A Cannabinoid CB 1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

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Tobacco\u27s Minor Alkaloids: Effects on Place Conditioning and Nucleus Accumbens Dopamine Release in Adult and Adolescent Rats

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated

Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators

A series of substituted 1-indole-2-carboxamides structurally related to compounds Org27569 (), Org29647 () and Org27759 () were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure–activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound () had an IC value of 79 nM which is ∼2.5 and 10 fold more potent than the parent compounds and , respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Sex differences in Δ9-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats

Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ9-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydroxy-Δ9-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC's effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role

Chronic ∆9-tetrahydrocannabinol during adolescence increases sensitivity to subsequent cannabinoid effects in delayed nonmatch-to-position in rats

Early-onset marijuana use has been associated with short- and long-term deficits in cognitive processing. In human users, self-selection bias prevents determination of the extent to which these effects result only from drug use. This study examined the long-term effects of Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive constituent of marijuana, in a delayed nonmatch-to-position task (DNMP). Male Long–Evans rats were injected daily with 10 mg/kg Δ9-THC during or after adolescence [postnatal days (PN) 21–50 or PN50–79, respectively] or with vehicle. On PN91, training in DNMP was initiated. Successful acquisition and pharmacological challenge began on approximately PN300. Decreases in accuracy were observed at lower doses of Δ9-THC in Δ9-THC-treated rats (versus vehicle-treated rats). Administration of chronic Δ9-THC at a younger age tended to enhance this effect. While anandamide did not decrease accuracy in any group, rats treated with Δ9-THC during adolescence initiated fewer trials at the 30 mg/kg dose of anandamide than did rats in the other two groups. To the extent tested, these differences were pharmacologically selective for cannabinoids, as scopolamine (positive control) decreased accuracy at the same dose in all groups and amphetamine (negative control) did not affect accuracy in any of the groups at doses that did not impair overall responding. These results suggest that repeated administration of a modest dose of Δ9-THC during adolescence (PN21–50) or shortly thereafter (PN50–79) produces a long-term increase in latent sensitivity to cannabinoid-induced impairment of performance in a complex operant task

Sex differences in cannabinoid pharmacology: A reflection of differences in the endocannabinoid system?

In this paper we examine how the relative position of a firm's Return on Equity (ROE) in industries affects the predictability of the next-year ROE levels, and the ROE changes from year to year. Using Nissim and Penman breakdown into operating and financing drivers, the significant role of the industry factor is established, although changes in signs suggest subtle non-linear relations in the drivers. Our study avoids problems originating from negative signs by analyzing sorts and by making new regressions with disaggregated second-order drivers by signs. This way, our results provide evidence of some different patterns in the influence of the first-level drivers of ROE (the operating factor and the financing factor), and the second-level drivers (profit margin, asset turnover, leverage and return spread) on future profitability, depending on the industry spread. The results on the role of contextual factors to improve the estimation of future profitability remain consistent for small and large firms, although adding some nuances.En este trabajo examinamos si la posición relativa del ROE de la empresa en el sector afecta a la estimación del nivel de ROE en el año posterior, y a la estimación de su variación. Empleando el desglose operativo-financiero de Nissim y Penman, encontramos que el factor sectorial es significativo, aunque las variaciones de los signos sugieren la presencia de relaciones no lineales. Nuestro trabajo evita los problemas generados por los signos negativos en los ratios al emplear cuantiles y realizar regresiones independientes para los diferentes signos que toman las variables. De esta forma, los resultados muestran diferentes patrones en el impacto de los inductores del ROE de primer nivel (los factores operativo y financiero) y de segundo nivel (margen de resultados, rotaciones de los activos, endeudamiento y diferencial de rentabilidad) sobre la rentabilidad futura, dependiendo del diferencial de rentabilidad con respecto al sector. Estos resultados, con alguna matización, se vuelven a encontrar cuando se controla por tamaño diferenciando entre empresas pequeñas y grandes

Gonadal hormones do not alter the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol in adult rats

The purpose of this study was to determine whether sex differences in the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) are due to activational effects of gonadal hormones. Rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX). GDX females received no hormone replacement (GDX+0), estradiol (GDX+E2), progesterone (GDX+P4), or both (GDX+E2/P4). GDX male rats received no hormone (GDX+0) or testosterone (GDX+T). Two weeks later, antinociceptive potency of THC was determined (pre-chronic test) on the warm water tail withdrawal and paw pressure assays. Vehicle or a sex-specific THC dose (females, 5.7mg/kg, males, 9.9mg/kg) was administered twice-daily for 9days, then the THC dose–effect curves were re-determined (post-chronic test). On the pre-chronic test (both assays), THC was more potent in sham-GDX females than males, and gonadectomy did not alter this sex difference. In GDX females, P4 significantly decreased THC's antinociceptive potency, whereas E2 had no effect. In GDX males, T did not alter THC's antinociceptive potency. After chronic THC treatment, THC's antinociceptive potency was decreased more in sham-GDX females than males, on the tail withdrawal test; this sex difference in tolerance was not altered in GDX or hormone-treated groups. These results suggest that greater antinociceptive tolerance in females, which occurred despite females receiving 40% less THC than males, is not due to activational effects of gonadal hormones.•On the pre-chronic test, THC was more potent in sham-GDX females than males.•In GDX females, progesterone decreased THC's antinociceptive potency.•In GDX males, testosterone did not alter THC's antinociceptive potency.•Tolerance to THC was greater in sham-GDX females than males, but this sex difference was not hormone-mediated

Sex differences in cannabinoid pharmacology: A reflection of differences in the endocannabinoid system?

Marijuana is the most widely used illicit drug in the U.S., and marijuana use by women is on the rise. Women have been found to be more susceptible to the development of cannabinoid abuse and dependence, have more severe withdrawal symptoms, and are more likely to relapse than men. The majority of research in humans suggests that women are more likely to be affected by cannabinoids than men, with reports of enhanced and decreased performance on various tasks. In rodents, females are more sensitive than males to effects of cannabinoids on tests of antinociception, motor activity, and reinforcing efficacy. Studies on effects of cannabinoid exposure during adolescence in both humans and rodents suggest that female adolescents are more likely than male adolescents to be deleteriously affected by cannabinoids. Sex differences in response to cannabinoids appear to be due to activational and perhaps organizational effects of gonadal hormones, with estradiol identified as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults. Many, but not all sexually dimorphic effects of exogenous cannabinoids can be attributed to a sexually dimorphic endocannabinoid system in rodents, although the same has not yet been established firmly for humans. A greater understanding of the mechanisms underlying sexually dimorphic effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

•Females show greater THC tolerance than males on two nociceptive assays.•Greater tolerance developed in females given a 30% lower tolerance induction dose.•A moderate dose of chronic THC did not disrupt estrous cycling.Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats.Cumulative dose-effect curves were obtained for THC (1.0–18mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined.On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4mg/kg/injection in females and 7.6mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females.These results demonstrate that—even when sex differences in acute THC potency are controlled—females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure