclidine (PCP) on NMDA-induced calcium increase was examined in primary cultured neocortical neurons using calcium-imaging technique combined with a confocal laser scanning microscope. PCP significantly blocked NMDA-induced increases in intracellular calcium. The blockade by PCP of NMDA response was attenuated by both MS-377 and another highly selective sigma1 ligand, 3-PPP. The results agree with the interpretation that sigma ligands may directly or indirectly modulate NMDA receptor complex functions, and may suggest that MS-377 might be therapeutically useful in cases of PCP-induced psychosis or schizophrenia.

Protection of Striatal Neurons by Joint Blockade of D1 and D2 Receptor Subtypes in an in Vitro Model of Cerebral Hypoxia

Massive increases in extracellular dopamine have been reported in the ischemic rodent striatum, implicating this neurotransmitter in toxic events. We have examined whether dopamine receptor antagonists are protective against hypoxic insult, using brain slices containing the rostral striatum obtained from adult male C57/BLIcrfat mice. Slices were subjected in vitro to 20 min nitrogen hypoxia, with or without addition of: (i) 50 μM haloperidol (D2 receptor antagonist and sigma ligand), (ii) 10 μM SCH23390 (selective D1 receptor antagonist), (iii) 10 μM eticlopride (selective D2 receptor antagonist), (iv) 10 μM SCH23390 and 10 μM eticlopride in combination, and (v) 10 μM MK-801 (noncompetitive NMDA receptor antagonist). Subsequently, slices were reoxygenated, fixed 2 h postinsult, and processed for light microscopy. Damage was assessed by calculating pyknotic profiles as a percentage of total neuronal profiles present. No pyknotic profiles were detected in normoxic control tissue, but this phenotype predominated in most slices subject to hypoxia alone (60.1 ± 30.6% pyknotic profiles). Marked protection was produced by haloperidol (7.1 ± 7.6%, P = 0.002), MK-801 (8.6 ± 6.9%, P = 0.007), and the combined application of SCH23390 and eticlopride (5.9 ± 9.4%, P = 0.001). No protection was demonstrated for SCH23390 or eticlopride when applied separately. These data suggest that hypoxic damage in the rostral mouse striatum is mediated via NMDA, D1, and D2 receptors. Protection against hypoxic damage by dopamine receptor antagonists requires the combined blockade of both classes of dopamine receptor.

Effect of sigma ligand haloperidol in guinea pig heart preparations

The effects of sigma ligand haloperidol in the multicellular guinea pig heart preparations were examined. Adult male guinea pigs were used. Left atrium and papillary muscle from right ventricle were examined. The stimulated twiches in horizontal bath were recorded isometrically. Sigma ligand haloperidol (10nM) was administered for 30 minutes. Its effect on the amplitude of contraction and on the mechanical restitution was evaluated. Marked positive inotropic effect (increase in the twitch amplitude ranging from 50 to 90 % for atria and 5 to 45% for ventricles, with maximal effect in the 5th minute of ligand administration for both preparations) has been observed. The mechanical restitution pattern under the effect of sigma receptor ligand is not altered. Thus, the positive inotropic effect of haloperidol was confirmed in guinea pig heart preparations. According to its effect on the mechanical restitution can be assumed that it is mediated via increased cytoplasmatic calcium concentration.

Synthesis of (+)-cis-N-(4-isothiocyanatobenzyl)-N-normetazocine, an isothiocyanate derivative of N-benzylnormetazocine as acylant agent for the sigma(1) receptor.

(+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine (BNIT) (+)-(4) was designed and synthesized as a derivative of the potent and selective sigma(1) receptor ligand (+)-cis-N-benzyl-N-normetazocine for irreversibly blocking sigma(1) binding sites. Pretreatment of guinea pig brain membranes with BNIT (0.1, 1, and 5 microM) caused a concentration-dependent loss of binding of the selective sigma(1) ligand [(3)H]-(+)-pentazocine. Binding experiments with [(3)H]-1,3-di(2-tolyl)guanidine ([(3)H]-DTG), a ligand of sigma(1) and sigma(2) receptors, showed that pretreatment with BNIT blocked only the sigma(1) component of [(3)H]-DTG binding.

Evidence for sigma-1-like receptors in isolated rat liver mitochondrial membranes.

1. Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible roles in various pathologies, including cytoprotection. Although the exact function of sigma-1 (sigma(1)) receptors is not yet known, their role in the regulation of intracellular Ca(2+) levels and sterol biosynthesis, functions that could be assigned to mitochondria, are the only mechanisms described. 2. Using preparations of purified rat liver and brain mitochondria we demonstrate herein the presence of sigma-like binding sites. [(3)H](+)-pentazocine, a sigma(1) radioligand was used to label these sites. 3. In the liver, [(3)H](+)-pentazocine labelled one class of binding sites with high affinity (K(d)=3 nM), similar to that observed in liver microsomes and synaptic membranes. These sites were located on the outer mitochondrial membranes and displayed high affinity for other sigma(1) ligands namely, haloperidol, ifenprodil, carbetapentane or 1,3-di(2-tolyl)guanidine (DTG). 4. The presence of sigma(1) receptors on liver mitochondria was confirmed using double fluorescence immunostaining. 5. [(3)H](+)-pentazocine binding sites were also found on brain mitochondria but they appeared pharmacologically distinct to the liver ones as [(3)H](+)-pentazocine and typical sigma(1) ligands displayed lower affinities for these sites. Nevertheless, [(3)H](+)-pentazocine binding on both liver and brain mitochondria was modulated by progesterone, a putative endogenous ligand for sigma receptors. 6. Our data demonstrates the presence of [(3)H](+)-pentazocine binding sites with pharmacological characteristics identical to sigma(1) receptors on rat liver mitochondrial membranes. The pharmacological significance of these sites and their role on mitochondrial function remain unknown.

Effects of sigma ligands on NMDA receptor function in the bulbectomy model of depression: a behavioural study in the rat

Sigma (sigma) ligands have been shown to modulate NMDA receptor activity. In the present study we used the olfactory bulbectomy (OBX) animal model of depression to assess the effects of the sigma1 ligand igmesine on OBX-induced behaviour. Behavioural experiments demonstrated OBX (saline-treated) rats to have increased dizocilpine-induced behavioural modifications, including locomotor and circling activity as compared to Sham rats (saline-treated). A short-term (7 d) treatment with low doses of igmesine (50-200 microg/kg.d s.c.) had no effect on dizocilpine-induced behaviour while long-term treatments (14 d) with low doses of igmesine reversed the effect of the bulbectomy such that the treated OBX rats' behaviour was not significantly different from Sham-saline rats. Short-term treatments with high doses of igmesine (500-1000 microg/kg.d) also reversed the increased locomotor and circling behaviour seen in OBX rats (saline-treated) while long-term treatments with the same high doses did not. These results provide behavioural evidence for sigma ligand's potential to reverse some OBX-induced behaviours. Moreover, they support the notion of a bell-shaped dose-response curve previously reported for sigma ligands.

Sigma receptor binding profile of a series of analgesic tropane derivatives.

The binding profile on sigma receptor subtypes of a family of tropane derivatives, previously studied as analgesic and nootropic drugs, is reported. The results show that the sigma receptors are not involved in the enhancement of acetylcholine release and of the consequent analgesic activity of this class of drugs. Structure-affinity relationships for sigma receptor subtypes are discussed. They lead to the identification of a few useful leads for further development of potent sigma ligands within the series.

N-Arylalkylpiperidines as High-Affinity Sigma-1 and Sigma-2 Receptor Ligands: Phenylpropylamines as Potential Leads for Selective Sigma-2 Agents

To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands.

Reduction of IL-10 and nitric oxide synthesis by SR31747A (sigma ligand) in RAW murine macrophages.

There are several subtypes of sigma receptor, one of which is found throughout the immune system. SR31747A is a unique sigma ligand that possesses potent immune modulatory properties. Previous in vivo studies have documented that administration of SR31747A in murine models of sepsis resulted in decreased proinflammatory (IL-1, IL-6, TNF-alpha) and increased anti-inflammatory (IL-10) response (serum, splenocyte). Studies regarding the effect of this sigma ligand on purified macrophages are lacking. We therefore sought to investigate the effect of SR31747A in LPS-stimulated murine macrophages (RAW 264.7). RAW cells were incubated at 2.5 x 10(5) cells/well; controls were incubated with media alone, experimental groups contained LPS (0.01 microg) and SR31747A (1 nM, 10 nM, 100 nM, 1 microM, 10 microM). Supernatant and cells were harvested at 24 and 48 h. Concentrations of nitric oxide (Greiss reaction) and IL-10 were determined in the supernatant; cellular IL-10 mRNA was assessed. SR31747A induced a dose-dependent reduction in NO and IL-10 protein release in LPS-stimulated murine macrophages. The decrease in IL-10 protein synthesis was paralleled by a significant dose-dependent reduction in IL-10 mRNA. SR31747A is a novel immunomodulator that down regulates nitric oxide and IL-10 protein and mRNA expression. This in vitro reduction of IL-10 protein and mRNA expression is in contrast to previous in vivo murine studies. These data suggest that peripheral macrophages are not the source of the increased anti-inflammatory (IL-10) response induced by SR31747A.

Expression pattern of sigma receptor 1 mRNA and protein in mammalian retina

Sigma receptors are nonopiate and nonphencyclidine binding sites that are thought to be neuroprotective due to modulation of N-methyl- d-aspartate (NMDA) receptors. Sigma receptor 1 expression has been demonstrated in numerous tissues including brain. Recently, studies using binding assays have demonstrated sigma receptor 1 in neural retina, however these studies did not demonstrate in which retinal cell type(s) sigma receptor 1 was present nor did they establish unequivocally the molecular identity of the receptor. The present study was designed to address these issues. Reverse transcription–polymerase chain reaction (RT–PCR) analysis amplified sigma receptor 1 in neural retina, RPE–choroid complex, and lens isolated from mice. A similar RT–PCR product was amplified also in three cultured cell lines, rat Müller cells, rat ganglion cells and human ARPE-19 cells. In situ hybridization analysis revealed abundant sigma receptor 1 expression in ganglion cells, cells of the inner nuclear layer, inner segments of photoreceptor cells and retinal pigment epithelial (RPE) cells. Immunohistochemical studies detected the sigma receptor 1 protein in retinal ganglion, photoreceptor, RPE cells and surrounding the soma of cells in the inner nuclear layer. These data provide the first cellular localization of sigma receptor 1 in neural retina and establish the molecular identity of sigma receptor 1 in retinal cells. The demonstration that sigma receptor 1 is present in ganglion cells is particularly noteworthy given the well-documented susceptibility of these cells to glutamate toxicity. Our findings suggest that retinal ganglion cells may be amenable to the neuroprotective effects of sigma ligands under conditions of neurotoxicity such as occurs in diabetes.

Modulation of serotonergic neurotransmission by short- and long-term treatments with sigma ligands.

1. Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma(1) and sigma(2). Although the endogenous ligand is yet to be elucidated, the sigma(1) receptor has recently been cloned. 2. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. 3. The goal of the present study was to assess the effects of various sigma(1) ligands on the firing activity of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. 4. The sigma(1) ligands (+)-pentazocine and 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP) (2 mg kg(-1) day(-1)) increased markedly 5-HT firing activity after 2 days of treatment and maintained the same increased firing rate after long-term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)-pentazocine was prevented by the co-administration of N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine (NE-100) (10 mg kg(-1) day(-1)) a selective sigma(1) antagonist, confirming the sigma(1) receptor's modulation of these effects. In contrast, the sigma(1) ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) and 2-(4-morpholinoethyl 1-phenyl-cyclohexane-1-carboxylate hydrochloride (PRE-084) had no effect. 5. Following a 21-day treatment with (+)-pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4-IBP and may represent a depolarization block. 6. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the 'antidepressant effects' reported and provide evidence toward sigma(1) ligands as potential antidepressants with a rapid onset of action.

Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands

The ability of dopamine (DA) antagonists and sigma receptor ligands to alter [ 3H]-DA uptake was examined using synaptosomes prepared from the nucleus accumbens of female rats. Pre-incubation with compounds having a high affinity for sigma (rimcazole, haloperidol, and spiperone) receptors produced dose dependent inhibition of 3H-DA uptake. Sulpiride, a pure DA D 2 antagonist had no effect. In contrast, DA uptake was potentiated in response to (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, a mixed sigma receptor antagonist and DA D 2 receptor agonist. Similarly, SKF-10,047, a selective sigma receptor agonist, and progesterone, a putative endogenous ligand for the sigma receptor, produced significant increases in 3[H]-DA uptake. These data suggest a potential role for sigma and DA ligands in the regulation of DA uptake in the nucleus accumbens.

Opioid and sigma receptor studies. New developments in the design of selective sigma ligands

Abstract New racemic and chiral methyl 2-{[4-(4-chlorophenyl)-4-hydroxypiperi-din-1-yl]methyl}-1-phenylcyclopropanecarboxylate derivatives were synthesized in order to obtain sigma ligands with increased affinity and selectivity compared to (+)-MPCB and haloperidol. The cis-(±)-7 racemic mixture showed a better binding affinity and selectivity than the (±)-8 trans isomers. Between the two cis enantiomers, (+)-7, with configuration (1R,2S), showed a very high affinity and the best selectivity for s1. All compounds synthesized (7­9) showed a reduced or negligible affinity for opioid and dopaminergic D1 and D2 receptors. Nociceptive in vivo test confirms that (+)-7 (namely MR200), such as non-selective antagonist haloperidol, increased the analgesic effect induced by the k opioid selective ligand U50,488H and reversed the inhibiting effect of (+)-pentazocine on analgesia.

Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant

Igmesine is a selective sigma (σ 1) ligand that was reported to exert antidepressant action through an unknown mechanism of action. A number of neurochemical measures were taken in this study in efforts to understand its mode of action. Following 21-day drug treatments, the actions of igmesine on a number of neurochemical measures were investigated. Data obtained showed significant decreases in the densities of β-adrenergic but not 5-HT 1A, σ 1 and GABA B receptors in fluoxetine (18%), desipramine (DMI, 32%) and igmesine (20%)-treated groups when compared with control. Tyrosine hydroxylase (TH) activity was significantly (30–32%) reduced in all treated groups. Further, fluoxetine and DMI excluding the igmesine-treated groups showed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) neuronal uptake, respectively. Following acute treatment, igmesine lacked activity for monoamine oxidase (MAO) A or B (IC 50>10 μM). In in vivo studies, at behaviorally active doses, igmesine showed weak effects on the NE uptake but lacked activity in altering 5-HT and DA synthesis or antagonizing selective drug-induced depletion of monoamine neuronal uptake. N-methyl- d-aspartate (NMDA)-induced increases in cGMP was blocked by igmesine indicating that igmesine may interfere with the NMDA receptor/nitric oxide synthase/cGMP pathway. Although it appears that part of the pharmacological actions of igmesine is mediated by the monoaminergic system, there is still need to explore other possible mechanisms of antidepressant action.

Some of the effects of the selective sigma ligand (+)pentazocine are mediated via a naloxone‐sensitive receptor

Recently, in an attempt to isolate the nonopioid σ receptor, Su and colleagues purified a protein from rat liver and brain which appeared to resemble the original σ opioid receptor as proposed by Martin in 1976, and for which the nonopiate σ1 ligand (+)pentazocine presents a high affinity. Previous in vivo electrophysiological studies from our laboratory have demonstrated that several selective σ1 ligands potentiate the neuronal response to NMDA. The goal of the present series of experiments was to assess the effects of some selective σ1 ligands on the potentiation of the NMDA response and to determine if this potentiation was mediated by the naloxone-sensitive σ receptor. Extracellular unitary recordings from pyramidal neurons of the CA3 region of the rat dorsal hippocampus were obtained. The σ1 ligands BD 737, L 687-384, and JO-1784 (igmesine), administered intravenously at low doses, potentiated the NMDA response but the opiate antagonist naloxone failed to reverse this potentiation. However, the potentiation of the NMDA response induced by the σ1 ligand (+)pentazocine was suppressed by naloxone but not by the μ antagonist cyprodime hydrobomide, the κ antagonist DIPPA nor by the δ antagonist naltrindole. (±) Cyclazocine, which presents a high affinity for the above-mentioned σ-opiate receptor acted as an antagonist by suppressing the potentiation of the NMDA response induced by both JO-1784 and (+)pentazocine. These results suggest that the effects induced by some σ1 ligands may, in fact, be sensitive to naloxone while others may not. The original classification of σ receptors as opiates might have been partly accurate. Synapse 39:323–331, 2001. © 2001 Wiley-Liss, Inc.

Some of the effects of the selective sigma ligand (+)pentazocine are mediated via a naloxone-sensitive receptor.

Recently, in an attempt to isolate the nonopioid sigma receptor, Su and colleagues purified a protein from rat liver and brain which appeared to resemble the original sigma opioid receptor as proposed by Martin in 1976, and for which the nonopiate sigma-1 ligand (+)pentazocine presents a high affinity. Previous in vivo electrophysiological studies from our laboratory have demonstrated that several selective sigma-1 ligands potentiate the neuronal response to NMDA. The goal of the present series of experiments was to assess the effects of some selective sigma-1 ligands on the potentiation of the NMDA response and to determine if this potentiation was mediated by the naloxone-sensitive sigma receptor. Extracellular unitary recordings from pyramidal neurons of the CA3 region of the rat dorsal hippocampus were obtained. The sigma-1 ligands BD 737, L 687-384, and JO-1784 (igmesine), administered intravenously at low doses, potentiated the NMDA response but the opiate antagonist naloxone failed to reverse this potentiation. However, the potentiation of the NMDA response induced by the sigma-1 ligand (+)pentazocine was suppressed by naloxone but not by the mu antagonist cyprodime hydrobomide, the kappa antagonist DIPPA nor by the delta antagonist naltrindole. (+/-) Cyclazocine, which presents a high affinity for the above-mentioned sigma-opiate receptor acted as an antagonist by suppressing the potentiation of the NMDA response induced by both JO-1784 and (+)pentazocine. These results suggest that the effects induced by some sigma-1 ligands may, in fact, be sensitive to naloxone while others may not. The original classification of sigma receptors as opiates might have been partly accurate.

Chapter 9 Sigma receptors and iboga alkaloids

Current evidence indicates that ibogaine and other iboga alkaloids might produce some of their neurotoxic effects by interaction with sigma-2 receptors. Sigma receptors are membrane proteins that bind several psychotropic drugs with high affinity. Two major subclasses of sigma receptors have been identified. These have been termed “sigma-1” and “sigma-2,” and they are differentiated by their pharmacological profile, function, and molecular size. Both subtypes have high to moderate affinity for typical neuroleptics, with haloperidol exhibiting the highest affinity for both sites. The sigma-1 receptor has been cloned in guinea pig, mouse, rat, and human, and shown to be a novel protein with > 90% species homology. Some of the functions attributed to sigma-1 receptors include the following: (1) modulation of synthesis and release of dopamine and acetylcholine, (2) modulation of NMDA-type glutamatergic receptor electrophysiology, (3) modulation of NMDA-stimulated neurotransmitter release, (4) modulation of muscarinic receptor-stimulated phosphoinositide turnover, (5) neuroprotective and antiamnesic activity, (6) modulation of opioid analgesia, and (7) alteration of cocaine-induced locomotor activity and toxicity. The ability of sigma ligands to induce morphological changes and apoptosis led to an investigation of the signaling mechanisms that are utilized by sigma-2 receptors.