RESUMO
Immune cells have a known role in pronociception, since they release a myriad of inflammatory algogens which interact with neurons to facilitate pain signaling. However, these cells also produce endogenous opioid peptides with analgesic potential. The sigma-1 receptor is a ligand-operated chaperone that modulates neurotransmission by interacting with multiple protein partners, including the µ-opioid receptor. We recently found that sigma-1 antagonists are able to induce opioid analgesia by enhancing the action of endogenous opioid peptides of immune origin during inflammation. This opioid analgesia is seen only at the inflamed site, where immune cells naturally accumulate. In this article we review the difficulties of targeting the opioid system for selective pain relief, and discuss the dual role of immune cells in pain and analgesia. Our discussion creates perspectives for possible novel therapeutic uses of sigma-1 antagonists as agents able to maximize the analgesic potential of the immune system.
Assuntos
Analgésicos Opioides/uso terapêutico , Terapia de Alvo Molecular/métodos , Dor/tratamento farmacológico , Receptores sigma/antagonistas & inibidores , Analgesia/métodos , Analgésicos Opioides/farmacologia , Animais , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/imunologia , Dor/complicações , Dor/imunologia , Receptores sigma/imunologia , Receptor Sigma-1RESUMO
Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.
Assuntos
Compostos de Bifenilo/farmacologia , Esclerose Múltipla/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Receptores sigma/agonistas , Animais , Compostos de Bifenilo/química , Modelos Animais de Doenças , Imunomodulação , Modelos Moleculares , Conformação Molecular , Esclerose Múltipla/imunologia , Fármacos Neuroprotetores/química , Piperidinas/química , Ratos , Receptores sigma/imunologia , Receptores sigma/metabolismo , Receptor Sigma-1RESUMO
Sigma-1 receptor (S1R) is a unique pluripotent modulator of living systems and has been reported to be associated with a number of neurological diseases including pathological pain. Intrathecal administration of S1R antagonists attenuates the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution, suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs. Since primary afferents are the major component in the pain pathway, we examined the mouse and rat DRGs for the presence of the S1R. At both mRNA and protein levels, quantitative RT-PCR (qRT-PCR) and Western confirmed that the DRG contains greater S1R expression in comparison to spinal cord, cortex, or lung but less than liver. Using a custom-made highly specific antibody, we demonstrated the presence of a strong S1R immuno-fluorescence in all rat and mouse DRG neurons co-localizing with the Neuron-Specific Enolase (NSE) marker, but not in neural processes or GFAP-positive glial satellite cells. In addition, S1R was absent in afferent terminals in the skin and in the dorsal horn of the spinal cord. Using immuno-electron microscopy, we showed that S1R is detected in the nuclear envelope and endoplasmic reticulum (ER) of DRG cells. In contrast to other cells, S1R is also located directly at the plasma membrane of the DRG neurons. The presence of S1R in the nuclear envelope of all DRG neurons suggests an exciting potential role of S1R as a regulator of neuronal nuclear activities and/or gene expression, which may provide insight toward new molecular targets for modulating nociception at the level of primary afferent neurons.
Assuntos
Gânglios Espinais/metabolismo , Gânglios Espinais/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Receptores sigma/metabolismo , Animais , Anticorpos , Western Blotting , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Imuno-Histoquímica , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia Imunoeletrônica , Membrana Nuclear/metabolismo , Fosfopiruvato Hidratase/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores sigma/genética , Receptores sigma/imunologia , Receptor Sigma-1RESUMO
The high-affinity sigma receptor 1 (σR1) ligand (+)-pentazocine ((+)-PTZ) affords profound retinal neuroprotection in vitro and in vivo by a yet-unknown mechanism. A common feature of retinal disease is Müller cell reactive gliosis, which includes cytokine release. Here, we investigated whether lipopolysaccharide (LPS) stimulates cytokine release by primary mouse Müller cells and whether (+)-PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins (MIP1γ, MIP2, MIP3α) and interleukin-12 (IL12 (p40/p70)) in LPS-treated cells compared to controls, and a significant decrease in secretion upon (+)-PTZ treatment. Müller cells from σR1 knockout mice demonstrated increased MIP1γ, MIP2, MIP3α and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFκB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFκB nuclear location, which was reduced significantly in (+)-PTZ-treated cells. Media conditioned by LPS-stimulated-Müller cells induced leukocyte-endothelial cell adhesion and endothelial cell migration, which was attenuated by (+)-PTZ treatment. The findings suggest that release of certain inflammatory cytokines by Müller cells can be attenuated by σR1 ligands providing insights into the retinal neuroprotective role of this receptor.
Assuntos
Citocinas/metabolismo , Células Ependimogliais/metabolismo , Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Pentazocina/farmacologia , Receptores sigma/metabolismo , Animais , Movimento Celular , Ensaio de Imunoadsorção Enzimática , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/imunologia , Imuno-Histoquímica , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptores sigma/imunologia , Receptor Sigma-1RESUMO
Interleukin-24 (IL-24), a member of the IL-10 cytokine family, is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. We show that Sigma 1 Receptor (S1R), a ligand-regulated protein chaperone contributes to IL-24 induction of apoptosis. IL-24 generated from an adenovirus expressing IL-24 (Ad.IL-24) induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress, reactive oxygen species production, and calcium mobilization. The present studies reveals that S1R is required for Ad.IL-24-induced cell death. We provide several lines of evidence to confirm a physical and functional interaction between IL-24 and S1R including: (a) S1R and IL-24 co-localize, as judged by immunocytochemical analysis studies; (b) S1R and IL-24 co-immunoprecipitate using either S1R or IL-24 antibody; (c) S1R agonist (+)-SKF10047 inhibits apoptosis by Ad.IL-24; (d) (+)-SKF10047-mediated inhibition of Ad.IL-24 results in: diminished ER stress protein expression; (e) Calcium mobilization; and (f) ROS production. Collectively, these data demonstrate that S1R interacts with IL-24 and suggest that IL-24:S1R interaction determines apoptosis induction by Ad.IL-24. These studies define Sigma 1 Receptor as a key initial mediator of IL-24 induction of cancer-specific killing. These findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine.
Assuntos
Apoptose , Interleucinas/imunologia , Neoplasias/imunologia , Receptores sigma/imunologia , Sinalização do Cálcio , Caspase 3/imunologia , Linhagem Celular Tumoral/imunologia , Estresse do Retículo Endoplasmático , Humanos , Neoplasias/patologia , Espécies Reativas de Oxigênio/imunologia , Receptores sigma/agonistas , Receptor Sigma-1RESUMO
Human immunodeficiency virus (HIV)-associated increase in monocyte adhesion and trafficking is exacerbated by cocaine abuse. The underlying mechanisms involve cocaine-mediated upregulation of adhesion molecules with subsequent disruption of the blood-brain barrier (BBB). Recently, a novel activated leukocyte cell adhesion molecule (ALCAM) has been implicated in leukocyte transmigration across the endothelium. We now show that upregulation of ALCAM in the brain endothelium seen in HIV(+)/cocaine drug abusers paralleled increased CD68 immunostaining compared with HIV(+)/no cocaine or uninfected controls, suggesting the important role of ALCAM in promoting leukocyte infiltration across the BBB. Furthermore, ALCAM expression was increased in cocaine-treated mice with concomitant increase in monocyte adhesion and transmigration in vivo, which was ameliorated by pretreating with the neutralizing antibody to ALCAM, lending additional support to the role of ALCAM. This new concept was further confirmed by in vitro experiments. Cocaine-mediated induction of ALCAM in human brain microvascular endothelial cells through the translocation of σ receptor to the plasma membrane, followed by phosphorylation of PDGF-ß (platelet-derived growth factor-ß) receptor. Downstream activation of mitogen-activated protein kinases, Akt, and NF-κB (nuclear factor-κB) pathways resulted in induced expression of ALCAM. Functional implication of upregulated ALCAM was confirmed using cell adhesion and transmigration assays. Neutralizing antibody to ALCAM ameliorated this effect. Together, these findings implicate cocaine-mediated induction of ALCAM as a mediator of increased monocyte adhesion/transmigration into the CNS.
Assuntos
Molécula de Adesão de Leucócito Ativado/metabolismo , Encéfalo/metabolismo , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Cocaína/farmacologia , Monócitos/metabolismo , Receptores sigma/metabolismo , Molécula de Adesão de Leucócito Ativado/imunologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/virologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Imunoprecipitação da Cromatina , Cocaína/imunologia , Transtornos Relacionados ao Uso de Cocaína/imunologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/virologia , Citometria de Fluxo , Transferência Ressonante de Energia de Fluorescência , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/imunologia , NF-kappa B/metabolismo , Receptores sigma/imunologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Sigma receptors once considered as a class of opioid receptors are now regarded as unique orphan receptors, distinguished by the ability to bind various pharmacological agents such as the progesterone (steroid), haloperidol (anti-psychotic), and drugs of abuse such as cocaine and methamphetamine. The sigma-1 receptor is a 223 amino acid protein, proposed to have two transmembrane segments. We have developed a scheme for the purification of the guinea pig sigma-1 receptor following overexpression in Escherichia coli as a maltose binding protein (MBP) fusion and extraction with Triton X-100. Affinity chromatography using an amylose column and Ni2+ affinity column was used to purify the sigma-1 receptor. The sigma-1 receptor purified by this method is a 26 kDa polypeptide as assessed by SDS-PAGE, binds sigma ligands with high affinity and can be specifically photoaffinity labeled with the sigma-1 receptor photoprobe, [125I]-iodoazidococaine. Ligand binding using [3H]-(+)-pentazocine indicated that approximately half of the purified protein in Triton X-100 bound to radioligand. The MBP-sigma-1 receptor and the sigma-1 receptor in 0.5% triton were maximally stable for approximately two weeks at -20 degrees C in buffer containing 30% glycerol.
Assuntos
Receptores sigma/isolamento & purificação , Receptores sigma/metabolismo , Animais , Proteínas de Transporte/genética , Estabilidade de Medicamentos , Escherichia coli/metabolismo , Fator Xa/metabolismo , Cobaias , Ligantes , Proteínas Ligantes de Maltose , Pentazocina/metabolismo , Receptores sigma/imunologia , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Receptor Sigma-1RESUMO
Cocaine is associated with an increased risk for, and progression of, clinical disease associated with human immunodeficiency virus (HIV) infection. A human xenograft model, in which human peripheral blood mononuclear cells were implanted into severe combined immunodeficiency mice (huPBL-SCID) and infected with a HIV reporter virus, was used to investigate the biological interactions between cocaine and HIV infection. Systemic administration of cocaine (5 mg/kg/d) significantly increased the percentage of HIV-infected PBL (two- to threefold) and viral load (100- to 300-fold) in huPBL-SCID mice. Despite the capacity for cocaine to increase corticosterone and adrenocorticotropic hormone levels in control mice, the hypothalamic-pituitary-adrenal axis was suppressed in HIV-infected animals, and corticosterone levels were further decreased when animals were exposed to HIV and cocaine. Activating huPBL in vitro in the presence of 10(-8) M cocaine increased expression of CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptors. Expression of CCR5 was also increased at early time-points in the huPBL-SCID model following systemic exposure to cocaine (54.1+/-9.4% increase over control, P<0.01). This effect preceded the boost in viral infection and waned as HIV infection progressed. Cocaine has been shown to mediate immunosuppressive effects by activating sigma-1 receptors in immune cells in vitro and in vivo. Consistent with these reports, a selective sigma-1 antagonist, BD1047, blocked the effects of cocaine on HIV replication in the huPBL-SCID mouse. Our results suggest that systemic exposure to cocaine can enhance HIV infection in vivo by activating sigma-1 receptors and by modulating the expression of HIV coreceptors.
Assuntos
Cocaína/toxicidade , Infecções por HIV/imunologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores de Quimiocinas/efeitos dos fármacos , Receptores sigma/efeitos dos fármacos , Animais , Transtornos Relacionados ao Uso de Cocaína/complicações , Transtornos Relacionados ao Uso de Cocaína/imunologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Modelos Animais de Doenças , Etilenodiaminas/farmacologia , Feminino , HIV/imunologia , Infecções por HIV/fisiopatologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Tolerância Imunológica/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/transplante , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores CCR5/efeitos dos fármacos , Receptores CCR5/imunologia , Receptores CXCR4/efeitos dos fármacos , Receptores CXCR4/imunologia , Receptores de Quimiocinas/imunologia , Receptores sigma/imunologia , Transplante Heterólogo , Carga Viral , Receptor Sigma-1RESUMO
Sigma receptors are intracellular receptors that interact with a variety of psychotropic ligands, including cocaine. Administration of cocaine to mice promoted the in vivo growth of a syngeneic lung cancer cell line and identical effects were observed with PRE 084, a selective sigma(1) receptor agonist. Increased tumor growth was accompanied by an increase in IL-10 and a decrease in IFN-gamma production in splenocytes and at the tumor site. The tumor-promoting effects produced by both cocaine and PRE 084 were abrogated by administration of specific antibodies to IL-10, or by administration of a sigma(1) receptor antagonist. We conclude that sigma(1) receptor ligands, including cocaine, augment tumor growth via a cytokine-dependent, receptor-mediated mechanism that involves regulation of T helper 1/T helper 2 cytokine balance.
Assuntos
Anestésicos Locais/farmacologia , Cocaína/farmacologia , Citocinas/metabolismo , Neoplasias/metabolismo , Receptores sigma/imunologia , Adenocarcinoma Bronquioloalveolar , Animais , Anticorpos/farmacologia , Linhagem Celular Tumoral , Tamanho Celular/efeitos dos fármacos , Interações Medicamentosas , Etilenodiaminas/farmacologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , TransplantesRESUMO
High concentrations of novel, haloperidol- and DTG-inaccessible (+)-[3H]-3-PPP binding sites were found in human peripheral blood leukocytes rat spleen and splenocytes, but not in rat brain. Splenic sites were localized in a course punctate pattern in the marginal zones and red pulp. The pharmacology of the splenic sites was: (-)-SKF 10,047 > or = naltrexone = (-)-pentazocine > (+)-pentazocine = (-)-3-PPP = (+)-SKF 10,047 > or = (+)-3-PPP > or = dextrorphan > dextromethorphan > PCP > clorgyline. DTG, haloperidol, TCP, (-)-deprenyl and SKF 525-A did not complete. Binding activity was destroyed by heating and phospholipase C, but not by proteases or glycosidases. These sites may be involved in immunomodulation by opiate and sigma receptor agonists.
Assuntos
Leucócitos/química , Leucócitos/imunologia , Receptores sigma/metabolismo , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Autorradiografia , Sítios de Ligação/imunologia , Ligação Competitiva , Química Encefálica/imunologia , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Feminino , Guanidinas/metabolismo , Guanidinas/farmacologia , Haloperidol/metabolismo , Haloperidol/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Monoaminoxidase/metabolismo , Monoaminoxidase/farmacologia , Naltrexona/metabolismo , Naltrexona/farmacologia , Antagonistas de Entorpecentes/metabolismo , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/imunologia , Entorpecentes/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/imunologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores sigma/imunologia , Baço/química , Baço/citologia , Baço/imunologia , Trítio/metabolismoRESUMO
SR 31747 is a new sigma ligand which has immunosuppressive properties. The immunopharmacology of SR 31747 was investigated in vivo by studying its effects on the thymuses of C3H mice. The action of SR 31747 was compared with the reference drugs cyclosporin-A and dexamethasone on the basis of several parameters which were: the thymus weight; the number of thymocytes per organ; the percentages of mature CD4+ or CD8+ thymocytes and of immature CD4+ CD8+ thymocytes. SR 31747 slightly but significantly decreased the thymus weight at the dose of 50 mg/kg whereas the number of thymocytes per organ was significantly decreased from 6.25 mg/kg to the 50 mg/kg dose. It had rather no effect on the percentages of immature and mature subsets. These data led to the conclusion that the effects of SR 31747 on the thymuses of C3H mice were close to those obtained with cyclosporin-A and different from those obtained with dexamethasone.
Assuntos
Cicloexanos/farmacologia , Imunossupressores/farmacologia , Receptores sigma/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Cicloexanos/imunologia , Ciclosporina/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta Imunológica , Feminino , Ligantes , Contagem de Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Receptores sigma/imunologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Timo/metabolismoRESUMO
In previous work on sigma (sigma) receptors, we established a hybridoma cell line, 10G9, producing a monoclonal anti-idiotypic antibody (anti-Id mAb) to the monoclonal and anti-haloperidol antibody. The anti-Id mAb showed specific binding affinity to sigma receptors in immunoprecipitation and competition experiments. Here we isolated and sequenced cDNA clones for the variable regions of the anti-Id mAb. These combinations of segments and formation of the unique CDR3 were considered to be the structural basis for the diversity of the antigen-binding site of our anti-Id mAb and, therefore, for its binding activity to sigma receptors.
Assuntos
Anticorpos Anti-Idiotípicos/genética , Anticorpos Monoclonais/genética , DNA Complementar/isolamento & purificação , Região Variável de Imunoglobulina/genética , Receptores sigma/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Linhagem Celular , Clonagem Molecular , DNA Complementar/química , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/genética , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
Anti-idiotypic monoclonal antibodies that interact with the binding site of sigma receptors were generated. First, BALB/c mice were immunized with a haloperidol-bovine serum albumin conjugate, and monoclonal anti-haloperidol antibodies that recognize the piperidinyl moiety of haloperidol molecule were obtained. Second, for generation of anti-idiotypic antibodies, BALB/c mice were immunized with the anti-haloperidol monoclonal antibodies coupled to keyhole limpet hemocyanin. Anti-idiotypic antisera and three hybridomas secreting anti-idiotypic monoclonal antibodies were obtained. All of them were shown to inhibit [3H]haloperidol binding to the anti-haloperidol antibodies. The anti-idiotypes were potent in displacing the binding of [3H]haloperidol to rat brain sigma receptors. Furthermore, they significantly immunoprecipitated the sigma receptors from a detergent-solubilized preparation. These findings demonstrate the generation of anti-idiotypic monoclonal antibodies specifically interacting with membrane-bound and solubilized sigma receptors.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Monoclonais/imunologia , Haloperidol/imunologia , Idiótipos de Imunoglobulinas/imunologia , Receptores sigma/imunologia , Animais , Encéfalo/metabolismo , Bovinos , Haloperidol/metabolismo , Soros Imunes/imunologia , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Precipitina , Ratos , Ratos Wistar , Receptores de Dopamina D2/imunologia , Receptores de Dopamina D2/metabolismo , Receptores sigma/metabolismo , Espiperona/imunologia , Espiperona/metabolismoRESUMO
(+)-Pentazocine, phencyclidine, and other sigma ligands including 1,3-di-(o)-tolylguanidine (DTG), (+)-1-propyl-3-(3-hydroxyphenyl) piperidine [(+)-PPP] and haloperidol were investigated for their potential immunoregulatory properties. High concentrations (10(-5) M) of DTG and haloperidol were found to suppress in vitro murine splenocyte natural killer activity while equivalent concentrations of (+)-pentazocine, (-)-pentazocine and (+)-PPP were without effect. In a reciprocal fashion, lower doses (10(-9) M) of DTG enhanced natural killer activity. Sigma ligands were also found to affect in vitro polyclonal immunoglobulin production following mitogen stimulation. Specifically, high concentrations (10(-6) M) of haloperidol significantly (P < 0.001) suppressed pokeweed mitogen (PWM)-stimulated IgG and IgM production, yet enhanced lipopolysaccharide (LPS)-stimulated IgM production by murine splenocytes. Lower concentrations (10(-8) to 10(-10) M) enhanced (two- to fourfold) PWM-induced IgM production and LPS-stimulated IgG and IgM production. At high concentrations (10(-6)), (+)-pentazocine suppressed (P < 0.01) LPS-induced polyclonal IgG and IgM but enhanced (P < 0.01) PWM-induced IgM production. Both DTG and (-)-pentazocine (10(-8) to 10(-10) M) significantly augmented (two- to threefold) LPS-stimulated murine splenocyte production of polyclonal IgM. Intracellularly, (-)-pentazocine (10(-9) M), haloperidol (10(-7) M), DTG (10(-7) M) and (+)-PPP (10(-5) to 10(-9) M) enhanced forskolin (10(-6) M)-induced cAMP production in splenic lymphocytes while (+)-pentazocine was without effect. Collectively, the data suggest functional and biologically relevant sigma receptors on cells of the immune system.