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At least 1,099 records · Page 61Linked to original sources
PubMed2002

Noradrenaline release-inhibiting receptors on PC12 cells devoid of alpha(2(-)) and CB(1) receptors: similarities to presynaptic imidazoline and edg receptors.

The aim of the present study was to classify release-inhibiting receptors on rat pheochromocytoma PC12 cells. Veratridine-evoked [3H]noradrenaline release from PC12 cells was inhibited by micromolar concentrations of the imidazoline and guanidine derivatives cirazoline, clonidine, aganodine, 1,3-di(2-tolyl)guanidine, BDF6143 and agmatine, and of the cannabinoid receptor agonist WIN55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-yl](1-naphthalenyl)methanone mesylate), but not by noradrenaline. The inhibitory effect of clonidine was antagonized by micromolar concentrations of rauwolscine and SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl]-4-methyl-1H-pyrazole-3-carboxamide). The potencies of the agonists and antagonists were compatible with an action at previously characterized presynaptic imidazoline receptors. 1-Oleoyl-lysophosphatidic acid, but not sphingosine-1-phosphate, produced an inhibition of release that was antagonized by 30 microM rauwolscine, 1 microM SR141716A and 10 microM LY320135 as well as by pretreatment of the cells with 100 microM clonidine for 72 h. Polymerase chain reaction (PCR) experiments on cDNA from PC12 mRNA suggest mRNA expression of lysophospholipid receptors encoded by the genes edg2, edg3, edg5 and edg7, but not of receptors encoded by edg1, edg4, edg6 and edg8, and not of alpha(2A(-))nd CB(1) receptors. In conclusion, PC12 cells are not endowed with alpha(2)-adrenoceptors and CB(1) cannabinoid receptors, but with an inhibitory receptor recognizing imidazolines, guanidines and WIN55,212-2 similar to that on sympathetic nerves. The PCR results and the ability of 1-oleoyl-LPA to mimic these drugs (also with respect to their susceptibility to antagonists) suggest that the release-inhibiting receptor may be an edg-encoded lysophospholipid receptor.

Animals↗
PubMed2000

[Venlafaxine withdrawal syndrome: report of six cases and review of the literature].

INTRODUCTION: Venlafaxine is an antidepressant that selectively inhibits serotonin reuptake and is a norepinephrine inhibitor. Withdrawal syndromes can occur after abrupt drug discontinuation of long-term regimens. EXEGESIS: We report six cases of withdrawal symptoms after venlafaxine discontinuation. CONCLUSION: Physicians must be aware of the frequency, rapidity and potent severity of these withdrawal syndromes.

Adult↗
PubMed2002

Venlafaxine versus stimulant therapy in patients with dual diagnosis ADD and depression.

BACKGROUND: Adult attention-deficit disorder (ADD) may either present as chronic depression or be comorbid with major depressive disorder (MDD). The present study examined treatment outcome with antidepressants and/or stimulants in adults with ADD who initially presented with a diagnosis of MDD. METHOD: Seventeen patients with comorbid MDD and ADD were identified: 65% had a history of hyperactivity in childhood, and 41% had a history of treatment nonresponse to two or more antidepressants. Retrospective analysis was performed with patients who received one of three treatments: (i) venlafaxine, bupropion, or tricyclic antidepressant (TCA) monotherapy; (ii) stimulant monotherapy; or (iii) stimulant plus antidepressant therapy. Outcome was based upon change in both MDD and ADD symptoms. RESULTS: Venlafaxine-treated patients (80%) versus patients taking stimulant therapy alone (33%) had at least a moderate reduction in both MDD and ADD symptoms (chi2=2.40, Fisher exact P=.13). Similarly, 88% of patients on stimulants plus antidepressant therapy also showed a reduction in both MDD and ADD symptoms (versus stimulant monotherapy) (chi2 = 7.22, Fisher exact P=.018). There was no difference in response rates between venlafaxine monotherapy and combination stimulant plus antidepressant therapy (chi2=0.13, Fisher exact p=ns). CONCLUSION: Although preliminary in nature, these data suggest that venlafaxine monotherapy may have similar efficacy to a treatment with a combination of stimulant plus antidepressant therapy, and superior to stimulant therapy alone, in patients with comorbid MDD and ADD. Controlled, prospective trials with larger patient samples will be needed to confirm these preliminary observations.

Adult↗
PubMed2002

Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors.

INTRODUCTION: Some studies suggest that venlafaxine, due to its pharmacodynamic characteristics, could be an effective drug in depression, resistant to other antidepressive agents. This investigation explores the efficacy and tolerability of venlafaxine in major depression, resistant to a selective serotonin reuptake inhibitor (SSRI). METHODS: A multicenter naturalistic study was performed during 6 months and included those patients diagnosed of major depression according to the criteria of DSM-IV who had a minimum score of 18 on the Hamilton Depression Rating Scale (HAM-D) and who had not responded to previous treatment with a SSRI at therapeutic doses for a minimum of 4 weeks. The assessment of efficacy was performed with the HAM-D scale, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A) and the Global Clinical Impression (GCI). Tolerability was evaluated by recording the adverse reactions and with the GCI score on overall drug tolerability. RESULTS: A total of 69 patients, of which 59 were evaluable for efficacy (they had fulfilled at least 4 weeks of treatment), were included. About 81% of all of them obtained a reduction of at least 50% in the HAM-D, 74% were considered as "quite improved" or "very improved" in the GCI and 69% met both criteria. The mean dose of venlafaxine used was 170.4 (S.D.=43.8) mg. Of the 21 patients who did not complete the 6 months of treatment, 3 were due to lack of efficacy, 6 due to adverse effects and 12 for other reasons. About 89.2% of side effects were considered as mild or moderate. CONCLUSION: The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to SSRI treatment.

Adult↗
PubMed2003

Selective serotonin reuptake inhibitors combined with venlafaxine in depressed patients who had partial response to venlafaxine: four cases.

One third of depressive patients show partial or no response to antidepressant treatment. With partial or nonresponders, treatment strategies are as follows: switching to another antidepressant, augmenting with other psychotropic agents, or combining antidepressants. There are no data in the literature about the positive effect of combining venlafaxine with selective serotonin reuptake inhibitors (SSRIs). In this report, the presented cases had been on at least two different classes of antidepressant medication (or combination of antidepressants) for an adequate time and dose. They showed only a partial response to high dose of venlafaxine but improved after the addition of an SSRI (sertraline, citalopram, or paroxetine) to venlafaxine. The combination treatment was well tolerated in all of the cases.

Adult↗
PubMed2002

Possible role of mast cells in cineole-induced scratching behavior in mice.

We examined the scratch (itch) inducing effect of 1,8-cineole (cineole), a monoterpene oxide present in many plant essential oils and the possible role of mast cells in the response. Subcutaneous injection of cineole (10, 20 and 40 microl/site) or the mast cell degranulating agent, compound 48/80 (25, 50 and 100 microg/site) into the rostral back of mice induced a scratching behavior. This response of cineole as well as that of 48/80 was markedly suppressed in mice subjected to mast cell desensitization by repeated injections of 48/80. The cineole-induced scratching was also significantly diminished in animals pretreated with diphenhydramine, the histamine H1-receptor antagonist or cyproheptadine, the dual histamine/serotonin-receptor antagonist. Furthermore, the scratch-inducing effect of cineole was greatly reduced in mice that received the opioid antagonist naloxone or the selective adenosine A1-receptor agonist, N6-cyclopentyladenosine (CPA), but not the more selective adenosine A2-receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA). The data suggest a likely role for mast cells in cineole-induced scratching behavior of mice, possibly involving adenosinergic and opioidergic mechanisms.

Adenosine↗
PubMed2002

Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?

Human variability in the kinetics of CYP2D6 substrates has been quantified using a database of compounds metabolised extensively (>60%) by this polymorphic enzyme. Published pharmacokinetic studies (after oral and intravenous dosing) in non-phenotyped healthy adults, and phenotyped extensive (EMs), intermediate or slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve) and primarily to acute exposure (peak concentration). Similar analyses were performed with the available data for subgroups of the population (age, ethnicity and disease). Interindividual differences in kinetics for markers of oral exposure were large for non-phenotyped individuals and for EMs (coefficients of variation were 67-71% for clearances and 54-63% for C(max)), whereas the intravenous data indicated a lower variability (34-38%). Comparisons between EMs, SEMs and PMs revealed an increase in oral internal dose for SEMs and PMs (ratio compared to EMs=3 and 9-12, respectively) associated with lower variability than that for non-phenotyped individuals (coefficients of variation were 32-38% and 30% for SEMs and PMs, respectively). In relation to the uncertainty factors used for risk assessment, most subgroups would not be covered by the kinetic default of 3.16. CYP2D6-related factors necessary to cover 95-99% of each subpopulation ranged from 2.7 to 4.1 in non-phenotyped healthy adults and EMs to 15-18 in PMs and 22-45 in children. An exponential relationship (R(2)=0.8) was found between the extent of CYP2D6 metabolism and the uncertainty factors. The extent of CYP2D6 involvement in the metabolism of a substrate is critical in the estimation of the CYP2D6-related factor. The 3.16 kinetic default factor would cover PMs for substrates for which CYP2D6 was responsible for up to 25% of the metabolism in EMs.

Adult↗
PubMed1997

Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors, venlafaxine and paroxetine.

We report on 2 patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) which developed a few weeks after they had started treatment with venlafaxine and paroxetine, respectively. Due to the temporal relationship and the exclusion of other potential causes, a causal relationship between the use of the antidepressants and SIADH seems likely. Diagnostic criteria for SIADH and the role of drugs, especially serotonin re-uptake inhibitors, are discussed.

Aged↗
PubMed1999

In vitro inhibition of liver monooxygenases by beta-ionone, 1,8-cineole, (-)-menthol and terpineol.

The present study was undertaken to investigate the inhibitory effects of beta-ionone, (-)-menthol, 1,8-cineole and alpha-terpineol on liver microsomal enzymes involved in the biotransformation of xenobiotic substances. The effects of beta-ionone and the foregoing monoterpenoid compounds on the activity of pentoxyresorufin-O-depentilase (PROD), a selective marker for CYP2B1, were determined in a pool of liver microsomes prepared from phenobarbital-treated rats. On the other hand, the inhibitory effects of these substances on the activities of ethoxyresorufin-O-deethylase (EROD), a marker for CYP1A1, and methoxyresorufin-O-demethylase (MROD), a marker for CYP1A2, were investigated in a pool of hepatic microsomes from beta-naphthoflavone-treated rats. Beta-ionone caused a concentration-related reduction of PROD activity with an IC50 value as low as 0.03 microM. The analysis of alterations produced by beta-ionone on PROD kinetic parameters (Lineweaver-Burk double-reciprocal plot) suggested that inhibition is non-competitive (Ki = 89.9 nM). Although being less potent than beta-ionone, 1,8-cineole (IC50 = 4.7 microM), (-)-menthol (IC50 = 10.6 microM) and terpineol (IC50 = 14.8 microM) also proved to be in vitro inhibitors of PROD reaction. Results also revealed that beta-ionone was a weak inhibitor of EROD (IC50 >100 microM) and MROD (IC50 >200 microM). Neither 1,8-cineole nor terpineol--tested in concentrations up to 150 microM--caused any decrease of EROD activity while (-)-menthol, at a concentration as high as 160 microM, produced only a slight reduction of the reaction rate. Terpineol (up to 150 microM) did not induce any reduction of MROD activity while 1,8-cineole (IC50 >300 microM) and (-)-menthol (IC50 >300 microM) caused only slight decreases of the reaction rate. The potent inhibitory effects on CYP2B1 suggest that beta-ionone, and the other monoterpenoids tested, may interfere with the metabolism of xenobiotics which are substrates for this isoenzyme.

Animals↗
PubMed2000

CP 55,940 protects against ischemia-induced electroencephalographic flattening and hyperlocomotion in Mongolian gerbils.

The effect of CP 55,940, on electroencephalographic (EEG) spectral power decrease and hyperlocomotion induced by transient global ischemia in gerbils, was investigated. Animals were treated with CP 55,940 (4 mg/kg intraperitoneal (i.p.)) 5 min after bilateral carotid occlusion or SR 141716A (3 mg/kg i.p.) 5 min before or with both. Mean total and relative spectral power was evaluated for 1 h before (basal) and 1 and 24 h, 3 and 7 days after ischemia. Spontaneous locomotor activity was evaluated at the same times. CP 55,940 antagonized the reduction in mean total spectral power and the hyperlocomotion induced by ischemia, in comparison with vehicle group, starting from 24 h and lasting 7 days (P<0.001). Pretreatment with SR 141716A completely blocked the neuroprotective effect of CP 55,940. These findings suggest a potential therapeutic role of cannabinoids in cerebral ischemia.

Analgesics↗
PubMed2001

Short-term administration of fluoxetine and venlafaxine decreases corticosteroid receptor mRNA expression in the rat hippocampus.

Chronic treatment with antidepressant drugs (2 weeks or longer) increases corticosteroid receptor mRNA expression in the hippocampus and reduces hypothalamic-pituitary-adrenal axis activity in parallel with improving mood and neuroendocrine function. Earlier effects are less well documented. We examined the effects of short term (9 days) treatment with fluoxetine (10 mg/kg) and venlafaxine (10 mg/kg) on hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression and spatial memory in adult rats. In situ hybridization histochemistry showed that the antidepressants decreased MR mRNA expression in all hippocampal subregions (e.g. 45% decrease in CA1 with venlafaxine, P<0.001), while GR mRNA expression was selectively reduced in the CA3 subregion. There was a trend for decreased plasma corticosterone levels following fluoxetine (50% fall, P=0.07) and venlafaxine (30% fall, P=0.18) but neither antidepressants affected spatial memory in the watermaze. Thus antidepressants can have complex and opposing actions on hippocampal corticosteroid receptor expression depending on the duration of treatment.

Animals↗
PubMed2003

The antihyperalgesic effect of venlafaxine in diabetic rats does not involve the opioid system.

Venlafaxine (VFX) is a structurally novel antidepressant that inhibits reuptake of serotonin and norepinephrine but, unlike tricyclic antidepressants, has few side effects. The present work studies the antihyperalgesic effect of repeated administrations of VFX (five successive injections of 2.5, 5 or 10 mg/kg, s.c., every half-life) in diabetic rats with the paw pressure test and the effect of the opioid receptor antagonist naloxone (1 mg/kg, i.v.) because an opioidergic mechanism is usually considered to be involved in the analgesic effect of antidepressants. VFX induced a significant dose-dependent increase in vocalization thresholds. This effect was not reversed by naloxone. Thus, we demonstrate a clear antinociceptive effect of VFX which, unlike that of most mixed tricyclic antidepressants, does not involve the endogenous opioid system.

Analgesics↗
PubMed1998

Cannabinoid effects in basal ganglia in a rat model of Parkinson's disease.

Cannabinoid receptors in the brain are highly concentrated in the basal ganglia, which is in accordance with their well known effects on motor behavior. In this study, rats with 6-hydroxydopamine lesions of the nigrostriatal pathway were implanted with cannulae in the striatum, globus pallidus and substantia nigra. The effect of unilateral infusion of the potent cannabinoid agonist CP55,940 on turning behavior was studied for each structure. Lesioned animals responded to intrapallidal and intrastriatal administration of the cannabinoid in a manner that was similar to that of unlesioned animals. However, lesioned animals showed greater contralateral turning in response to the cannabinoid infusions in the substantia nigra than unlesioned animals.

Animals↗
PubMed1998

Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment.

In vitro receptor binding and quantitative autoradiography were used to determine whether cannabinoid receptors in rat lumbar spinal cord are localized to the central terminals of nociceptive primary afferents. Rats were treated as neonates with capsaicin to destroy sensory C-fibers. The densities of cannabinoid and mu opioid receptors in the spinal cord of the adult rats were compared with age-matched vehicle controls. Neonatal capsaicin produced a moderate but reliable suppression (16%) of [3H]CP55,940 binding to cannabinoid receptors. By contrast, the binding of [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin (DAMGO) to mu receptors was depleted by approximately 60% in near adjacent sections. These data suggest that only a subpopulation of cannabinoid receptors is situated on the central terminals of primary afferent C-fibers. The present data provide anatomical evidence for a dissociation between cannabinoid and mu opioid modulation of sensory transmission at the level of the primary afferent inputs to the spinal cord.

Analgesics, Opioid↗
PubMed1999

The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms.

The antinociceptive effects of the novel phentylethylamine antidepressant drug venlafaxine and its interaction with various opioid, noradrenaline and serotonin receptor subtypes were evaluated. When mice were tested with a hotplate analgesia meter, venlafaxine induced a dose-dependent antinociceptive effect following i.p. administration with an ED50 of 46.7 mg/kg (20.5; 146.5; 95% CL). Opioid, adrenergic and serotoninergic receptor antagonists were tested for their ability to block venlafaxine antinociception. Venlafaxine-induced antinociception was significantly inhibited by naloxone, nor-BNI and naltrindole but not by beta-FNA or naloxonazine, implying involvement of kappa1- and delta-opioid mechanisms. When adrenergic and serotoninergic antagonists were used, yohimbine (P < 0.005) but not phentolamine or metergoline, decreased antinociception elicited by venlafaxine, implying a clear alpha2- and a minor alpha1-adrenergic mechanism of antinociception. When venlafaxine was administered together with various agonists of the opioid and alpha2- receptor subtypes, it significantly potentiated antinociception mediated by kappa1- kappa3- and delta-opioid receptor subtypes. The alpha2-adrenergic agonist clonidine significantly potentiated venlafaxine-mediated antinociception. Summing up these results, we conclude that the antinociceptive effect of venlafaxine is mainly influenced by the kappa- and delta-opioid receptor subtypes combined with the alpha2-adrenergic receptor. These results suggest a potential use of venlafaxine in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of venlafaxine when prescribed for pain.

Adrenergic Agonists↗
PubMed2001

The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain.

We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3-10 mg kg(-1)), CP-55,940 (0.03-1 mg kg(-1)) and HU-210 (0.001-0.03 mg kg(-1)) were all active in a 'tetrad' of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210 > CP-55,940 > WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg(-1), respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.

Analgesics↗
PubMed2002

'Knock-down' of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice.

Recent studies demonstrate the possible existence of tonic modulatory control of nociceptive input mediated by spinal cannabinoid receptors (CB1). Accordingly, it is predicted that a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists. An antisense oligodeoxynucleotide (ODN) specific to the CB1 receptor was used to 'knock-down' CB1 receptors in the lumbar spinal cord and dorsal root ganglia by the local, repeated intrathecal (i.th.) administration of the ODN. This treatment resulted in a decrease in lumbar spinal CB1 receptor expression accompanied by a decrease in the response thresholds to both innocuous tactile and noxious thermal stimuli. The antinociceptive action of the CB1 agonist, WIN 55,212-2, by i.th. administration was also significantly attenuated after treatment with the antisense ODN. Similar treatment using a mismatch control ODN had no effect on receptor protein or on sensory thresholds. The effects of the antisense ODN treatment on sensory thresholds were fully reversed after discontinuation of the ODN injection. The antisense ODN treated rats also showed a significant increase in lumbar spinal dynorphin A. Acute i.th. injection of MK-801 or an antidynorphin antiserum blocked the antisense ODN-induced tactile and thermal hypersensitivity. These data support the possibility of endogenous inhibitory cannabinoid tone to limit spinal afferent input of thermal and tactile stimuli. Lifting of this inhibitory tone through a 'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input, as reflected by the actions of MK-801 to block tactile and thermal hypersensitivity. The increased spinal dynorphin may act to further promote afferent outflow and abnormal pain because sequestration of spinal dynorphin with antiserum also reverses the manifestations of abnormal pain following knock-down of CB1 receptors.

Analgesics↗