RESUMO
While the excessive inflammation in cancer cachexia is well-known to be induced by the overproduction of inflammatory mediators in the periphery, microflora disruption and brain dysfunction are also considered to contribute to the induction of cancer cachexia. Hypothalamic microglia play a crucial role in brain inflammation and central-peripheral immune circuits via the production of inflammatory mediators. In the present study, we evaluated possible changes in excessive secretion of gut microbiota-derived endotoxin and the expression timeline of several inflammation-regulatory mediators and their inhibiting modulators in hypothalamic microglia of a mouse model of cancer cachexia following transplantation of pancreatic cancer cells. We demonstrated that the plasma level of lipopolysaccharide (LPS) was significantly increased with an increase in anaerobic bacteria, especially Firmicutes, in the gut at the late stage of tumor-bearing mice that exhibited dramatic appetite loss, sarcopenia and severe peripheral immune suppression. At the early stage, in which tumor-bearing mice had not yet displayed "cachexia symptoms", the mRNA expression of pro-inflammatory cytokines, but not of the neurodegenerative and severe inflammatory modulator lipocalin-2 (LCN2), was significantly increased, whereas at the late "cachexia stage", the level of LCN2 mRNA was significantly increased along with significant decreases in levels of inhibitory immune checkpoint receptors programmed death receptor-1 (PD-1) and CD112R in hypothalamic microglia. In addition, a high density of activated neurons in the paraventricular nucleus (PVN) of the hypothalamus region and a significant increase in corticosterone secretion were found in cachexia model mice. Related to the cachexia state, released corticosterone was clearly increased in normal mice with specific activation of PVN neurons. A marked decrease in the natural killer cell population was also observed in the spleen of mice with robust activation of PVN neurons as well as mice with cancer cachexia. On the other hand, in vivo administration of LPS in normal mice induced hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. These findings suggest that the induction of cancer cachexia may parallel exacerbation of the hypothalamic inflammatory status with polarization to microglia expressed with low levels of inhibitory immune checkpoint receptors following LPS release from the gut microflora.
Assuntos
Caquexia , Hipotálamo , Lipocalina-2 , Lipopolissacarídeos , Microglia , Animais , Caquexia/complicações , Caquexia/patologia , Microglia/metabolismo , Hipotálamo/metabolismo , Lipocalina-2/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Linhagem Celular Tumoral , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Microbioma Gastrointestinal , Citocinas/metabolismo , Neoplasias/complicações , Camundongos Endogâmicos C57BL , Mediadores da Inflamação/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Persistent pain signals cause brain dysfunction and can further prolong pain. In addition, the physical restriction of movement (e.g., by a cast) can cause stress and prolong pain. Recently, it has been recognized that exercise therapy including rehabilitation is effective for alleviating chronic pain. On the other hand, physical stress and the restriction of movement can prolong pain. In this review, we discuss the neural circuits involved in the control of pain prolongation and the mechanisms of exercise-induced hypoalgesia (EIH). We also discuss the importance of the mesolimbic dopaminergic network in these phenomena.
RESUMO
A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.
Assuntos
Linfócitos T CD8-Positivos , Núcleo Hipotalâmico Paraventricular , Núcleo Hipotalâmico Paraventricular/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Hipotálamo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Corticosterona , Neurônios/metabolismo , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: It has been considered that activation of peripheral µ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS: The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and ß-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS: Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in ß-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS: The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.
Assuntos
Neoplasias , Receptores Opioides mu , Analgésicos Opioides/efeitos adversos , Animais , Sistema Imunitário/metabolismo , Camundongos , Derivados da Morfina , Naltrexona/análogos & derivados , Neoplasias/induzido quimicamente , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Receptor 4 Toll-Like/metabolismo , beta-Arrestinas/metabolismoRESUMO
Neuropathic pain is refractory to opioid analgesics. Since there are functional linkages between µ-opioid receptors (MOR) and cannabinoid receptors (CBR), the present study was designed to investigate the interactions between MOR and CB1R based on antinociceptive effects for neuropathic pain mediated through G protein-coupled inwardly-rectifying potassium channels (GIRKs). The antinociceptive effects against pseudonociceptive response or neuropathic pain of MOR and CBR agonists were assessed in mice with or without partial sciatic nerve ligation. To investigate the functional interaction between MOR and CB1R, electrophysiological recording through GIRK was performed using the two-electrode voltage-clamp method in oocytes along with Western blotting in the spinal cord of mice. Co-administration of the MOR agonist DAMGO and the CB1R agonist CP55,940 augmented inwardly rectifying K+ currents in Xenopus oocytes co-expressing MOR, CB1R and GIRK1/2. Further, combination of morphine and the CBR agonist WIN-55,212-2 produced prominent antinociceptive effects in an i.t. GIRK1 inhibitor-reversible manner. Furthermore, CB1R was upregulated under neuropathic pain in the spinal cord, and such upregulation and antinociceptive effects were not altered by repeated treatment with morphine plus WIN-55,212-2. Our findings suggest that co-administration of MOR and CBR agonists could enhance their antinociceptive effects through GIRK1 in the spinal cord of mice.
Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Neuralgia , Receptores de Canabinoides , Receptores Opioides mu , Animais , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Camundongos , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Receptores de Canabinoides/metabolismo , Receptores Opioides mu/metabolismoRESUMO
Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.
Assuntos
Dopamina , Núcleo Accumbens , Animais , Linfócitos T CD8-Positivos , Camundongos , Camundongos Transgênicos , NeurôniosRESUMO
Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.
Assuntos
Neuralgia , Núcleo Accumbens , Animais , Dopamina , Neurônios Dopaminérgicos/metabolismo , Receptores de Dopamina D2/metabolismoRESUMO
Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.
Assuntos
Dopamina , Receptores de Dopamina D1 , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Ergolinas/farmacologia , Quimpirol/farmacologia , Ratos , Receptores de Dopamina D2/agonistasRESUMO
Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification.
Assuntos
Anexinas/biossíntese , Proteínas Ricas em Prolina do Estrato Córneo/biossíntese , Eletrocoagulação/efeitos adversos , Código das Histonas , Hiperalgesia/etiologia , Proteínas do Tecido Nervoso/biossíntese , Neuralgia/genética , Neurônios/fisiologia , Dor Pós-Operatória/genética , Medula Espinal/fisiopatologia , Animais , Anexinas/genética , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Proteínas Ricas em Prolina do Estrato Córneo/genética , Modelos Animais de Doenças , Feminino , Traumatismos do Pé/fisiopatologia , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Genes Reporter , Genes fos , Histonas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Lisina/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Neurônios/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/fisiopatologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologiaRESUMO
Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Metanfetamina/farmacologia , Metilfenidato/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Orexinas/deficiência , Recompensa , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismoRESUMO
Polydrug abuse is common among drug abusers. In particular, psychostimulants are often taken with ethanol, and the combination of 3,4-methylenedioxymethamphetamine (MDMA) and alcohol is one of the most common forms of polydrug abuse. However, the mechanism by which these drugs influence behavior remains unclear. The present study was designed to delineate the mechanisms that underlie the effects of the interaction between MDMA and ethanol on behavior in rodents. The combination of MDMA with ethanol enhanced their locomotor-increasing, rewarding, and discriminative stimulus effects without enhancing their effects on the release of dopamine from the nucleus accumbens in rodents. In addition, ethanol potently enhanced locomotor activity produced by the dopamine receptor agonist apomorphine in mice. In antagonism tests, the dopamine D1 -receptor antagonist SCH23390, but not the D2 -receptor antagonist haloperidol, completely suppressed hyperlocomotion induced by MDMA. However, hyperlocomotion induced by the co-administration of MDMA and ethanol was potently suppressed by haloperidol. These results suggest that the synergistic effects of MDMA and ethanol are mediated through dopamine transmission, especially through postsynaptical regulation of D2 -receptor-mediated functions.
Assuntos
Etanol/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Receptores de Dopamina D1RESUMO
In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.
Assuntos
Prurido/fisiopatologia , Prurido/psicologia , Recompensa , Área Tegmentar Ventral/fisiopatologia , Doença Aguda , Animais , Comportamento Animal/fisiologia , Doença Crônica , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica , Histamina/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleo Accumbens/fisiopatologia , Testes Farmacogenômicos , Cloreto de Picrila/administração & dosagem , Prurido/genética , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
TRV130 (oliceridine), a G protein-biased ligand for µ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 µM) did not produce any µ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3-10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased µ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses.
Assuntos
Analgésicos/uso terapêutico , Proteínas de Ligação ao GTP/metabolismo , Neuralgia/tratamento farmacológico , Receptores Opioides mu/metabolismo , Compostos de Espiro/uso terapêutico , Tiofenos/uso terapêutico , Analgésicos/farmacologia , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/metabolismo , Receptores Opioides mu/agonistas , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Fatores de TempoRESUMO
Methylmercury (MeHg) is known to cause neurobehavioral impairment in human and experimental animals. We previously reported that MeHg (5 mg Hg/kg) induced severe neurobehavioral dysfunction in 4-week-old KK-Ay mice, although it is difficult to evaluate quantitatively the neurobehavioral impairment in MeHg-treated KK-Ay mice because of their obesity. The aim of this study was to evaluate MeHg-induced neurobehavioral dysfunction in KK-Ay mice using the dynamic weight-bearing test, which analyzes the animal's weight distribution between the four limbs. Male 12-week-old KK-Ay mice were treated with MeHg (5 mg Hg/kg) three times per week for 5 weeks. Body weight loss began after approximately 2 weeks of MeHg treatment, and decreased significantly at 4 weeks. Seven of the nine MeHg-treated mice exhibited overt neurological symptoms such as ataxia and gait disturbance. The weight-bearing load was lower for the forelimb than for the hindlimb at baseline and until 1 week after MeHg treatment was initiated. In weeks 2-4, the dynamic weight-bearing loads on the forelimb and hindlimb were similar. The load on the forelimb exceeded the load on the hindlimb after 5 weeks of treatment. This finding indicates that the dynamic weight-bearing test is useful for semi-quantitative evaluation of neurobehavioral impairment in MeHg-treated rodents, and is less stressful for the animals. Infiltration of CD204-positive macrophages was observed in the sciatic nerve of MeHg-treated mice, suggesting that CD204 can serve as a useful marker of tissue injury in peripheral nerves and a possible target in regenerating peripheral nerves and controlling neuropathies.
Assuntos
Comportamento Animal/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Mercúrio/fisiopatologia , Compostos de Metilmercúrio/toxicidade , Atividade Motora/efeitos dos fármacos , Suporte de Carga/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/sangue , Intoxicação do Sistema Nervoso por Mercúrio/urina , Compostos de Metilmercúrio/sangue , Compostos de Metilmercúrio/urina , Camundongos , Camundongos Endogâmicos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismoRESUMO
Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/efeitos adversos , Metanfetamina/toxicidade , Comportamento Autodestrutivo/induzido quimicamente , Animais , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Radicais Livres/efeitos adversos , Radicais Livres/toxicidade , Humanos , Dose Letal Mediana , Metanfetamina/administração & dosagem , Morfina/administração & dosagem , Morfina/efeitos adversos , Morfina/toxicidade , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Comportamento Autodestrutivo/etiologia , Transtornos Relacionados ao Uso de SubstânciasRESUMO
The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers have been trying to elucidate the mechanisms that underlie the discriminative stimulus properties of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), ketamine, and cannabinoid, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. In particular, the abuse of designer drugs, which aim to mimic the subjective effects of psychostimulants (e.g., MDMA or amphetamines), has been problematic. However, the mechanisms of the discriminative stimulus effects of hallucinogenic and dissociative anesthetic drugs are not yet fully clear. This chapter focuses on recent findings regarding hallucinogenic and dissociative anesthetic drug-induced discriminative stimulus properties in animals.
Assuntos
Anestésicos Dissociativos/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Alucinógenos/farmacologia , Animais , HumanosRESUMO
Background: µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioidopioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without ß-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. Results: In the present study, we confirmed that fentanyl produced a profound increase in ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of ß-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions: These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the ß-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and ß-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.
Assuntos
Tolerância a Medicamentos/fisiologia , Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides mu/metabolismo , beta-Arrestinas/metabolismo , Analgésicos Opioides/farmacologia , Animais , Fentanila/farmacologia , Ligantes , Masculino , Camundongos , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Receptores Opioides/metabolismo , Receptores Opioides mu/efeitos dos fármacosRESUMO
BACKGROUND: Methadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated ß-arrestin recruitment. RESULTS: We found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of ß-arrestin-2 in µ-opioid receptor-overexpressing cells. CONCLUSIONS: These results suggest that methadone may, at least partly, produce its pharmacological effect as a ß-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone.
Assuntos
Metadona/farmacologia , Receptores Opioides mu/agonistas , beta-Arrestinas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Maleato de Dizocilpina/farmacologia , Endocitose/efeitos dos fármacos , Fentanila/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Nociceptividade/efeitos dos fármacos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
RATIONALE: Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds. OBJECTIVES: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice. RESULTS: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT. CONCLUSION: These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Narcolepsia/tratamento farmacológico , Narcolepsia/metabolismo , Orexinas/deficiência , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microdiálise/métodos , Polissonografia/métodos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.