Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality.

Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.

Methods to Identify Cognitive Alterations from Animals to Humans: A Translational Approach.

The increasing prevalence of cognitive dysfunction and dementia in developed countries, associated with population aging, has generated great interest in characterizing and quantifying cognitive deficits in these patients. An essential tool for accurate diagnosis is cognitive assessment, a lengthy process that depends on the cognitive domains analyzed. Cognitive tests, functional capacity scales, and advanced neuroimaging studies explore the different mental functions in clinical practice. On the other hand, animal models of human diseases with cognitive impairment are essential for understanding disease pathophysiology. The study of cognitive function using animal models encompasses multiple dimensions, and deciding which ones to investigate is necessary to select the most appropriate and specific tests. Therefore, this review studies the main cognitive tests for assessing cognitive deficits in patients with neurodegenerative diseases. Cognitive tests, the most commonly used functional capacity scales, and those resulting from previous evidence are considered. In addition, the leading behavioral tests that assess cognitive functions in animal models of disorders with cognitive impairment are highlighted.

Inflammatory Biomarkers in the Diagnosis and Prognosis of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

This study aimed to identify inflammatory factors and soluble cytokines that act as biomarkers in the diagnosis and prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We performed a nested prospective observational case-control study of patients with RA-ILD matched by sex, age, and time since the diagnosis of RA. All participants underwent pulmonary function testing and high-resolution computed tomography. ILD was defined according to the criteria of the American Thoracic Society/European Respiratory Society; the progression of lung disease was defined as the worsening of FVC > 10% or DLCO > 15%. Inflammation-related variables included the inflammatory activity measured using the DAS28-ESR and a multiplex cytokine assay. Two Cox regression models were run to identify factors associated with ILD and the progression of ILD. The study population comprised 70 patients: 35 patients with RA-ILD (cases) and 35 RA patients without ILD (controls). A greater percentage of cases had higher DAS28-ESR (p = 0.032) and HAQ values (p = 0.003). The variables associated with RA-ILD in the Cox regression analysis were disease activity (DAS28) (HR [95% CI], 2.47 [1.17-5.22]; p = 0.017) and high levels of ACPA (HR [95% CI], 2.90 [1.24-6.78]; p = 0.014), IL-18 in pg/mL (HR [95% CI], 1.06 [1.00-1.12]; p = 0.044), MCP-1/CCL2 in pg/mL (HR [95% CI], 1.03 [1.00-1.06]; p = 0.049), and SDF-1 in pg/mL (HR [95% CI], 1.00 [1.00-1.00]; p = 0.010). The only variable associated with the progression of ILD was IL-18 in pg/mL (HR [95% CI], 1.25 [1.07-1.46]; p = 0.004). Our data support that the inflammatory activity was higher in patients with RA-ILD than RA patients without ILD. Some cytokines were associated with both diagnosis and poorer prognosis in patients with RA-ILD.

CBD-mediated regulation of heroin withdrawal-induced behavioural and molecular changes in mice.

Cannabidiol (CBD) may represent a promising therapeutic tool for treating opioid use disorder (OUD). This study was aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous heroin withdrawal. Thirty hours after cessation of 8-day heroin treatment (5, 10, 20 and 40 mg·kg-1 /12 h; s.c.), spontaneous heroin withdrawal was evaluated in CD1 male mice. The effects of CBD (5, 10 and 20 mg·kg-1 ; i.p.) on withdrawal-related behaviour were evaluated by measuring anxiety-like behaviour, motor activity and somatic signs. Furthermore, gene expression changes of mu-opioid receptor (Oprm1), proopiomelanocortin (Pomc), cannabinoid CB1 (Cnr1) and CB2 (Cnr2) receptors in the nucleus accumbens (NAcc) and tyrosine hydroxylase (TH) and Pomc in the ventral tegmental area (VTA) were also evaluated by real-time PCR. Anxiety-like behaviour, motor activity and withdrawal-related somatic signs were significantly increased in heroin-treated mice compared to the control group. Interestingly, CBD treatment significantly reduced these behavioural impairments and normalized gene expression of Cnr1 and Pomc in the NAcc and TH in the VTA of mice exposed to spontaneous heroin withdrawal. Also, CBD induced an up-regulation of Cnr2, whereas it did not change the increased gene expression of Oprm1 in the NAcc of abstinent animals. The results suggest that CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for the treatment of heroin withdrawal.

Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies.

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: "Receptor, Cannabinoid, CB2" AND "Alcohol-Related Disorders" AND "human/or patients"; "Receptor, Cannabinoid, CB2" AND "Alcohol" OR "Ethanol" AND "rodents/or mice/or rats". Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders.

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

Incidence and case fatality rate of COVID-19 in patients with inflammatory articular diseases.

OBJECTIVE: To describe the incidence and fatality of coronavirus disease 2019 (COVID-19) and identify risk factors to fatality in patients with inflammatory articular diseases (IAD). METHODS: This is a cross-sectional observational study of IAD patients and COVID-19 with controls matched for age, sex, and RT-PCR. A control group was used to compare the cumulative incidence (CI) and case fatality rate (CFR). The main outcomes of the study were CI and CFR. Other variables included comorbidities, treatments, and characteristics of the COVID-19. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with IAD. RESULTS: Of the 1537 patients who fulfilled the inclusion criteria, 23/1537 (1.49%) had IAD 13 (0.8%) had rheumatoid arthritis (RA), 5 psoriatic arthritis (PsA) (0.3%) and 5 axial spondyloarthritis (0.3%). There were no significant differences in CI of COVID-19 and CFR in patients with IAD compared with COVID-19 patients without IAD. In RT-PCR positive patients, the CI of COVID-19 in PsA and AS was higher. Of the 23 IAD patients, 2 RA patients (8.6%) died. The patients did no show characteristics of the COVID-19 disease different from the population. In multivariate analysis, the factor associated with fatality in patients with IAD was older age (OR [95% CI], 1.1 [1.0-1.2]). CONCLUSION: COVID-19 CI, fatality rate and other features do not seem to be increased in IAD patients. Older age was associated with fatality in patients with IAD.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Measurement of CSF α-synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer's disease.

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α-synuclein (α-syn) to be an additional biomarker for improving differential diagnosis of Alzheimer's disease (AD). We evaluated α-syn diagnostic performance across a well-characterized patient cohort with long-term follow-up. For this purpose, CSF α-syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI-AD; n = 32), 24 MCI cases due to Lewy body disease (MCI-LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α-syn levels discriminate between the four groups. There were higher α-syn levels in MCI-AD patients and lower levels in MCI-LBD patients. The combination of α-syn and P-tau resulted in a specificity of 99% and a sensitivity of 97% for MCI-AD. MCI-AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P-tau and α-syn compared to the MCI-AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α-syn to central core AD biomarkers improves an early differential diagnosis of MCI-AD from other forms of MCI. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Cannabidiol does not display drug abuse potential in mice behavior.

Recent evidence suggests that cannabidiol (CBD) may be useful for the treatment of different neuropsychiatric disorders. However, some controversy regarding its profile as a drug of abuse hampers the further development of basic and clinical studies. In this study, the behavioral profile of CBD as a potential drug of abuse was evaluated in C57BL/6J mice. Reinforcing properties of CBD (15, 30, and 60 mg/kg; i.p.) were assessed using the conditioned place preference (CPP) paradigm. Spontaneous withdrawal symptoms and motor activity in the open field were examined 12 h after the last CBD administration (30 mg/kg/12 h, i.p., 6 days). CBD plasma concentrations were measured at 2, 4, 8, 12, and 24 h after the administration of CBD (30 mg/kg, i.p.). Furthermore, an oral CBD self-administration paradigm (50 mg/kg; CBD water-soluble 1.2 mg/mL) was performed to evaluate whether this drug produced any effects on motivation compared with a non-reinforcing substance (water). We found that CBD failed to induce CPP, withdrawal symptoms, or altered motor behavior 12 h after its administration. At that time, only traces of CBD were detected, ensuring that the lack of alterations in somatic signs and locomotor activity was not due to residual drug in plasma. Interestingly, mice displayed similar motivation and consumption of CBD and water. Taken together, these results show that CBD lacks activity as a drug of abuse and should stimulate the development of the basic and clinical studies needed to elucidate its potential therapeutic use for the treatment of neuropsychiatric and drug use disorders.

Epigenetic Mechanisms and Posttranslational Modifications in Systemic Lupus Erythematosus.

The complex physiology of eukaryotic cells is regulated through numerous mechanisms, including epigenetic changes and posttranslational modifications. The wide-ranging diversity of these mechanisms constitutes a way of dynamic regulation of the functionality of proteins, their activity, and their subcellular localization as well as modulation of the differential expression of genes in response to external and internal stimuli that allow an organism to respond or adapt to accordingly. However, alterations in these mechanisms have been evidenced in several autoimmune diseases, including systemic lupus erythematosus (SLE). The present review aims to provide an approach to the current knowledge of the implications of these mechanisms in SLE pathophysiology.

Cannabidiol reduces ethanol consumption, motivation and relapse in mice.

This study evaluated the effects of cannabidiol (CBD) on ethanol reinforcement, motivation and relapse in C57BL/6 J mice. The effects of CBD (60 mg/kg, i.p.) on blood ethanol concentration, hypothermia and handling-induced convulsions associated to acute ethanol administration were evaluated. The two-bottle choice paradigm was performed to assess the effects of CBD (30, 60 and 120 mg/kg/day, i.p.) on ethanol intake and preference. In addition, an oral ethanol self-administration experiment was carried out to evaluate the effects of CBD [a single s.c. administration of a microparticle formulation providing CBD continuous controlled release (30 mg/kg/day)] on the reinforcement and motivation for ethanol. The effects of CBD (60 and 120 mg/kg/day, i.p.) on ethanol-induced relapse were also evaluated. Gene expression analyses of tyrosine hydroxylase in ventral tegmental area and µ-opioid (Oprm1), cannabinoid (CB1 r and CB2 r) and GPR55 receptors in nucleus accumbens (NAcc) were carried out by real-time polymerase chain reaction. Cannabidiol reduced the ethanol-induced hypothermia and handling-induced convulsion but failed to modify blood ethanol concentration. CBD reduced ethanol consumption and preference in the two-bottle choice, significantly decreased ethanol intake and the number of effective responses in the oral ethanol self-administration, and reduced ethanol-induced relapse. Furthermore, the administration of CBD significantly reduced relative gene expression of tyrosine hydroxylase in the ventral tegmental area, Oprm1, CB1 r and GPR55 in the NAcc and significantly increased CB2 r in the NAcc. Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.

The Modulation of the Startle Reflex as Predictor of Alcohol Use Disorders in a Sample of Heavy Drinkers: A 4-Year Follow-Up Study.

BACKGROUND: Previous studies demonstrated that patients with alcohol use disorders (AUDs) show altered startle reflex responses to alcohol-related stimuli. However, there is little information about the role of these altered responses in the development of AUDs. This study examined the startle reflex response to different visual stimuli and the role of these patterns in the development of AUDs in a 4-year follow-up. METHODS: Two hundred and thirty-nine (nondependent) heavy-drinking participants were selected. In the baseline period, the startle reflex responses to alcohol-related, aversive, appetitive, and neutral pictures were assessed. Startle reflex responses to these pictures were used as predictive variables. Status drinking (alcohol dependence and nondependence) assessed at 4-year follow-up was used as outcome measure. RESULTS: At the 4-year follow-up assessment, 46% of participants fulfilled DSM-IV alcohol abuse or dependence criteria. Alcohol dependence status was predicted by an attenuated startle reflex response to alcohol-related and aversive pictures. CONCLUSIONS: This study revealed that an attenuated modulation of startle reflex response to alcohol-related and aversive stimuli could be used as a clinical marker to predict the development of AUDs in participants with previous alcohol consumption.

Social defeat in adolescent mice increases vulnerability to alcohol consumption.

This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.

Increased vulnerability to ethanol consumption in adolescent maternal separated mice.

The purpose of this study was to evaluate the effects of early life stress on the vulnerability to ethanol consumption in adolescence. To this aim, mice were separated from their mothers for 12 hours/day on postnatal days 8 and 12. Emotional behavior (light-dark box, elevated plus maze and tail suspension tests) and pre-attentional deficit (pre-pulse inhibition) were evaluated in adolescent maternal separated (MS) mice. Alterations of the corticotropin-releasing factor (CRF), glucocorticoid receptor (NR3C1), tyrosine hydroxylase (TH), mu-opioid receptor (MOr), brain-derived neurotrophic factor (BDNF), neuronal nuclei (NeuN), microtubule-associated protein 2 (MAP2) and neurofilament heavy (NF200)-immunoreactive fibers were studied in the paraventricular nucleus of the hypothalamus (PVN), ventral tegmental area (VTA), nucleus accumbens (NAc) or hippocampus (HIP). The effects of maternal separation (alone or in combination with additional stressful stimuli) on ethanol consumption during adolescence were evaluated using the oral ethanol self-administration paradigm. MS mice presented mood-related alterations and pre-attentional deficit. Increased CRF, MOr and TH, and reduced BDNF, NR3C1, NeuN, MAP2 and NF200-immunoreactive fibers were observed in the PVN, NAc and HIP of adolescent MS mice. In the oral ethanol self-administration test, adolescent MS mice presented higher ethanol consumption and motivation. Exposure to additional new stressful stimuli during adolescence significantly increased the vulnerability to ethanol consumption induced by maternal separation. These results clearly demonstrated that exposure to early life stress increased the vulnerability to ethanol consumption, potentiated the effects of stressful stimuli exposure during adolescence on ethanol consumption and modified the expression of key targets involved in the response to stress, ethanol reinforcing properties and cognitive processes.

Psychiatric comorbidity in a sample of cocaine-dependent outpatients seen in the Community of Madrid drug addiction care network.

The objective of this study was to estimate the current prevalence of psychiatric disorders in cocaine-dependent patients who attend different treatment centres in the Community of Madrid. A prospective multicentre study was used, and a total of 197 cocaine-dependent subjects were assessed. The assessment instrument used for diagnosis was the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV). The main findings of this study were a high prevalence of psychiatric comorbidity in cocaine-dependent patients seeking treatment (64.0%). The most common Non Substance Use Disorders found were attention-deficit/hyperactivity Disorders (34.5%) and depressive disorders (13.7%). The most common Substance Use Disorder was alcohol dependence (28.4%). Cocaine-dependent patients who had a depressive disorder and were alcohol dependent presented a more severe clinical profile and a higher degree of psychopathology, measured using different assessment tools, than the patients who were only cocaine dependent. These data suggest that the presence of psychiatric comorbidity could constitute a risk factor associated with the severity of cocaine dependence. The clinical heterogeneity found also indicates the need to search for individualised treatments that more specifically fit the needs of this population.

El objetivo de este estudio fue estimar la prevalencia actual de trastornos psiquiátricos en pacientes dependientes de cocaína atendidos en los diferentes centros de tratamiento en la Comunidad de Madrid. Se trata de un estudio multicéntrico prospectivo realizado con una muestra de 197 sujetos con dependencia de cocaína. El instrumento de evaluación utilizado fue la Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV) (Entrevista de Investigación Psiquiátrica para Trastornos Mentales y Sustancias). La prevalencia actual de comorbilidad psiquiátrica encontrada fue del 64.0%. Los trastornos psiquiátricos más frecuentes no relacionados con el consumo fueron el trastorno por déficit de atención e hiperactividad (34,5%) y los trastornos depresivos (13,7%). El trastorno por uso de sustancias más frecuente fue la dependencia del alcohol (28.4%). Los pacientes dependientes de cocaína que presentaron un trastorno depresivo y los que presentaron dependencia del alcohol mostraron un perfil clínico de mayor gravedad y un mayor grado de psicopatología medido a través de diferentes instrumentos de evaluación en relación con los pacientes que sólo presentaban dependencia de la cocaína. Estos datos sugieren que la presencia de comorbilidad psiquiátrica podría constituir un factor de riesgo asociado a la gravedad de la dependencia de la cocaína. La heterogeneidad clínica encontrada recomienda la búsqueda de tratamientos individualizados que se ajusten de manera mas especifica a las necesidades de esta población.

Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol.

This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption. The time-related and dose-response effects of ethanol on rectal temperature, handling-induced convulsions (HIC) and blood ethanol concentrations were evaluated in CB2 KO and wild-type (WT) mice. The reinforcing properties of ethanol were evaluated in conditioned place preference (CPP), preference and voluntary ethanol consumption and oral ethanol self-administration. Water-maintained behavior schedule was performed to evaluate the degree of motivation induced by a natural stimulus. Preference for non-alcohol tastants assay was performed to evaluate the differences in taste sensitivity. Tyrosine hydroxylase (TH) and µ-opioid receptor gene expressions were also measured in the ventral tegmental area and nucleus accumbens (NAcc), respectively. CB2 KO mice presented increased HIC score, ethanol-CPP, voluntary ethanol consumption and preference, acquisition of ethanol self-administration, and increased motivation to drink ethanol compared with WT mice. No differences were found between genotypes in the water-maintained behavior schedule or preference for non-alcohol tastants. Naïve CB2 KO mice presented increased µ-opioid receptor gene expression in NAcc. Acute ethanol administration (1-2 g/kg) increased TH and µ-opioid receptor gene expressions in CB2 KO mice, whereas the lower dose of ethanol decreased TH gene expression in WT mice. These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption, at least in part, by increased ethanol-induced sensitivity of the TH and µ-opioid receptor gene expressions in mesolimbic neurons. Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.

Effects of naltrexone plus topiramate on ethanol self-administration and tyrosine hydroxylase gene expression changes.

The purpose of this study was to evaluate the effects of naltrexone (0.7 mg/kg) and/or topiramate (25 mg/kg) on ethanol consumption and the motivation to drink in an oral-operant conditioning paradigm in C57BL/6 mice. Subsequent real-time polymerase chain reaction (PCR) experiments were performed to analyze gene expression changes in tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). The administration of naltrexone significantly reduced ethanol consumption and the motivation to drink during the different stages of the experiment, whereas the treatment with topiramate resulted in a much lower effect. Interestingly, the administration of naltrexone plus topiramate reduced ethanol consumption markedly compared with single-drug treatment. The water self-administration paradigm was also performed using the same drugs and no differences were found between treatment groups. Real-time PCR analyses revealed that naltrexone significantly normalized the increase of TH gene expression in the VTA induced by ethanol, whereas the administration of topiramate did not produce any significant effect. In the ethanol self-administration procedure, the combination of both drugs further reduced TH gene expression, reaching statistical significance compared with the vehicle, naltrexone or topiramate groups. Taken together, these findings indicate that the administration of naltrexone plus topiramate further reduced ethanol consumption and the motivation to drink in comparison with single-drug treatment. This action may be due, at least in part, to a greater decrease in TH gene expression in the VTA. These results suggest that the combination of both drugs deserves further exploration for the treatment of problems related to alcohol consumption.

Understanding the Biological Relationship between Migraine and Depression.

Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities.