RESUMEN
The molecular processes that underlie long-term memory formation involve signaling pathway activation by neurotransmitter release, which induces the expression of immediate early genes, such as Zif268, having a key role in memory formation. In this work, we show that the cannabinoid CB1 receptor signaling is necessary for the effects of dexamethasone on the behavioral response in an inhibitory avoidance task, on dexamethasone-induced ERK phosphorylation, and on dexamethasone-dependent Zif268 expression. Furthermore, we provide primary evidence for the mechanism responsible for this crosstalk between cannabinoid and glucocorticoid-mediated signaling pathways, showing that dexamethasone regulates endocannabinoid metabolism by inhibiting the activity of the Fatty acid amide hydrolase (FAAH), an integral membrane enzyme that hydrolyzes endocannabinoids and related amidated signaling lipids. Our results provide novel evidence regarding the role of the endocannabinoid system, and in particular of the CB1 receptor, as a mediator of the effects of glucocorticoids on the consolidation of aversive memories.
Asunto(s)
Cannabinoides , Consolidación de la Memoria , Endocannabinoides/metabolismo , Receptor Cannabinoide CB1/genética , Cannabinoides/farmacología , Transducción de Señal , Glucocorticoides/farmacología , Dexametasona/farmacología , Amidohidrolasas , Moduladores de Receptores de Cannabinoides/farmacologíaRESUMEN
We made an observational cross-sectional study to evaluate the prevalence of cannabis use, characteristics and results perceived by a group of PD patients. Semi-structured questionnaire was applied to patients. Until obtaining more information we suggest to incorporate into regular medical practice the question about the use of cannabis.
Asunto(s)
Moduladores de Receptores de Cannabinoides/farmacología , Conocimientos, Actitudes y Práctica en Salud , Marihuana Medicinal/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Argentina , Moduladores de Receptores de Cannabinoides/administración & dosificación , Moduladores de Receptores de Cannabinoides/efectos adversos , Estudios Transversales , Femenino , Humanos , Masculino , Marihuana Medicinal/administración & dosificación , Marihuana Medicinal/efectos adversos , Persona de Mediana Edad , Evaluación de Resultado en la Atención de SaludRESUMEN
INTRODUCTION: Patients with multiple sclerosis (MS) may suffer from spasticity and pain during their disease course. Baclofen, dantrolene, diazepam and gabapentin have been used as first-line options to treat these conditions, with modest results. Medical use of marijuana smoking has bypassed traditional clinical trials and has been legalized as a therapeutic option for MS-related spasticity and pain in some countries. Cannabis-derived drugs have been tested and approved for medical use. AREAS COVERED: With the development of nabiximols by the pharmaceutical industry, more countries have made it possible for patients with MS to have legal access to cannabis-related therapies. The evidence-based data on nabiximols and MS-related spasticity, pain, and urinary symptoms is consistent. There are over 7,500 patients reported in 33 studies (12 from the United Kingdom and 11 from Italy). EXPERT OPINION: Nabiximols is safe and effective for patients with MS whose spasticity could not be treated with the first-line oral drugs. At present, legislation, bureaucracy and costs involved in prescribing this drug limit the experience of neurologists from many countries. There is no scientific evidence that smoking marijuana can be beneficial to patients with MS.
Asunto(s)
Cannabidiol/uso terapéutico , Moduladores de Receptores de Cannabinoides/uso terapéutico , Dronabinol/uso terapéutico , Marihuana Medicinal/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Espasticidad Muscular/tratamiento farmacológico , Dolor/tratamiento farmacológico , Enfermedades Urológicas/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Esclerosis Múltiple/complicaciones , Espasticidad Muscular/etiología , Dolor/etiología , Enfermedades Urológicas/etiologíaRESUMEN
Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a ß-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antidepresivos/uso terapéutico , Moduladores de Receptores de Cannabinoides/uso terapéutico , Depresión/tratamiento farmacológico , Dopaminérgicos/uso terapéutico , Monoterpenos/uso terapéutico , Animales , Sitios de Unión , Depresión/etiología , Suspensión Trasera/efectos adversos , Lipopolisacáridos/toxicidad , Masculino , Ratones , Simulación del Acoplamiento Molecular , Unión Proteica , Receptores de Cannabinoides/química , Receptores de Cannabinoides/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismoRESUMEN
RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/administración & dosificación , Inhibición Prepulso/fisiología , Receptor de Serotonina 5-HT2A/fisiología , Receptores de Cannabinoides/fisiología , Esquizofrenia/tratamiento farmacológico , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Benzoxazinas/administración & dosificación , Moduladores de Receptores de Cannabinoides/administración & dosificación , Cannabinoides/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Fluorobencenos/administración & dosificación , Masculino , Ratones , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/administración & dosificación , Inhibición Prepulso/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Resultado del TratamientoRESUMEN
The endocannabinoid system participates in the regulation of CNS homeostasis and functions, including neurotransmission, cell signaling, inflammation and oxidative stress, as well as neuronal and glial cell proliferation, differentiation, migration and survival. Endocannabinoids are produced by multiple cell types within the CNS and their main receptors, CB1 and CB2, are expressed in both neurons and glia. Signaling through these receptors is implicated in the modulation of neuronal and glial alterations in neuroinflammatory, neurodegenerative and psychiatric conditions, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, epilepsy, anxiety and depression. The therapeutic potential of endocannabinoid receptors in neurological disease has been hindered by unwelcome side effects of current drugs used to target them; however, due to their extensive expression within the CNS and their involvement in physiological and pathological process in nervous tissue, they are attractive targets for drug development. The present review highlights the potential applications of the endocannabinoid system for the prevention and treatment of neurologic and psychiatric disorders.
Asunto(s)
Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/prevención & control , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/prevención & control , Receptores de Cannabinoides/efectos de los fármacos , Receptores de Cannabinoides/fisiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Moduladores de Receptores de Cannabinoides/fisiología , Endocannabinoides , Humanos , Inflamación/metabolismo , Trastornos Mentales/fisiopatología , Enfermedades del Sistema Nervioso/fisiopatología , Plasticidad Neuronal/fisiología , Neuronas/metabolismoRESUMEN
Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Moduladores de Receptores de Cannabinoides/uso terapéutico , Receptores de Cannabinoides/fisiología , Animales , Antiinflamatorios , Artritis Reumatoide , Diabetes Mellitus Tipo 1 , Humanos , Ligandos , Esclerosis MúltipleRESUMEN
Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.
Asunto(s)
Síntomas Afectivos/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Endocannabinoides/metabolismo , Esquizofrenia/metabolismo , Síntomas Afectivos/inducido químicamente , Animales , Ácidos Araquidónicos/agonistas , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Ácidos Araquidónicos/uso terapéutico , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Disfunción Cognitiva/inducido químicamente , Endocannabinoides/agonistas , Endocannabinoides/antagonistas & inhibidores , Masculino , Alcamidas Poliinsaturadas/agonistas , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Esquizofrenia/inducido químicamente , Esquizofrenia/prevención & controlRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options. Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD. In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD. We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia). We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD. We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.
Asunto(s)
Cannabidiol/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective. ß-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy. Male Swiss mice receiving PTX (2 mg kg-1, ip, four alternate days) were treated with BCP (25 mg kg-1, po, twice a day) either during or after PTX administration. Some groups were also pretreated with AM630 (CB2 antagonist, 3 mg kg-1, ip) or AM251 (CB1 antagonist, 1 mg kg-1, ip). Spinal cord samples were collected in different time points to perform immunohistochemical analysis. BCP attenuated the established mechanical allodynia induced by PTX (p < 0.0001) in a CB2-dependent manner. Of note, when given concomitantly with PTX, BCP was able to attenuate the development of PINP (p < 0.0001). Spinal cord immunohistochemistry revealed that preventive treatment with BCP reduced p38 MAPK and NF-κB activation, as well as the increased Iba-1 and IL-1ß immunoreactivity promoted by PTX. Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Sesquiterpenos/farmacología , Administración Oral , Animales , Antineoplásicos Fitogénicos/toxicidad , Moduladores de Receptores de Cannabinoides/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/inducido químicamente , Hiperalgesia/inmunología , Hiperalgesia/patología , Indoles/farmacología , Masculino , Neuralgia/inducido químicamente , Neuralgia/inmunología , Neuralgia/patología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/patología , Piperidinas/farmacología , Sesquiterpenos Policíclicos , Pirazoles/farmacología , Distribución Aleatoria , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
Because activation of D2 receptors reverses the neurochemical effects of cannabinoids, we examined whether increasing dopaminergic tone in the globus pallidus (GPe) switches cannabinoid induced depression of synaptic transmission. GABAergic synaptic currents evoked in pallidal neurons by stimulation of striatal projections (IPSCs) were depressed by perfusion with the CB1R agonist ACEA. Coactivation of D2Rs with quinpirole converted the depression into stimulation. Pretreatment with pertussis toxin (PTX) to limit Gi/o protein coupling also switched the CB1R-induced depression of IPSCs. The stimulation of IPSCs was blocked by the selective PKA blocker H89. Changes in the paired pulse ratio during both inhibitory and stimulatory responses indicate that the effects are due to changes in transmitter release. Postsynaptic depolarization induces endocannabinoid release that inhibits transmitter release (DSI). When D2Rs were activated with quinpirole, depolarization increased transmission instead of depressing it. This increase was blocked by AM251. We also examined the effects of CB1R/D2R coactivation on cAMP accumulation in the GPe to further verify that the AC/PKA cascade is involved. CB1R/D2R coactivation converted the inhibition of cAMP seen when each receptor is stimulated alone into a stimulation. We also determined the effects on turning behavior of unilateral injection of ACEA into the GPe of awake animals and its modification by dopamine antagonists. Blockade of D2 family receptors with sulpiride antagonized the motor effects of ACEA. We show, for the first time, that cannabinoid-inhibition of synaptic transmission in the GPe becomes a stimulation after D2Rs or PTX treatment and that the switch is probably relevant for the control of motor behavior.
Asunto(s)
Dopamina/metabolismo , Endocannabinoides/metabolismo , Globo Pálido/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Moduladores de Receptores de Cannabinoides/farmacología , AMP Cíclico/metabolismo , Globo Pálido/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de Dopamina D2/metabolismo , Transmisión Sináptica/efectos de los fármacos , Técnicas de Cultivo de TejidosRESUMEN
The endocannabinoid system (SEC) is an important modulator of several metabolic functions. This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome. Liver steatosis of different origins constitutes a physiopathological condition where an altered hepatic SEC is observed. In this condition, there is an increased expression of RCB1 and/or higher endocannabinoid levels in different hepatic cells, which may exert an autocrine/paracrine hyperstimulation of RCB1/RCB2. Activation of RCB1 stimulate the expression of several hepatocyte lipogenic factors, thus leading to increased de novo fatty acids synthesis and consequently to an abnormal accumulation of triglycerides. The effect of RCB2 activity on hepatic function is still controversial because, on one side its stimulation has an interesting protective effect on alcoholic liver disease while, on the other, it may enhance the development of hepatic steatosis in experimental models of diet-induced obesity. In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.
Asunto(s)
Moduladores de Receptores de Cannabinoides/fisiología , Endocannabinoides/fisiología , Hígado Graso/etiología , Receptor Cannabinoide CB1/fisiología , Hígado Graso/fisiopatología , Humanos , Receptor Cannabinoide CB2/fisiologíaRESUMEN
The endocannabinoid system plays an important role in thermal control and modulates several behaviors, such as locomotion and food intake (FI) that may affect the body temperature (Tb). To test whether the changes in Tb induced by anandamide (AEA) are related to behavioral changes, adult Wistar rats received an intracerebroventricular injection of AEA (0.1, 1.0 and 10.0 µg) and vehicle. Total FI was weighted daily, and Tb and spontaneous locomotor activity (SLA) were simultaneously and continuously recorded. AEA induced an increase in Tb without changing SLA and FI. For all doses tested, the Tb average in the post-injection period was higher than in the pre-injection period. The higher thermal effect was verified using a dose of 10.0 µg AEA, starting within the first hour post-injection, and was maintained for 8h after treatment. A dose-dependent thermal effect was observed (r=0.953; p<0.05) at 1h post-injection. Hypoactivity was verified only at a dose of 1.0 µg AEA. As expected, both the Tb and SLA values during the dark phase were always higher than during the light phase and were positively correlated (r=0.834, p<0.001); however, this correlation was inverted (r=-0.852, p<0.01) after the rats received 10.0 µg AEA. In summary, our results suggest that brain AEA induces an increase in Tb, and that this effect may occur independently of changes in both locomotion and FI. Moreover, it is possible that the hypolocomotion induced by AEA could be an adaptive response to the increased Tb.
Asunto(s)
Ácidos Araquidónicos/farmacología , Temperatura Corporal/efectos de los fármacos , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides/farmacología , Actividad Motora/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Animales , Ritmo Circadiano/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratas Wistar , Factores de TiempoRESUMEN
The endocannabinoid system (SEC) is an important modulator of several metabolic functions. This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome. Liver steatosis of different origins constitutes a physiopathological condition where an altered hepatic SEC is observed. In this condition, there is an increased expression of RCB1 and/or higher endocannabinoid levels in different hepatic cells, which may exert an autocrine/paracrine hyperstimulation of RCB1/RCB2. Activation of RCB1 stimulate the expression of several hepatocyte lipogenic factors, thus leading to increased de novo fatty acids synthesis and consequently to an abnormal accumulation of triglycerides. The effect of RCB2 activity on hepatic function is still controversial because, on one side its stimulation has an interesting protective effect on alcoholic liver disease while, on the other, it may enhance the development of hepatic steatosis in experimental models of diet-induced obesity. In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.
Asunto(s)
Humanos , Moduladores de Receptores de Cannabinoides/fisiología , Endocannabinoides/fisiología , Hígado Graso/etiología , Receptor Cannabinoide CB1/fisiología , Hígado Graso/fisiopatología , /fisiologíaRESUMEN
Studies have suggested that the endocannabinoid system is implicated in the pathophysiology of schizophrenia. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs display hyperlocomotion - reverted by atypical and typical antipsychotics. These results suggest that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia and the effects of potential drugs with an antipsychotic profile. The aim of this study was to investigate the effects of WIN55-212,2 (CB1/CB2 agonist), ACEA (CB1 agonist), rimonabant (CB1 inverse agonist), AM404 (anandamide uptake/metabolism inhibitor), capsaicin (agonist TRPV1) and capsazepine (antagonist TRPV1) on the social interaction and locomotion of control animals (Wistar rats) and SHRs. The treatment with rimonabant was not able to alter either the social interaction or the locomotion presented by Wistar rats (WR) and SHR at any dose tested. The treatment with WIN55-212,2 decreased locomotion (1mg/kg) and social interaction (0.1 and 0.3mg/kg) of WR, while the dose of 1mg/kg increased social interaction of SHR. The treatment with ACEA increased (0.3mg/kg) and decreased (1mg/kg) locomotion of both strain. The administration of AM404 increased social interaction and decreased locomotion of SHR (5mg/kg), and decreased social interaction and increased locomotion in WR (1mg/kg). The treatment with capsaicin (2.5mg/kg) increased social interaction of both strain and decreased locomotion of SHR (2.5mg/kg) and WR (0.5mg/kg and 2.5mg/kg). In addition, capsazepine (5mg/kg) decreased locomotion of both strains and increased (5mg/kg) and decreased (10mg/kg) social interaction of WR. Our results indicate that the schizophrenia-like behaviors displayed by SHR are differently altered by cannabinoid and vanilloid drugs when compared to control animals and suggest the endocannabinoid and the vanilloid systems as a potential target for the treatment of schizophrenia.
Asunto(s)
Moduladores de Receptores de Cannabinoides/uso terapéutico , Relaciones Interpersonales , Actividad Motora/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Canales Catiónicos TRPV/metabolismo , Análisis de Varianza , Animales , Ácidos Araquidónicos/administración & dosificación , Benzoxazinas/administración & dosificación , Capsaicina/análogos & derivados , Capsaicina/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Rimonabant , Esquizofrenia/fisiopatología , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
It is well known that physical exercise has positive effects on cognitive functions and hippocampal plasticity. However, the underlying mechanisms have remained to be further investigated. Here we investigated the hypothesis that the memory-enhancement promoted by physical exercise relies on facilitation of the endocannabinoid system. We observed that the spatial memory tested in the object location paradigm did not persist in sedentary mice, but could be improved by 1 week of treadmill running. In addition, exercise up-regulated CB1 receptor and BDNF expression in the hippocampus. To verify if these changes required CB1 activation, we treated the mice with the selective antagonist, AM251, before each period of physical activity. In line with our hypothesis, this drug prevented the exercise-induced memory enhancement and BDNF expression. Furthermore, AM251 reduced CB1 expression. To test if facilitating the endocannabinoid system signaling would mimic the alterations observed after exercise, we treated sedentary animals during 1 week with the anandamide-hydrolysis inhibitor, URB597. Mice treated with this drug recognized the object in a new location and have increased levels of CB1 and BDNF expression in the hippocampus, showing that potentiating the endocanabinoid system equally benefits memory. In conclusion, the favorable effects of exercise upon spatial memory and BDNF expression depend on facilitation of CB1 receptor signaling, which can be mimic by inhibition of anandamide hydrolysis in sedentary animals. Our results suggest that, at least in part, the promnesic effect of the exercise is dependent of CB1 receptor activation and is mediated by BDNF.
Asunto(s)
Hipocampo/metabolismo , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Condicionamiento Físico Animal/fisiología , Receptor Cannabinoide CB1/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides/metabolismo , Masculino , RatonesRESUMEN
Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal-maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2 ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E(2) (P<0.001) and prostaglandin F(2α) (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10 mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4 mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies.
Asunto(s)
Ácidos Araquidónicos/farmacología , Dinoprost/metabolismo , Dinoprostona/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Alcamidas Poliinsaturadas/farmacología , Animales , Canfanos/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Endocannabinoides , Femenino , Óxido Nítrico Sintasa/metabolismo , Seudoembarazo , Pirazoles/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB2/efectos de los fármacos , Receptor Cannabinoide CB2/metabolismo , Útero/efectos de los fármacos , Útero/metabolismoRESUMEN
CB1, TRPV1 and NO can regulate glutamate release and modify defensive behaviors in regions related to defensive behavior such as the dorsolateral periaqueductal gray (dlPAG). A possible interaction between the endocannabinoid and nitrergic systems in this area, however, has not been investigated yet. The objective of the present work was to verify if activation of CB1 or TRPV1 receptors could interfere in the flight responses induced in rats by the injection of SIN-1, an NO donor, into the dlPAG. The results showed that local administration of a low dose (5 pmol) of anandamide (AEA) attenuated the flight responses, measured by the total distance moved and maximum speed in an open arena, induced by intra-dlPAG microinjection of SIN-1 (150 nmol). URB597 (0.1 nmol), an inhibitor of anandamide metabolism, produced similar effects. When animals were locally treated with the CB1 receptor antagonist AM251 the effective AEA dose (5 pmol) increased, rather than decreased, the flight reactions induced by SIN1-1. Higher (50-200 nmol) doses of AEA were ineffective and even tended to potentiate the SIN-1 effect. The TRPV1 antagonist capsazepine (CPZ, 30 nmol) prevented SIN-1 effects and attenuated the potentiation of its effect by the higher (200 nmol) AEA dose. The results indicate that AEA can modulate in a dual way the pro-aversive effects of NO in the dlPAG by activating CB1 or TRPV1 receptors.
Asunto(s)
Ácidos Araquidónicos/farmacología , Conducta Animal/fisiología , Reacción de Fuga/fisiología , Óxido Nítrico/metabolismo , Sustancia Gris Periacueductal/metabolismo , Alcamidas Poliinsaturadas/farmacología , Receptor Cannabinoide CB1/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides , Reacción de Fuga/efectos de los fármacos , Masculino , Donantes de Óxido Nítrico/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidoresRESUMEN
The most commonly used drugs against pain act by inhibiting the cyclooxygenases (COXs). Metamizol (dipyrone) inhibits the COXs and is widely used in Europe and Latin America as a non-opioid analgesic. One target of metamizol and other non-opioid analgesics is the periaqueductal grey matter (PAG), where they trigger descending inhibition of spinal nociceptive transmission. Also, cannabinoids exert an analgesic action at several structures in the peripheral and central nervous system, including the PAG. The present study investigates whether the antinociceptive action of metamizol in the lateral-ventrolateral (LVL) PAG during inflammation is related to endocannabinoids. In anaesthetized rats, unitary action potentials were recorded from spinal nociceptive neurons with receptive fields in the ipsilateral hind paw. Inflammation of the paw induced neuronal hyperexcitability, which was attenuated by intra-LVL-PAG microinjection of metamizol either at the beginning of inflammation or when hyperexcitability was fully established. In both cases, the antinociceptive effect of metamizol was reduced by a microinjection of AM251, an antagonist at the CB1 cannabinoid receptor, either into the LVL-PAG or into the rostral ventromedial medulla (RVM). The RVM is a downstream structure that funnels PAG-derived descending inhibition into the spinal cord. These results show that endocannabinoids and their CB1 receptor (1) contribute at the LVL-PAG to the antinociceptive effects of metamizol, and possibly other non-opioid analgesics; and (2) participate in the PAG-derived activation of RVM descending antinociceptive influences.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Moduladores de Receptores de Cannabinoides/metabolismo , Dipirona/uso terapéutico , Endocannabinoides , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Bulbo Raquídeo/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacología , Dipirona/farmacología , Hiperalgesia/metabolismo , Inflamación/metabolismo , Masculino , Bulbo Raquídeo/metabolismo , Microinyecciones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nociceptores/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidoresRESUMEN
Neural reflex mechanisms, such as the baroreflex, are involved in the regulation of cardiovascular system activity. Previous results from our group (Resstel LB, Correa FM. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Eur J Neurosci 23: 481-488, 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB(1) receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB(1) receptors modulate baroreflex activity. We found that bilateral microinjection of the CB(1) receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB(1) receptors, which modulate local glutamate release.