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At least 847 records · Page 47Linked to original sources
PubMed2004

Species comparison and pharmacological characterization of rat and human CB2 cannabinoid receptors.

Pharmacological effects of cannabinoid ligands are thought to be mediated through cannabinoid CB1 and CB2 receptor subtypes. Sequence analysis revealed that rat and human cannabinoid CB2 receptors are divergent and share 81% amino acid homology. Pharmacological analysis of the possible species differences between rat and human cannabinoid CB2 receptors was performed using radioligand binding and functional assays. Pronounced species selectivity at the rat cannabinoid CB2 receptor (50- to 140-fold) was observed with AM-1710 (3-(1,1-Dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo[c]chromen-6-one) and AM-1714 (3-(1,1-Dimethyl-heptyl)-1-9-dihydroxy-benzo[c]chromen-6-one). In contrast, JWH-015 ((2-Methyl-1-propyl-1H-indol-3-yl)-napthalen-1-yl-methanone) was 3- to 10-fold selective at the human cannabinoid CB2 receptor. Endocannabinoid ligands were more human receptor selective. Cannabinoid CB2 receptor antagonist, AM-630 ((6-Iodo-2-methyl-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)-(4-methoxy-phenyl)-methanone) was more potent at the rat receptor in radioligand binding and functional assays than that of the human receptor. The findings of the pharmacological differences between the human and rat cannabinoid CB2 receptors in this study provide critical information for characterizing cannabinoid ligands in in vivo rodent models for drug discovery purpose.

Animals↗
PubMed2005

Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat.

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

Analysis of Variance↗
PubMed2005

The serotonin/noradrenaline reuptake inhibitor venlafaxine attenuates acquisition, but not maintenance, of intravenous self-administration of heroin in rats.

Opioids and antidepressants are frequently used for the treatment of various pain conditions. A combination of both drug classes may be more effective than either treatment alone, and combined treatment with an antidepressant may result in an opiate-sparing effect. Although it has been shown that antidepressants can attenuate self-administration of psychomotor stimulant and depressant drugs, it is not known whether they also attenuate self-administration of opiates. To determine whether venlafaxine, a serotonin/noradrenaline reuptake inhibitor with antidepressive and analgesic properties, affects acquisition and maintenance of intravenous heroin self-administration in rats, male Long-Evans rats were trained to press a lever in order to receive heroin (0.05 mg/kg/infusion) under a fixed ratio or a progressive ratio schedule. A control group was trained in a fixed ratio food-reinforced operant procedure. The effect of venlafaxine on operant responding for heroin and food was assessed both during acquisition and, in separate groups of rats, during maintenance (i.e., after acquisition) of self-administration behaviour. Daily treatment with venlafaxine (10 mg/kg i.p.) before the operant session attenuated the acquisition of responding for heroin, but not for food. However, when tested during the maintenance phase in rats showing stable responding, acute treatment with venlafaxine only marginally affected operant responding for heroin under a fixed ratio:10 schedule of reinforcement, and neither acute nor subchronic (once daily during 4 weeks) venlafaxine treatment affected responding under a progressive ratio schedule. Thus, daily treatment with an antidepressant attenuates the acquisition of heroin self-administration in a behaviourally specific manner, while having only marginal effects on maintenance of heroin self-administration.

Animals↗
PubMed2005

Chronic corticosterone treatment increases the endocannabinoid 2-arachidonylglycerol in the rat amygdala.

This research was designed to examine the effect of three weeks of administration of corticosterone (20 mg/kg) on endocannabinoid content and cannabinoid CB1 receptor binding in the amygdala. It was found that the endocannabinoid 2-arachidonylglycerol was significantly increased in the amygdala following chronic corticosterone treatment. However, there was no change in either the maximal binding (Bmax) or binding affinity (KD) of [3H]-CP 55,940 to the CB1 receptor in the amygdala. Given the role of amygdalar endocannabinoids in the regulation of emotionality, this suggests that the ability of glucocorticoids to influence affective behavior may involve interactions with regulation of endocannabinoid content.

Amygdala↗
PubMed2006

F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist.

To investigate how specific amino acid residues affect human cannabinoid CB1 receptor binding and activation, CHO cell lines stably expressing wild type and the phenylalanine 200 to alanine mutant of human cannabinoid CB1 receptor (F200A) were examined. AM2233 functions as an agonist at the wild type receptor (EC50=0.93 nM), but behaves as an inverse agonist at F200A (EC50=4.8 nM). The F200A mutant has significantly lower forskolin-stimulated basal cAMP accumulation than that of the wild type, indicating that the F200A mutant possesses higher constitutive activity. F200 doesn't contribute substantially to the high affinity binding of AM2233 at human cannabinoid CB1 receptor. CP55940, HU-210 and Win55212-2 still function as agonists at the F200A mutant, with similar efficacy, potency, and apparent binding affinity for both wild type human cannabinoid CB1 receptor and F200A mutant. These data indicate that the phenylalanine 200 residue in human cannabinoid CB1 receptor is involved in the receptor activation induced by a specific class of agonists, and supports a model of agonist-structure-dependent conformational changes.

Alanine↗
PubMed2006

Suppression by WIN55212-2, a cannabinoid receptor agonist, of inflammatory reactions in mouse ear: Interference with the actions of an endogenous ligand, 2-arachidonoylglycerol.

The effect of WIN55212-2, a cannabinoid receptor agonist, on acute inflammation of mouse ear was investigated. We found that topical application of WIN55212-2 suppressed ear swelling induced by 12-O-tetradecanoylphorbol 13-acetate or 2-arachidonoylglycerol. Similar inhibition was observed with CP55940, another cannabinoid receptor agonist, and HU-308, a cannabinoid CB(2) receptor-selective agonist. WIN55212-2 also suppressed the infiltration of leukocytes induced by 12-O-tetradecanoylphorbol 13-acetate. On the other hand, WIN55212-3, an inactive enantiomer of WIN55212-2, exerted only small effects on inflammation. Notably, SR144528, a cannabinoid CB(2) receptor antagonist, also suppressed inflammatory reactions in mouse ear. Thus, both the cannabinoid CB(2) receptor agonist and antagonist are capable of reducing inflammatory reactions. We then investigated the mechanism underlying WIN55212-2-induced suppression of inflammation using cultured cells. We found that the addition of WIN55212-2 together with 2-arachidonoylglycerol blocked 2-arachidonoylglycerol-induced migration of human promyelocytic leukemia HL-60 cells that had been differentiated into macrophage-like cells. The restoration of 2-arachidonoylglycerol-desensitized cells and WIN55212-2-desensitized cells from an anergic condition was examined next. We found that 2-arachidonoylglycerol-treated cells rapidly recovered the capacity to respond to 2-arachidonoylglycerol. On the other hand, the anergic condition toward 2-arachidonoylglycerol continued for a longer period after pretreatment with WIN55212-2. These results suggest that the anti-inflammatory activity of WIN55212-2 is attributable, at least in part, to interference with the actions of the endogenous ligand, 2-arachidonoylglycerol.

Administration, Cutaneous↗
PubMed2006

The cannabinoid agonist WIN 55,212-2 inhibits TNF-alpha-induced neutrophil transmigration across ECV304 cells.

Cannabinoids are known to possess both anti-inflammatory and neuroprotective effects. In the present study, we have investigated the ability of cannabinoids to inhibit the transmigration of neutrophils in response to chemotaxic stimuli. The cannabinoid receptor agonist WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) significantly decreased the number of migrating neutrophils across a monolayer of tumour necrosis factor alpha (TNF-alpha) activated ECV304 cells at concentrations >or=1 microM. In contrast, the agonists HU210 and CP 55,940 (0.01-1 microM) and the endocannabinoid anandamide (0.1-10 microM) were without significant effect on the response to TNF-alpha. The ability of WIN 55,212-2 to reduce the neutrophil transmigration was still seen in the presence of the cannabinoid CB(1) receptor antagonist/inverse agonist AM251 (0.1-1 microM) and the cannabinoid CB(2) receptor antagonist/inverse agonist AM630 (0.1-1 microM). TNF-alpha treatment of ECV304 cells caused release of interleukin-8 (IL-8), but WIN 55,212-2 did not affect either the ability of neutrophils to migrate across chemotaxis plates in response to an IL-8 stimulus, or to change the percentage of CXC 1 and CXC 2 receptors expressed by the neutrophils. WIN 55,212-2 at a concentration of 1 microM, but not at lower concentrations, produced a significant inhibition of IL-8 release from ECV304 cells in response to TNF-alpha-stimulation. Thus WIN 55,212-2 reduces the transmigration of neutrophils across a monolayer of TNF-alpha-activated ECV304 cells by an indirect action upon the release of IL-8 and/or other chemokine release from the ECV304 cells, and that this effect is brought about mainly by a cannabinoid CB receptor-independent mechanism.

Analysis of Variance↗
PubMed2005

Chronic administration of the SSRI fluvoxamine markedly and selectively reduces the sensitivity of cortical serotonergic neurons to footshock stress.

We have evaluated, with the use of vertical microdialysis, the effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on the increase in serotonin and norepinephrine output elicited in rats prefrontal cortex by exposure to footshock stress. Exposure to footshock stress induced a marked increase in the cortical extracellular concentration of both serotonin and norepinephrine (+70% and +100%, respectively) in control rats. Long term, but not acute administration of fluvoxamine (10 mg/kg, i.p. once a days for 21 days) completely antagonized the stress induced increase in cortical serotonin extracellular concentration, while failed to modify the sensitivity of cortical noradrenergic neurons to the same stressful stimulus. Our results have shown that it is possible to independently modulate the sensitivity of cortical serotonergic neurons to stressful stimuli without altering the responsiveness of noradrenergic neurons to the same stress. Given the different role played by serotonin and norepinephrine in the modulation of the stress response, the availability of drugs able to selectively modulate the plastic response of serotonergic neurons to stress in specific brain areas might be important for the pharmacotherapy of anxiety disorders.

Animals↗
PubMed2003

Lithium augmentation in venlafaxine non-responders: an open study.

Thirteen major depressive patients not responding to a 4-week venlafaxine 300 mg treatment were eligible for a 4-week open trial of lithium addition. Two patients had to stop lithium for a possible moderate serotonin syndrome and five patients became responders, including one dramatic response and two semi-rapid responses.

Adult↗
PubMed2004

A case of social phobia and avoidant personality disorder with erectile dysfunction successfully treated with venlafaxine and add-on reboxetine.

A 25-year-old man with DSM-IV-TR Axis I social phobia and Axis II avoidant personality disorder and erectile dysfunction, presenting with depression, anxiety and insomnia, responded partially to extended release oral venlafaxine (75 mg/die for 6 weeks), but developed side effects and worsening symptoms when dose was increased to 150 mg/die; he responded to a combination of 75 mg/die venlafaxine and 4 mg/die reboxetine and improved on most of his symptoms.

Adult↗
PubMed2004

Social adjustment in generalised anxiety disorder: a long-term placebo-controlled study of venlafaxine extended release.

The objective of this analysis was to evaluate the short- (8 weeks) and long-term (24 weeks) efficacy of three fixed doses of venlafaxine extended release (ER) and placebo on the social adjustment of patients with generalised anxiety disorder (GAD). We analysed data from 544 outpatients who participated in a 24-week, double-blind, multicentre, parallel-group, placebo-controlled study conducted at 55 centres in five countries. All patients meet the DSM-IV criteria for GAD and were randomly assigned to receive venlafaxine ER 37.5, 75, and 150 mg or matched placebo administered orally once daily. Social adjustment was measured using the Social Adjustment Scale-Self Report, which explores social adaptation in the areas of work, social and leisure, extended family, primary relationship (marital), parental, and family unit. At baseline, the GAD patients had a high level of social dysfunction. Venlafaxine ER showed a dose-related improvement in social impairment during short-term treatment and in sustaining this improvement over the long-term. In the most severely socially impaired subgroup, placebo remission rates on the HAM-A were low, and the magnitude of the venlafaxine-placebo difference on the mean HAM-A total score was high, reaching more than 7 points. The benefits of venlafaxine ER treatment of GAD extend beyond that of improvement of anxiety symptoms to a significant improvement in the impairment of functioning that is associated with the illness.

Adjustment Disorders↗
PubMed2005

Stimulation of cannabinoid (CB1) and prostanoid (EP2) receptors opens BKCa channels and relaxes ocular trabecular meshwork.

Prostanoids and cannabinoids have ocular hypotensive and neuroprotective properties. The effect of the prostanoid AH13205 (EP2), the thromboxane-mimetic U46619, the cannabinoid (CB) agonists WIN55212-2 and CP 55,940, endothelin-1 (ET-1) and 8-bromo-cAMP on the membrane currents of trabecular meshwork (TM) cells were measured using the patch-clamp technique and compared to their effects on TM contractility. Previous studies show relaxation of TM to AH 13205 and other substances that elevate cAMP, while U46619 and endothelin-1 contract TM. This study shows that after contraction (100%) with carbachol (10(-6)m), the CB agonist CP 55,940 dose-dependently reduced contractility to 83+/-4% (n=9) (10(-6)m) and 61+/-10%, (n=7) (10(-5)m). In the presence of both the CB1 antagonist AM251 (10(-6)m) and CP 55,940 (10(-5)m), the contractile response to carbachol reached 84+/-3% (n=6) of the original level. In patch-clamp experiments, membrane permeable 8-bromo-cAMP (10(-4)m) had no effect on currents of TM cells. In contrast, AH 13205 and two cannabinoids reversibly enhanced outward current through high-conductance Ca(2+)-activated K(+) channels (BKCa, BK, maxi-K) to the following values (in % of the initial value at 100 mV): AH 13205 (10(-5)m): 200+/-28% (n=6), CP 55,940 (10(-6)m): 196+/-33% (n=7), CP 55,940 (10(-5)m): 484+/-113% (n=7), WIN55212-2 (10(-5)m): 205+/-41% (n=10). Iberiotoxin (10(-7)m) completely blocked these responses. The current response to CP 55,940 (10(-5)m) could be partially blocked by the CB1 antagonist AM251 (10(-6)m). Conversely, the contractile agents in this study either caused a transient reduction in outward current (ET-1(5x10(-8)m)) or had no effect (U46619 (10(-6)m)). We conclude that stimulation of EP2 and CB1 receptors in TM is coupled to the activation of BKCa channels via a non-diffusible second messenger cascade. This effect may contribute to the relaxant activity of EP2 and CB1 agonists in isolated TM strips, modulating ocular outflow.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

1,8-cineole (eucalyptol), a monoterpene oxide attenuates the colonic damage in rats on acute TNBS-colitis.

The monoterpene oxide, 1,8-cineole (cineole, eucalyptol) was examined for its possible influence on the acute phase of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The test compound, 1,8-cineole (200 and 400 mg/kg) or vehicle (1 ml, 2% Tween 80) was instilled rectally, 24, and 2 h before (pre-treatment) or 2 and 24 h after (post-treatment) the induction of colitis by intracolonic administration of TNBS (0.25 ml of 25 mg of TNBS in 50% ethanol). Rats were killed 48 h after colitis induction and colonic segments were analysed for gross damage scores, changes in wet weights, myeloperoxidase activity, an indicator of neutrophilic infiltration and glutathione level, a major cellular antioxidant. TNBS induced an extensive inflammation and ulceration in the colon. Colonic damage was associated with an increase in myeloperoxidase activity and by a decrease in glutathione. When compared to vehicle-treated TNBS controls, a marked reduction in gross damage scores and wet weights (mg/cm) of colonic segments were evident in animals pre-treated but not post-treated with 1,8-cineole. Cineole also significantly reduced the myeloperoxidase activity, and caused repletion of glutathione. These results confirm the anti-inflammatory action of 1,8-cineole and suggest its potential value as a dietary flavoring agent in the prevention of gastrointestinal inflammation and ulceration.

Acute Disease↗
PubMed2006

The redistribution of selected psychiatric drugs in post-mortem cases.

The post-mortem redistribution of a number of psychiatric drugs was investigated. A portion of liver, the gastric contents and blood collected from heart and femoral sites was obtained from 13 cases and analyzed by liquid chromatography-mass spectrometry. Drugs detected included five selective serotonin reuptake inhibitors; venlafaxine, a serotonin/noradrenaline reuptake inhibitor; and risperidone, an atypical antipsychotic. Heart blood concentrations were significantly higher (3.4-fold on average) than those measured in femoral blood when results from all drugs were included together. The range for parent drug concentrations in these two blood specimens was 0.5-6.2. There was no significant correlation of the post-mortem interval, the liver concentration and content of drugs in the gastric contents to the heart:femoral blood concentration ratio. These data serve to demonstrate that variable increases in blood concentration occur post-mortem and limit the interpretative value of such toxicological data.

Antipsychotic Agents↗
PubMedDate not supplied

Syndrome of inappropriate secretion of antidiuretic hormone due to citalopram and venlafaxine.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are often used to treat depression in the elderly due to their low incidence of side effects. All five of the SSRIs currently available and venlafaxine have been associated with hyponatremia. CASE REPORT: This article describes the case of an 87-year-old man with depression who presented with hyponatremia after starting treatment with citalopram. After excluding other common causes of hyponatremia, a diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was confirmed. Sodium levels returned to the normal range following discontinuation of citalopram. Subsequently, due to the persistence of depression, treatment with venlafaxine was initiated. Three weeks later, hyponatremia associated with SIADH was once again diagnosed and venlafaxine was discontinued. The hyponatremia resolved in 2 weeks. DISCUSSION: Both SSRIs and venlafaxine have been associated with SIADH in numerous case reports and retrospective studies. Risk factors for developing hyponatremia with these drugs are advanced age and treatment with other medications. To our knowledge, this is the first case report in which SIADH was associated with two different families of antidepressants in the same patient. CONCLUSION: Physicians should be aware of the risk of hyponatremia when prescribing SSRIs and venlafaxine in elderly patients with multiple drug therapies. Sodium levels should be monitored during treatment.

Aged, 80 and over↗