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PubMed2004

Interactions between aqueous Hypericum perforatum extracts and drugs: in vitro studies.

Physico-chemical interactions between drugs and plant extracts can result in the formation of nanoparticles, microparticles and precipitates. The extraction method may have an influence on the components of the plant preparations and the interactions between drugs and plant extracts. In this study the particle formation in different drug-containing preparations of Hypericum perforatum L. was compared. The formation of nanoparticles was investigated by PCS and scanning electron microscopy. Precipitates were separated from nanoparticles by centrifugation or filtration. The particle formation in drug-containing infusions and reconstituted methanolic extracts of Hypericum perforatum L. was different. In reconstituted dry extracts 21.5% 17alpha-ethinylestradiol and 36.6% levonorgestrel was bound to precipitates, in aqueous Hypericum infusions less than 4% of the hormones was bound. In infusions containing desipramine nanoparticles were formed while the formation of nanoparticles in desipramine-containing reconstituted extracts was negligible. Up to 10% of desipramine was bound to precipitates in reconstituted extracts, but only 4% was associated with the precipitate of infusions. The interactions between extracts of Hypericum perforatum L. and drugs depended on the extraction method. Reconstituted methanolic extracts showed a more intensive binding with oral contraceptives than aqueous infusions.

Chromatography, High Pressure Liquid↗
PubMed1990

Alpha 2-adrenoceptor-mediated autoinhibition of sympathetic transmitter release in guinea-pig vas deferens studied by intracellular and focal extracellular recording of junction potentials and currents.

Excitatory junction potentials (e.j.ps; intracellular electrodes) and excitatory junction currents (e.j.cs; extracellular electrodes) elicited by stimulation (20 pulses at 1 Hz every minute) of the hypogastric nerve trunk were recorded from guinea-pig isolated vas deferens. Intracellular recording. At a variety of stimulation intensities, bath-applied yohimbine (0.1-1 mumol/l) did not change the first one to three e.j.ps in a train but increased the amplitude of subsequent e.j.ps. The effect of yohimbine was abolished in tissues from reserpine-pretreated guinea pigs. Bath-applied desipramine (0.1 mumol/l) diminished the amplitude of all but the first one to three e.j.ps in a train.--Extracellular recording. Yohimbine (0.1-1 mumol/l), when applied locally through the recording suction electrode, increased the number of e.j.cs per given number of stimuli, i.e., enhanced the probability of occurrence of e.j.cs. When desipramine (0.1 mumol/l) was present both in the bath and in the recording electrode, the probability of the occurrence of e.j.cs was decreased. In the presence of desipramine, yohimbine (0.1-1 mumol/l) increased the number of e.j.cs even more markedly. Neither the nerve terminal impulse nor the number of spontaneous e.j.cs was changed by yohimbine. A mixture of tetraethylammonium (2 mmol/l) and 4-aminopyridine (0.2 mmol/l), when applied locally, both increased the number of e.j.cs and changed markedly the shape of the nerve terminal impulse.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

The functional role of the noradrenergic neurons in the thermoregulatory circuits in mice.

Intracerebroventricular (i.c.v.) treatment of mice with 6-hydroxydopamine (6-OHDA; 20--50 micrograms per mouse), which depletes brain noradrenaline (NA) and DA, completely prevents or significantly diminishes the hypothermic effect of various classes of drugs: dopaminomimetics--apomorphine (0.5--10 mg/kg), piribedil (40--100 mg/kg), bromocriptine (3 to 10 mg/kg), CM 29-712 (2--10 mg/kg), d, l-amphetamine (1--2 mg/kg), and L-DOPA (10--100 mg/kg) in combination with Ro 4-4602 (5--40 mg/kg); cholinomimetics--oxotremorine (0.04--0.05 mg/kg), arecoline (5--10 mg/kg) and pilocarpine (2--3 mg/kg); neuroleptics--chlorpromazine, promazine, perphenazine, chlorprothixene, haloperidol, fluanisone (5--10 mg/kg); central alpha-adrenoblocker aceperone (20--40 mg/kg); inhibitor of tyrosine-hydroxylase alpha-methyltyrosine (200--300 mg/kg); inhibitor of dopamine-beta-hydroxylase--disulfiram (150--250 mg/kg) and FLA-63 (15--25 mg/kg). This antihypothermic effect was demonstrated up to 3 months after administration of 6-OHDA for DA-mimetics and neuroleptics and up to 3 weeks for cholinomimetics. The hypothermic effect of presumable GABA-mimetics Phenybut (100--150 mg/kg) and Lioresal (10--25 mg/kg) was enhanced by a prior 6-OHDA treatment. Pretreatment of mice with desipramine (25 to 30 mg/kg i.p.), protriptyline (20 mg/kg) or AW 15(1)1129 (15--20 mg/kg) 20--45 min before 6-OHDA administration protects the central NA-ergic neurons from a destructive effect of 6-OHDA and partially or completely counteracts the antihypothermic as well as prohypothermic (in the case of GABA-mimetics) effect of 6-OHDA. In rats desipramine counteracted antihypothermic effect of 6-OHDA in the case of piribedil, but not of apomorphine. Intracerebroventricular treatment of mice with a low (15 microgram) dose of 5, 6-dihydroxytryptamine (5, 6-DHT) enhanced the hypothermic effects of DA-mimetics; higher doses of 5, 6-DHT (26 and 30 micrograms) and 5, 7-DHT (40 and 46 micrograms) diminished the hypothermic effects; the antihypothermic effect of 6-OHDA was stronger than that of equimolar doses of 5, 6- or 5,7-DHT; desipramine pretreatment counteracted antihypothermic effects of 5, 6-DHT and 5, 7-DHT as well as depletion of brain NA they produce. The data presented reveal the key position for NA-ergic neurons in a temperature regulation and, particularly, in effects of various drugs on body temperature in mice. The tentative fragment of the neuronal thermoregulatory circuit is proposed in attempt to account for the presented an other known data concerning drug action (and interactions) on core temperature in mice.

Animals↗
PubMed1991

Biochemical evidence of sympathetic denervation of the heart in pure autonomic failure.

Primary autonomic failure is a heterogenous group of diseases with evidence for lesions in both the central and peripheral elements of the autonomic nervous system. We determined the extent of peripheral sympathetic dysfunction in six patients with primary autonomic failure without clinical evidence of central nervous system involvement (pure autonomic failure) using biochemical methods for studying regional noradrenaline spillover and removal. The results were compared with those from 14 age-matched normal subjects, seven of whom were studied before and after pharmacological neuronal uptake-blockade with desipramine. Total, cardiac and renal noradrenaline spillover to plasma were 78%, 98% and 66% lower respectively in pure autonomic failure than in normal subjects (p less than 0.001). Total noradrenaline plasma clearance was 20% lower in pure autonomic failure (p less than 0.005) than in normal subjects and similar to the level observed in normal subjects following neuronal noradrenaline uptake-blockade with desipramine, mean transcardiac extraction of tritiated noradrenaline was 74% in normal subjects and 20% in pure autonomic failure, identical to the value post-desipramine in normal subjects. Cardiac spillover of the noradrenaline precursor, dihydroxyphenylanine, and the primary intra-neuronal metabolite dihydroxyphenylglycol, were 78% and 94% lower respectively in pure autonomic failure than in normal subjects (p less than 0.001). These data indicate a marked reduction in the apparent release rate and neuronal uptake of noradrenaline in the hearts of patients with pure autonomic failure, and provide biochemical evidence of almost total postganglionic sympathetic denervation in this condition.

Aged↗
PubMed1990

Behavioral evidence implicating dopamine in sensorimotor arousal and norepinephrine in the sedative effects of antidepressant drugs.

The effects of acute and chronic antidepressant treatment on acoustic startle were evaluated in three experiments. Administration of 2.5-10.0 mg/kg desipramine, amitriptyline, and nortriptyline depressed acoustic startle responding after repeated sensory stimulation. In contrast to the tricyclic drugs, the serotonin reuptake inhibitor zimelidine increased acoustic startle, and inhibition of dopamine reuptake following acute nomifensine and bupropion administration did not influence startle reactivity in the doses examined. The response reducing effects of desipramine and amitriptyline persisted following chronic exposure to these drugs, and these findings were discussed in relation to the inhibitory actions of the tricyclics on locus coeruleus neurons. A second major finding in this study was that animals challenged with d-amphetamine during desipramine and amitriptyline withdrawal showed a facilitated startle response. Enhanced startle reactivity to amphetamine was also observed following long-term exposure to iprindole, and a withdrawal hyperactivity of acoustic startle was evident after chronic treatment with amoxapine, bupropion, and nomifensine. These results agree with evidence that repeated administration of antidepressants increases dopamine neurotransmission which modulates sensorimotor arousal.

Acoustic Stimulation↗
PubMed1990

Effects of single and repeated treatment with antidepressants on apomorphine-induced yawning in the rat: the implication of alpha-1 adrenergic mechanisms in the D-2 receptor function.

Acute (10 or 20 mg/kg IP) and subchronic (2 x 5 or 10 mg/kg IP daily for 7 days) effects of desipramine, imipramine, maprotiline, (+)- and (-)-oxaprotiline enantiomers as well as selective 5-HT-uptake inhibitors citalopram and ifoxetine on yawning, induced by low doses of apomorphine, were investigated in the rat. In addition, the effects of alpha-1 receptor agonist adrafinil and antagonist prazosin were also tested. After acute treatment, desipramine, the stereoselective NA-uptake inhibiting (+)-enantiomer of oxaprotiline, and the alpha-1 agonist adrafinil, markedly and significantly suppressed yawning. Prazosin, in contrast, clearly potentiated it. This potentiating effect was abolished by the pretreatment with (+)-oxaprotiline and adrafinil. Other drugs were inactive. After subchronic administration, yawning was antagonized by NA-uptake-inhibiting antidepressants, including imipramine and maprotiline. By comparison to the acute treatment, the inhibitory effects of desipramine and (+)-oxaprotiline were considerably enhanced. Neither selective 5-HT-uptake inhibitors nor (-)-oxaprotiline (levoprotiline) were active. Antidepressants therefore modulate the functional activity of D-2 receptors, activated by low doses of apomorphine, predominantly by the virtue of their noradrenergic enhancing properties. This modulatory effect appears to be mediated by alpha-1 adrenergic receptors.

Adrenergic alpha-Agonists↗
PubMed2004

Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice.

Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions.UFP-101 (10 nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean+/-SEM) from 179+/-11 to 111+/-10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP(-/-) CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP(+/+)) littermates (75+/-11 vs. 144+/-17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (-65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K(+)-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3 microM) fully prevented N/OFQ-induced currents, but was inactive per se. Fluoxetine, desipramine (both 30 mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4 x 100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.

Animals↗
PubMed1999

The pharmacology of impulsive behaviour in rats V: the effects of drugs on responding under a discrimination task using unreliable visual stimuli.

Impulsivity is widely considered to be multifactorial. One factor, frequently termed "reflection-impulsivity", refers to the need to give time to information analysis and reflection before making a response. In most reaction time tasks employed for non-human subjects, responding is expected immediately after a specific stimulus has been presented. In the present experiment, the need to wait before responding was made explicit by using a signal which increased in predictive value the longer the subject (a rat) waited before responding. First, the rats learned that a light signal indicated the availability of a food reinforcer if one of two levers was pressed. In the test procedure, on each trial, when the light was turned on it was only 50% likely to indicate the "correct" lever. After a brief interval it was turned off and on again, this time with a slightly higher probability (>50%) of indicating the correct lever. Over a period of a few seconds the probability that the light indicated the correct lever increased to almost 100%. Thus a quick response to the light would result in many errors, whereas a slow response could always result in food delivery. Once trained the rats were treated with a series of drugs: haloperidol (0.01-0.1 mg/kg), chlordiazepoxide (1-10mg/kg), ethanol (100-1000 mg/kg), d-amphetamine (0.4-1.2 mg/kg), metergoline (0.3-3.0 mg/kg), imipramine, desipramine and clomipramine (all 1, 3 and 10 mg/kg), as well as being given additional food just prior to testing. Ethanol and clomipramine had no effects on behaviour in the dose range tested. Amphetamine did not affect accuracy and had no effect on reaction time. The other drugs all reduced the number of short reaction times and thereby increased overall accuracy. Additional feeding, chlordiazepoxide and haloperidol also increased selectively the accuracy of responses made with short reaction times. These results can be interpreted by supposing that desipramine and imipramine specifically reduced impulsivity whereas additional feeding, chlordiazepoxide, haloperidol increased the response criterion. The pharmacological specificity of the tricyclics suggests that stimulation principally of the noradrenergic system (via desipramine), but not necessarily the serotonergic (clomipramine) or dopaminergic (amphetamine) improves performance in this procedure.

Animals↗
PubMed1990

Determination of imipramine and seven of its metabolites in human liver microsomes by a high-performance liquid chromatographic method.

The metabolism of the widely used antidepressant drug imipramine is subject to marked interindividual variation. A sensitive and specific reversed-phase high-performance liquid chromatography method for the simultaneous determination of imipramine and seven of its metabolites in human liver microsomal preparations was developed. These metabolites include 10-hydroxy-desipramine, 10-hydroxyimipramine, 2-hydroxydesipramine, 2-hydroxyimipramine, desipramine, didesmethylimipramine, and imipramine N-oxide. The detection limit for imipramine and the metabolites was approximately 20 pmol. At concentrations of 100 and 500 pmol per tube, the reproducibility showed a coefficient of variation less than 10%, except for the 2-hydroxy-desipramine (16%), 2-hydroxyimipramine (15%), and imipramine N-oxide (17%), all three at 100 pmol per tube. Linear standard curves were obtained for all the compounds within a concentration range of 50 to 1000 pmol per tube. This assay will provide a tool to assess the contribution of different enzymes to the formation of imipramine metabolites.

Calibration↗
PubMed1979

Differential binding of antidepressants to noradrenaline and serotonin transport sites in central nerve endings.

Imipramine and mianserin are equipotent inhibitors of noradrenaline (NA) uptake in synaptosomes. However, after in vivo administration, NA uptake was inhibited only in synaptosomes from imipramine-treated rats, suggesting that imipramine, or its metabolite desipramine, binds to the NA carrier in a manner outlasting the preparation of synaptosomes, whereas mianserin is washed away. To evaluate binding to the NA carrier, synaptosomes prelabeled with 3H-NA were pretreated with an antidepressant and the release of 3H-NA was then stimulated with unlabeled NA. Any reduction of release was taken as an indication of binding. Pretreatment with desipramine, but not with imipramine or mianserin, reduced 3H-NA release suggesting that desipramine is responsible for NA uptake inhibition in synaptosomes from imipramine-treated rats. Transformation of tertiary into secondary amines seems to be crucial for binding to the NA carrier, as confirmed by the stronger binding of nortriptyline and chlordesipramine compared to amitryptiline and chlorimipramine, respectively. In contrast, tertiary amines bound more strongly than secondary amines to the serotonin carrier. Adult and 8-day old synaptosomes showed similar binding properties towards imipramine and desipraine.

Animals↗
PubMed1992

Effects of presynaptic alpha-adrenoceptors and neuronal reuptake on noradrenaline overflow and cardiac response.

Using an in situ perfused, innervated rat heart model, we studied the effects of presynaptic alpha-adrenergic and neuronal reuptake inhibition on evoked noradrenaline (NA) overflow and the postsynaptic response by sympathetic ganglion stimulation. NA overflow was significantly increased by neuronal reuptake inhibitors (desipramine and (+)-oxaprotiline) or by alpha-adrenoceptor antagonists (phentolamine and yohimbine), but the inotropic response was augmented only by alpha-antagonists. In the presence of desipramine, nerve stimulation induced a frequency-dependent increase in NA overflow and postsynaptic response, both were enhanced by yohimbine. In the absence of desipramine, however, postsynaptic response was potentiated by yohimbine despite an unchanged (at 2 and 5 Hz) or even reduced NA overflow (at 10 Hz). Thus, this study suggests that NA release and cardiac response are modulated by presynaptic alpha-adrenoceptors, and that the neuronal reuptake modifies the amount of NA overflow but has little effect on the postsynaptic response.

Adrenergic alpha-Antagonists↗
PubMed1993

Benzodiazepines reverse the anti-immobility effect of antidepressants in the forced swimming test in mice.

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.

Analysis of Variance↗
PubMed1988

The effects of long-term administration of antidepressant drugs on intracranial self-stimulation responding in rats.

A discrimination procedure employing a two hole nose-poke technique was used to evaluate the effects of chronic administration of desipramine, amitriptyline, bupropion, nomifensine and zimelidine on intracranial self-stimulation (ICSS). Analysis of ICSS as a function of descending and ascending current presentation revealed that long-term exposure to desipramine significantly facilitated rates of responding from the medial forebrain bundle, and resulted in a shift to the left of the rate-intensity functions. The use of a discrimination paradigm allowed for the assessment of incorrect responses which proved to be a sensitive measure of the motor activating properties associated with electrical brain stimulation. These data indicated that the positive reinforcing effects of desipramine were not accompanied by concomitant increases in motor arousal. No changes in ICSS responding were evident after long-term treatment with amitriptyline, or the atypical antidepressants, bupropion, nomifensine and zimelidine. The implications of these findings were discussed in terms of the effects of these drugs on reward processes and the role of dopamine in the therapeutic efficacy of antidepressant drugs.

Animals↗
PubMed1991

Strain-specific enhancement of splenic T cell mitogenesis and macrophage phagocytosis following peripheral axotomy.

The inbred mouse strains C57BL/6 and DBA/2 were subjected to the selective depletion of peripheral nervous system norepinephrine (NE) by the administration of the neurotoxin 6-hydroxydopamine (6-OH-DA). Measurement of mitogen-induced lymphocyte proliferation following peripheral axotomy with 6-OH-DA revealed that significant enhancement (up to 200% of control values) of T, but not B, cell proliferative responses occurred in DBA/2, while no effect was observed in C57BL/6. Enhancement (up to 196% of control values) of luminol-enhanced chemiluminescence resulting from the phagocytosis of opsonized zymosan was also observed following 6-OH-DA treatment in DBA/2, but not C57BL/6. This strain-specific enhancement of immune responses occurred even though the administration of 6-OH-DA resulted in a similar depletion of splenic NE content (greater than 97% reduction of control values) in both strains as determined by high-pressure liquid chromatography-electrochemical detection. Blockage of the neurotoxic effects of 6-OH-DA was achieved by the use of the catecholamine uptake blocker desipramine-HCl. Administration of desipramine prior to 6-OH-DA blocked the reduction of splenic NE content and abrogated the enhancement of mitogen-induced T cell proliferation. The enhancement of phagocytosis by 6-OH-DA was not, however, altered by the prior administration of desipramine.

Animals↗
PubMed1988

Effects of antidepressants on monoamine transporters.

1. Using [3H]antidepressants, high affinity binding sites associated with the neuronal transporter for serotonin, noradrenaline, dopamine and adrenaline have been identified. 2. The association of high affinity [3H]imipramine binding with the serotonin transporter in brain and platelets is well established. Although the exact relationship between the [3H]imipramine recognition site and the serotonin transporter remains to be elucidated, it appears that the [3H]imipramine labelled component of the serotonin transporter represents a novel receptor that functions to modulate serotonin uptake. 3. Most data available to date support the hypothesis that [3H]imipramine binding to platelet represents a biological marker in depression. The majority of studies indicate that the Bmax of platelet [3H]imipramine binding is lower in depressed, untreated patients than in the control population and that this finding is relatively specific to depression. 4. Among the [3H]antidepressant binding sites associated with the other monoaminergic transporters, the recent identification of [3H]desipramine binding to the neuronal transporter for adrenaline offers novel perspectives. Thus, given the high affinity for [3H]desipramine binding to the adrenaline transporter in the frog heart for not only desipramine but also imipramine and the atypical antidepressants mianserin and iprindol, it is possible that an interaction with the adrenaline transporter is of significance to the clinical effects of antidepressant drugs.

Anti-Anxiety Agents↗
PubMed1989

Blockade of tolerance to morphine analgesia by cocaine.

Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system.

Analgesics↗
PubMed1992

Antinociceptive effects of acute and 'chronic' injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats.

The tricyclic antidepressant drugs (TCAs) are commonly used in the treatment of chronic, especially neuropathic, pain. We evaluated their possible effect on a new model of neuropathic pain-related behaviour induced by ligatures tied loosely around the common sciatic nerve. The effects of 3 TCAs with different monoaminergic spectra (clomipramine, amitriptyline and desipramine) were assessed 2 weeks after surgery, the time of the maximum hyperalgesia, on a 'phasic' test (vocalization threshold to paw pressure) and on a 'tonic' test (score of the spontaneous pain-related behaviour). TCAs were acutely (0.5 and 2 mg/kg, i.v.) and 'chronically' injected (7 injections, once every half-life of the drug: 0.75 and 1.5 mg/kg, s.c., for clomipramine and 1.5 and 3 mg/kg, s.c., for amitriptyline and desipramine). Acutely injected clomipramine and amitriptyline (0.5 mg/kg, i.v.) and desipramine (2 mg/kg, i.v.) showed an antinociceptive naloxone-reversible effect, assessed by an increase in the vocalization threshold to the paw pressure test and, for amitriptyline, by a decrease in tonic pain scores. Chronically injected TCAs induced a significant and progressive increase in the vocalization threshold with a time course parallel to that of their suspected plasma or nerve tissue levels: (i) a regular increase of scores for the first 3-4 injections, (ii) then a plateau until the last injection, and (iii) a progressive decrease with a dose-dependent duration of the effect, longer than that obtained with a corresponding acute dose. This study showed that in this new model of mononeuropathy, acutely and chronically injected TCAs induce an antinociceptive effect and suggested that their analgesic action could be related to the monoaminergic spectrum of the drug in relation to the opiate systems.

Animals↗
PubMed1995

Evidence for reduction of norepinephrine uptake sites in the failing human heart.

OBJECTIVES: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.

Adult↗