RESUMEN
Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin (BE) concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol and plasma anandamide) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for BE and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, body mass index at time of delivery, and race revealed significant multiplicative interactions between EC and BE concentrations on number of opioid tablets used (based on pill count), days of opioid use, and total milligram morphine equivalents used in the 2-week follow-up period. Elevated preoperative plasma and CSF 2-arachidonoylglycerol predicted reduced outpatient opioid analgesic use, particularly for patients low in CSF BE. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (P < .02) characterized by higher preoperative BE concentrations being associated with lower subsequent pain only for individuals with low preoperative plasma anandamide concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide the development of precision pain management approaches. PERSPECTIVE: In the postoperative setting of patients undergoing cesarean delivery, elevated ECs were linked to reduced outpatient opioid analgesic use in individuals who had low endogenous opioid concentrations in CSF. Further exploration of interactions between these 2 inhibitory systems as they impact responses to pain management interventions appears warranted.
Asunto(s)
Analgésicos Opioides , Ácidos Araquidónicos , Cesárea , Endocannabinoides , Glicéridos , Dolor Postoperatorio , Alcamidas Poliinsaturadas , Humanos , Femenino , Endocannabinoides/sangre , Endocannabinoides/líquido cefalorraquídeo , Embarazo , Adulto , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/líquido cefalorraquídeo , Dolor Postoperatorio/sangre , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/líquido cefalorraquídeo , Analgésicos Opioides/farmacología , Glicéridos/sangre , Glicéridos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/líquido cefalorraquídeo , betaendorfina/sangre , betaendorfina/líquido cefalorraquídeo , Estudios Prospectivos , Adulto JovenRESUMEN
This work describes the development and validation of an ultra-high performance liquid chromatography tandem mass spectrometry method that uses disposable pipette extraction (DPX-UHPLC-MS/MS) to determine the endocannabinoid anandamide (AEA) in cerebrospinal fluid samples (CSF). The DPX parameters sorption equilibrium time, sample volume, number of draw-eject cycles, washing solvent volume, and elution solvent volume were optimized by design of experiments (DOE) techniques. The simple DPX protocol proposed herein required a reduced amount of CSF sample and organic solvent. The DPX-UHPLC-MS/MS method presented linear range from 0.10â¯ngâ¯mL-1 (LLOQ) to 3.0â¯ngâ¯mL-1, inter- and intra-assay accuracy with EPR values varying from -8.2% to 9.6%, inter- and intra-assay precision with CV values ranging from 1.3% to 14.8% (except for the LLOQ), and no significant matrix effect. The innovative DPX-UHPLC-MS/MS method was successfully applied to determine AEA in CSF samples from Parkinson's disease (PD) patients and should therefore be used in clinical studies.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión/métodos , Endocannabinoides/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Espectrometría de Masas en Tándem/métodos , Ácidos Araquidónicos/aislamiento & purificación , Endocannabinoides/aislamiento & purificación , Humanos , Modelos Lineales , Alcamidas Poliinsaturadas/aislamiento & purificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Despite the lack of clinical data about the role of the endocannabinoid system (ECS) in affective disorders, preclinical work suggests that the ECS is relevant in both with regard to the etiology of depression as well as the mediation of antidepressant effects. We measured the intraindividual levels of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the cerebrospinal fluid of 12 patients suffering from a major depressive episode before and after the antidepressant treatment by electroconvulsive therapy (ECT). AEA was significantly elevated after ECT as compared to baseline. The AEA increase positively correlated with the number of individually performed ECT sessions. Although the sample size was small and confounders were not rigorously controlled for, our finding corroborates preclinical work and should encourage further exploration of the involvement of the ECS in depressive disorder.
Asunto(s)
Trastorno Depresivo Mayor/líquido cefalorraquídeo , Trastorno Depresivo Mayor/terapia , Terapia Electroconvulsiva/métodos , Endocannabinoides/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Araquidónicos/líquido cefalorraquídeo , Femenino , Glicéridos/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana Edad , Alcamidas Poliinsaturadas , Estudios Prospectivos , Adulto JovenRESUMEN
Endocannabinoids, a class of lipid messengers, have emerged as crucial regulators of synaptic communication in the CNS. Dysregulation of these compounds has been implicated in many brain disorders. Although some studies have identified and quantified a limited number of target compounds, a method that provides comprehensive quantitative information on endocannabinoids and related N-acylethanolamines (NAEs) in cerebrospinal fluid (CSF) is currently lacking, as measurements are challenging due to low concentrations under normal physiological conditions. Here we developed and validated a high-throughput nano LC-ESI-MS/MS platform for the simultaneous quantification of endocannabinoids (anandamide and 2-arachidonoylglycerol), ten related NAEs, and eight additional putatively annotated NAEs in human CSF. Requiring only 200 µl of CSF, our method has limits of detection from 0.28 to 61.2 pM with precisions of relative SD <15% for most compounds. We applied our method to CSF from 45 healthy humans and demonstrated potential age and gender effects on concentrations of endocannabinoids and NAEs. Notably, our results show that docosahexaenoylethanolamide concentrations increase with age in males. Our method may offer new opportunities to gain insight into regulatory functions of endocannabinoids in the context of (ab)normal brain function.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Endocannabinoides/líquido cefalorraquídeo , Etanolaminas/líquido cefalorraquídeo , Glicéridos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Adulto , Factores de Edad , Cromatografía Liquida/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVES: Binocular depth inversion illusion (BDII) represents an illusion of visual perception that involves higher-order visual and cognitive processes. Its impairment has been linked to psychotic conditions and identified as a marker for at-risk mental states. The endogenous cannabinoid system (ECS) is involved in various neurophysiological processes. One of its key components, anandamide, is involved in the pathophysiology of schizophrenia. Little is known about its impact on BDII alterations. Therefore, we explored associations between BDII and anandamide levels. METHODS: BDII was conducted and blood and CSF were taken in 28 first-episode antipsychotic-naïve schizophrenia (SZ) patients and 81 healthy controls (HC). Serum and CSF anandamide levels were determined by high-performance liquid chromatography/mass spectrometry. RESULTS: BDII scores were significantly elevated in SZ versus HC, indicating a disruption of illusionary revision of percepts in SZ. Anandamide levels were significantly higher in CSF of SZ compared to HC, while serum anandamide was not. However, we found specific association differences of anandamide levels and BDII scores between schizophrenia patients and controls in serum. CONCLUSIONS: These findings support the hypothesis of an involvement of anandamide in cognitive processes impaired in schizophrenia and are consistent with a protective effect of elevated anandamide levels herein.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Percepción de Profundidad/fisiología , Endocannabinoides/metabolismo , Ilusiones/fisiología , Alcamidas Poliinsaturadas/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Percepción Visual/fisiología , Adulto , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/líquido cefalorraquídeo , Endocannabinoides/sangre , Endocannabinoides/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Adulto JovenRESUMEN
BACKGROUND: There is compelling evidence in humans that peripheral endocannabinoid signaling is disrupted in obesity. However, little is known about the corresponding central signaling. Here, we have investigated the relationship between gender, leptin, body mass index (BMI) and levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the serum and cerebrospinal fluid (CSF) of primarily overweight to obese patients with osteoarthritis. METHODOLOGY/PRINCIPAL FINDINGS: Patients (20 females, 15 males, age range 44-78 years, BMI range 24-42) undergoing total knee arthroplasty for end-stage osteoarthritis were recruited for the study. Endocannabinoids were quantified by liquid chromatography - mass spectrometry. AEA and 2-AG levels in the serum and CSF did not correlate with either age or BMI. However, 2-AG levels in the CSF, but not serum, correlated negatively with CSF leptin levels (Spearman's ρ -0.48, P=0.0076, n=30). No such correlations were observed for AEA and leptin. CONCLUSIONS/SIGNIFICANCE: In the patient sample investigated, there is a negative association between 2-AG and leptin levels in the CSF. This is consistent with pre-clinical studies in animals, demonstrating that leptin controls the levels of hypothalamic endocannabinoids that regulate feeding behavior.
Asunto(s)
Endocannabinoides/sangre , Endocannabinoides/líquido cefalorraquídeo , Leptina/sangre , Osteoartritis/sangre , Osteoartritis/líquido cefalorraquídeo , Adulto , Anciano , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/líquido cefalorraquídeo , Artroplastia de Reemplazo de Rodilla , Índice de Masa Corporal , Cromatografía Liquida , Femenino , Glicéridos/sangre , Glicéridos/líquido cefalorraquídeo , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Obesidad/sangre , Obesidad/líquido cefalorraquídeo , Osteoartritis/cirugía , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/líquido cefalorraquídeoRESUMEN
BACKGROUND: Epilepsy is one of the most common chronic neurological disorders in dogs characterized by recurrent seizures. The endocannabinoid (EC) system plays a central role in suppressing pathologic neuronal excitability and in controlling the spread of activity in an epileptic network. Endocannabinoids are released on demand and their dysregulation has been described in several pathological conditions. Recurrent seizures may lead to an adverse reorganization of the EC system and impairment of its protective effect. In the current study, we tested the hypothesis that cerebrospinal fluid (CSF) concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2AG) are altered in epileptic dogs. Concentrations of AEA and total AG (sum of 2AG and 1AG) were measured in 40 dogs with idiopathic epilepsy and in 16 unaffected, healthy control dogs using liquid chromatography combined with tandem mass spectrometry. RESULTS: AEA and total AG were measured at 4.94 (3.18 - 9.17) pM and 1.43 (0.90 - 1.92) nM in epileptic dogs and at 3.19 (2.04 - 4.28) pM and 1.76 (1.08 - 2.69) nM in the control group, respectively (median, 25 - 75% percentiles in brackets). The AEA difference between epileptic and healthy dogs was statistically significant (p < 0.05). Values correlated with seizure severity and duration of seizure activity. Dogs with cluster seizures and/or status epilepticus and with seizure activity for more than six months displayed the highest EC concentrations. CONCLUSION: In conclusion, we present the first endocannabinoid measurements in canine CSF and confirm the hypothesis that the EC system is altered in canine idiopathic epilepsy.
Asunto(s)
Enfermedades de los Perros/líquido cefalorraquídeo , Endocannabinoides/líquido cefalorraquídeo , Convulsiones/veterinaria , Animales , Ácidos Araquidónicos/líquido cefalorraquídeo , Estudios de Casos y Controles , Perros , Femenino , Cromatografía de Gases y Espectrometría de Masas/veterinaria , Glicéridos/líquido cefalorraquídeo , Masculino , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Recurrencia , Convulsiones/líquido cefalorraquídeoRESUMEN
Anandamide is a ligand of the endocannabinoid system. Animals show a depletion following repeated Δ(9)-tetrahydrocannabinol (THC) administration but the effect of cannabis use on central nervous system levels of endocannabinoids has not been previously examined in humans. Cerebrospinal fluid (CSF) levels of the endocannabinoids anandamide, 2-arachidonoylglycerol (2-AG) and related lipids were tested in 33 volunteers (20 cannabis users). Lower levels of CSF anandamide and higher levels of 2-AG in serum were observed in frequent compared with infrequent cannabis users. Levels of CSF anandamide were negatively correlated with persisting psychotic symptoms when drug-free. Higher levels of anandamide are associated with a lower risk of psychotic symptoms following cannabis use.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Endocannabinoides/líquido cefalorraquídeo , Abuso de Marihuana/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Trastornos Psicóticos/líquido cefalorraquídeo , Análisis de Varianza , Femenino , Glicéridos/líquido cefalorraquídeo , Humanos , Masculino , Abuso de Marihuana/psicología , Trastornos Psicóticos/etiología , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
There is epidemiological evidence that frequent cannabis use in general and during puberty in particular increases the risk to suffer psychosis and psychotic symptoms. Based on these observations, there is growing interest in the role of the endogenous cannabinoid system (eCB system) - the point of action for psychoactive cannabinoids - in psychiatric disorders and schizophrenia in particular. It has been hypothesized nearly two decades ago that the eCB system may play a pathophysiological role in schizophrenia either in terms of an endogenous malfunction of the system itself and/or of a secondary malfunction as a result of the use of exogenous cannabinoids like Δ(9)-tetrahydrocannabinol, the major psychoactive phytocannabinoid in Cannabis sativa. To test this hypothesis, several studies have been performed investigating endogenous ligands to cannabinoid CB1-receptors such as anandamide both in cerebrospinal fluid and plasma of patients and controls. Here a mini-review of the role of anandamide in schizophrenia is provided.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Endocannabinoides/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Síntomas Prodrómicos , Psicosis Inducidas por Sustancias/metabolismo , Animales , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/líquido cefalorraquídeo , Endocannabinoides/sangre , Endocannabinoides/líquido cefalorraquídeo , Humanos , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Psicosis Inducidas por Sustancias/sangre , Psicosis Inducidas por Sustancias/líquido cefalorraquídeoRESUMEN
A correct balance between endocannabinoid and dopamine-dependent systems is believed to underlie physiological motor control. We measured the levels of the endocannabinoid anandamide in the cerebrospinal fluid of Parkinson's disease (PD) patients. Subjects were divided into three groups: newly diagnosed de novo patients, subjects undergoing drug withdrawal, and patients under pharmacological therapy. These groups were compared to age-matched control subjects. Anandamide levels in untreated patients were more than doubled as compared to controls. However, chronic dopaminergic replacement restored control anandamide levels. Abnormal anandamide increase might reflect a compensatory mechanism occurring in course of PD, aimed at normalizing dopamine depletion.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Anciano , Biomarcadores , Agonistas de Dopamina/uso terapéutico , Endocannabinoides , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
PURPOSE: The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE). METHODS: We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE. RESULTS: A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48). DISCUSSION: Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Moduladores de Receptores de Cannabinoides/líquido cefalorraquídeo , Endocannabinoides , Epilepsia del Lóbulo Temporal/líquido cefalorraquídeo , Epilepsia del Lóbulo Temporal/fisiopatología , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Ácidos Araquidónicos/fisiología , Moduladores de Receptores de Cannabinoides/análisis , Moduladores de Receptores de Cannabinoides/fisiología , Modelos Animales de Enfermedad , Epilepsia/líquido cefalorraquídeo , Epilepsia/fisiopatología , Epilepsia/prevención & control , Epilepsia del Lóbulo Temporal/prevención & control , Femenino , Glicéridos/líquido cefalorraquídeo , Glicéridos/fisiología , Hipocampo/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Receptor Cannabinoide CB1/fisiología , Receptor Cannabinoide CB2/fisiologíaRESUMEN
Anandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for anandamide has been suggested in schizophrenia. We investigated its role in initial prodromal states of psychosis. We measured the levels of anandamide and its structural analog oleoylethanolamide in cerebrospinal fluid and serum of patients in the initial prodromal state (n=27) alongside healthy volunteers (n=81) using high-performance liquid chromatograph/mass spectrometry. Cerebrospinal anandamide levels in patients were significantly elevated. Patients with lower levels showed a higher risk for transiting to psychosis earlier. This anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Moduladores de Receptores de Cannabinoides/líquido cefalorraquídeo , Ácidos Oléicos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Trastornos Psicóticos/líquido cefalorraquídeo , Adulto , Ácidos Araquidónicos/sangre , Moduladores de Receptores de Cannabinoides/sangre , Endocannabinoides , Femenino , Humanos , Masculino , Espectrometría de Masas , Ácidos Oléicos/sangre , Alcamidas Poliinsaturadas/sangre , Trastornos Psicóticos/sangre , Adulto JovenRESUMEN
This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12 months. We found increased levels of oleoylethanolamide in CSF (P = 0.011) but not in serum (P = 0.068) after 24 h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-alpha (PPAR-alpha) with nanomolar potency. Exogenous PPAR-alpha agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Metabolismo de los Lípidos , Fármacos Neuroprotectores/metabolismo , Ácidos Oléicos/líquido cefalorraquídeo , PPAR alfa/metabolismo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Privación de Sueño/metabolismo , Adulto , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/metabolismo , Moduladores de Receptores de Cannabinoides/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Endocannabinoides , Femenino , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Ácidos Oléicos/sangre , Ácidos Oléicos/metabolismo , PPAR alfa/agonistas , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/metabolismo , Privación de Sueño/sangre , Privación de Sueño/líquido cefalorraquídeo , Adulto JovenRESUMEN
OBJECTIVE: Endocannabinoids (eCBs) play a role in the modulation of neuroinflammation, and experimental findings suggest that they may be directly involved in the pathogenesis of multiple sclerosis (MS). The objective of our study was to measure eCB levels in the cerebrospinal fluid (CSF) of patients with MS. PATIENTS AND METHODS: Arachidonoylethanolamine (anandamide, AEA), palmotylethanolamide (PEA), 2-arachidonoylglycerol (2-AG) and oleoylethanolamide (OEA) levels were measured in the CSF of 50 patients with MS and 20 control subjects by isotope dilution gas-chromatography/mass-spectrometry. Patients included 35 patients with MS in the relapsing-remitting (RR) form of the disease, 20 in a stable clinical phase and 15 during a relapse, and 15 patients with MS in the secondary progressive (SP) form. RESULTS: Significantly reduced levels of all the tested eCBs were found in the CSF of patients with MS compared to control subjects, with lower values detected in the SP MS group. Higher levels of AEA and PEA, although below those of controls, were found in the CSF of RR MS patients during a relapse. Higher levels of AEA, 2-AG and OEA were found in patients with MRI gadolinium-enhancing (Gd+) lesions. DISCUSSION: The present findings suggest the presence of an impaired eCB system in MS. Increased CSF levels of AEA during relapses or in RR patients with Gd+ lesions suggest its potential role in limiting the ongoing inflammatory process with potential neuroprotective implications. These findings provide further support for the development of drugs targeting eCBs as a potential pharmacological strategy to reduce the symptoms and slow disease progression in MS.
Asunto(s)
Moduladores de Receptores de Cannabinoides/líquido cefalorraquídeo , Endocannabinoides , Esclerosis Múltiple/líquido cefalorraquídeo , Adulto , Ácidos Araquidónicos/líquido cefalorraquídeo , Encéfalo/patología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glicéridos/líquido cefalorraquídeo , Humanos , Inflamación/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/diagnóstico , Ácidos Oléicos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Índice de Severidad de la EnfermedadRESUMEN
The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19-43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not. Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.
Asunto(s)
Encéfalo/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Endocannabinoides , Esclerosis Múltiple/metabolismo , Enfermedad Aguda , Adulto , Animales , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/líquido cefalorraquídeo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dronabinol/análogos & derivados , Dronabinol/farmacología , Electrofisiología , Femenino , Glicéridos/sangre , Glicéridos/líquido cefalorraquídeo , Humanos , Linfocitos/metabolismo , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Técnicas de Placa-Clamp , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Transmisión Sináptica/efectos de los fármacos , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Previous studies have shown that cerebrospinal fluid (CSF) from schizophrenic patients contains significantly higher levels of the endogenous cannabinoid anandamide than does CSF from healthy volunteers. Moreover, CSF anandamide levels correlated inversely with psychotic symptoms, suggesting that anandamide release in the central nervous system (CNS) may serve as an adaptive mechanism countering neurotransmitter abnormalities in acute psychoses. In the present study we examined whether cannabis use may alter such a mechanism. METHODS: We used liquid chromatography/mass spectrometry (LC/MS) to measure anandamide levels in serum and CSF from first-episode, antipsychotic-naïve schizophrenics (n=47) and healthy volunteers (n=81). Based on reported patterns of cannabis use and urine delta9-tetrahydrocannabinol (delta9-THC) tests, each subject group was further divided into two subgroups: 'low-frequency' and 'high-frequency' cannabis users (lifetime use < or = 5 times and > 20 times, respectively). Serum delta9-THC was investigated to determine acute use and three patients were excluded from the analysis due to detectable delta9-THC levels in serum. RESULTS: Schizophrenic low-frequency cannabis users (n=25) exhibited > 10-fold higher CSF anandamide levels than did schizophrenic high-frequency users (n=19, p=0.008), healthy low-frequency (n=55, p<0.001) or high-frequency users (n=26, p<0.001). In contrast, no significant differences in serum anandamide levels were found among the four subgroups. CSF anandamide levels and disease symptoms were negatively correlated in both user groups. CONCLUSIONS: The results indicate that frequent cannabis exposure may down-regulate anandamide signaling in the CNS of schizophrenic patients, but not of healthy individuals. Thus, our findings suggest that alterations in endocannabinoid signaling might be an important component of the mechanism through which cannabis impacts mental health.
Asunto(s)
Ácidos Araquidónicos/líquido cefalorraquídeo , Abuso de Marihuana/epidemiología , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Esquizofrenia/líquido cefalorraquídeo , Esquizofrenia/epidemiología , Enfermedad Aguda , Adulto , Cannabinoides/líquido cefalorraquídeo , Cromatografía Liquida , Endocannabinoides , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Prevalencia , Trastornos Psicóticos/líquido cefalorraquídeo , Trastornos Psicóticos/epidemiología , Factores de TiempoRESUMEN
Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=-0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.
Asunto(s)
Moduladores de Receptores de Cannabinoides/líquido cefalorraquídeo , Endocannabinoides , Trastornos Migrañosos/líquido cefalorraquídeo , Adulto , Amidas , Ácidos Araquidónicos/líquido cefalorraquídeo , Péptido Relacionado con Gen de Calcitonina/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Enfermedad Crónica , Etanolaminas , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glicéridos/líquido cefalorraquídeo , Cefaleas Secundarias/líquido cefalorraquídeo , Humanos , Masculino , Nitritos/líquido cefalorraquídeo , Ácidos Palmíticos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas/líquido cefalorraquídeo , Encuestas y CuestionariosRESUMEN
The diurnal variations of the endocannabinoid arachidonoylethanolamine (anandamide, ANA) as well as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were detected and quantified in cerebrospinal fluid (CSF), pons, hippocampus, and hypothalamus in the rat over 24 h using HPLC/MS. In CSF, the 3 compounds presented an increase in their concentration during the lights-on period and a remarkable decrease in their values during the lights-off period. In the pons, ANA, PEA and OEA showed the maximum values during the dark phase. On the other hand, we found that in the hippocampus, ANA increased its concentration during the lights-off period and PEA showed the highest peak at the beginning of the same period. OEA concentration showed no diurnal variations in the hippocampus. Finally, in the hypothalamus, ANA rose during the lights-on period whereas PEA and OEA presented the highest concentration at the end of the lights-off period. We postulate that all compounds are likely to be accumulated in parenchyma during the lights-off period (when animal is awake) and then, released into the CSF in order to reach target regions in turn to modulate diverse behaviors, such as feeding and sleep.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Química Encefálica/fisiología , Ritmo Circadiano/fisiología , Ácidos Oléicos/metabolismo , Ácidos Palmíticos/metabolismo , Amidas , Animales , Ácidos Araquidónicos/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Endocannabinoides , Etanolaminas , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Espectrometría de Masas , Ácidos Oléicos/líquido cefalorraquídeo , Ácidos Palmíticos/líquido cefalorraquídeo , Alcamidas Poliinsaturadas , Puente/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The endocannabinoids are a family of bioactive lipids that activate CB1 cannabinoid receptors in the brain and exert intense emotional and cognitive effects. Here, we have examined the role of endocannabinoid signaling in psychotic states by measuring levels of the endocannabinoid anandamide in cerebrospinal fluid (CSF) of acute paranoid-type schizophrenic patients. We found that CSF anandamide levels are eight-fold higher in antipsychotic-naive first-episode paranoid schizophrenics (n = 47) than healthy controls (n = 84), dementia patients (n = 13) or affective disorder patients (n = 22). Such an alteration is absent in schizophrenics treated with 'typical' antipsychotics (n = 37), which antagonize dopamine D2-like receptors, but not in those treated with 'atypical' antipsychotics (n = 34), which preferentially antagonize 5HT(2A) receptors. Furthermore, we found that, in nonmedicated acute schizophrenics, CSF anandamide is negatively correlated with psychotic symptoms (rS = -0.452, P = 0.001). The results suggest that anandamide elevation in acute paranoid schizophrenia may reflect a compensatory adaptation to the disease state.