![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by ed_uk on January 14, 2005, at 16:53:22
If you have tried memantine....
What side effects did you experience?
Any unexpected side effects?
Any serious side effects?Ed.
Posted by SLS on January 16, 2005, at 8:57:44
In reply to Memantine (Namenda, Ebixa), posted by ed_uk on January 14, 2005, at 16:53:22
> If you have tried memantine....
>
> What side effects did you experience?
> Any unexpected side effects?
> Any serious side effects?
>
> Ed.At 20mg/day, I don't recall experiencing any side-effects at all. Within a few days of pushing the dosage to 40mg, I felt an abrupt switch into a state of what I could describe as drunkeness or being stoned. It was not at all pleasant. I reduced the dosage back down to 20mg immediately and the effect dissipated. Because no one had yet described such an experience, and that it might pass, I wasn't inclined to continue with it. Maybe I should have. I had received a brief antidepressant effect from memantine a few weeks prior at the 20mg.
Memantine is a drug that I would have no qualms returning to if data becomes available suggesting 40mg is a necessary dosage to treat depression.
- Scott
Posted by emme on January 16, 2005, at 20:39:25
In reply to Re: Memantine (Namenda, Ebixa), posted by SLS on January 16, 2005, at 8:57:44
Scott,
Did the drunkenness you felt at 40 mg have any dissociative aspects to it? Feelings of unreality?
em
> At 20mg/day, I don't recall experiencing any side-effects at all. Within a few days of pushing the dosage to 40mg, I felt an abrupt switch into a state of what I could describe as drunkeness or being stoned. It was not at all pleasant. I reduced the dosage back down to 20mg immediately and the effect dissipated. Because no one had yet described such an experience, and that it might pass, I wasn't inclined to continue with it. Maybe I should have. I had received a brief antidepressant effect from memantine a few weeks prior at the 20mg.
>
> Memantine is a drug that I would have no qualms returning to if data becomes available suggesting 40mg is a necessary dosage to treat depression.
>
>
> - Scott
Posted by SLS on January 17, 2005, at 0:47:23
In reply to Re: Memantine (Namenda, Ebixa) » SLS, posted by emme on January 16, 2005, at 20:39:25
> Did the drunkenness you felt at 40 mg have any dissociative aspects to it? Feelings of unreality?
Hi Emme.I think both of these things were possible. It was a pretty weird state to be in. I really didn't pay that much attention to it, though. I was just concerned that the state would pass, and kept myself distracted by watching TV until it did.
- Scott
Posted by River1924 on January 17, 2005, at 1:56:31
In reply to Re: Memantine (Namenda, Ebixa), posted by SLS on January 17, 2005, at 0:47:23
In a week of taking it at only 5mg, I notice I am calmer. Not sedated, just calmer.
Posted by young chem on January 17, 2006, at 12:49:38
In reply to Re: Memantine (Namenda, Ebixa), posted by River1924 on January 17, 2005, at 1:56:31
Hi All,
Does anyone out there have an HPLC method for the detection of Mentantine (Namenda, Ebixa) in-vitro?Young Chem
Posted by SJW on January 17, 2006, at 18:35:45
In reply to Memantine (Namenda, Ebixa), posted by ed_uk on January 14, 2005, at 16:53:22
> If you have tried memantine....
>
> What side effects did you experience?
> Any unexpected side effects?
> Any serious side effects?
>
> Ed.
Hello,
I'm on day ten of 10mg bid; I feel slightly more relaxed. No side effects yet.steve
Posted by mike99 on January 19, 2006, at 13:36:14
In reply to Re: Memantine (Namenda, Ebixa), posted by SJW on January 17, 2006, at 18:35:45
I am going to talk to my doc about memantine for ADHD, dysthymia. This thread is very interesting. Please keep the updates coming. Also any info on why you're taking it would be great also :)
Posted by JackD on February 22, 2006, at 23:23:02
In reply to Please keep the memantine updates coming!, posted by mike99 on January 19, 2006, at 13:36:14
Pharmacological challenges to the endogenous opioid system in affective illness.Cohen MR, Pickar D.
The discovery of an endogenous opioid system has been rapidly followed by animal studies suggesting its importance in neuroendocrine regulation and behavior. Abnormalities of these functions in affective illness suggest that evaluation of behavioral and hormonal responses following the clinical administration of opiate agonists or antagonists might yield information pertinent to the pathogenesis, diagnosis, and treatment of depression. However, initial double-blind controlled clinical studies have yielded little evidence to support this suggested involvement of the opioid system in affective illness. Acute administration of opiate agonists has sometimes yielded a mild antidepressant response in depression, and naloxone has occasionally been reported beneficial in mania. There is, however, little to suggest that these responses are specific to affective illness. A decreased prolactin response to morphine administration has been reported in depression, but is not direct evidence of opioid system dysfunction in depression since abnormal prolactin responses to other challenges in depression have previously been reported. The endogenous opioid system is actually multiple systems marked by distinct distributions of multiple endogenous opioid peptides and opiate receptor subtypes, as well as varying accessibility to drug administration. Future challenges in depression may rely upon the development of opiate agonists and antagonists with preferential binding to opiate receptor subtypes and preferential distributions to stress particular endogenous opioid systems. Opiate peptide challenges may well be administered intrathecally to overcome the blood-brain barrier. Opiate antagonist challenges will rely upon increasing doses of naloxone, up to 10 mg/kg, in order to increase the range of blocked endogenous opiate systems. Chronic administration of challenges has been a seldom used strategy but may be important in evaluation of the physiology of sensitization and tolerance to pleasure in affective illness.
Publication Types:
· ReviewPMID: 7028803 [PubMed - indexed for MEDLINE]
Endorphins in psychiatry: an overview and a hypothesis.Verebey K, Volavka J, Clouet D.
This article presents an overview of the biochemistry, pharmacology, and physiology of endogenous opioid peptides (endorphins). Clinical psychopharmacology of exogenous opiate agonists and antagonists is reviewed. The evidence presented in the review is compatible with a hypothesis that the level of functional endorphins may be related to psychological events, with a normal level needed for psychological homeostasis. One corollary of this hypothesis is that the level of opioids in the brains of the mentally ill may be disturbed. Therapeutic implications of this hypothesis are considered.
Publication Types:
· Clinical TrialAlpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on startle reactivity and brain monoamines.
Lahdesmaki J, Sallinen J, MacDonald E, Scheinin M.
1Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). alpha2-Adrenoceptors (alpha2-ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto- and heteroreceptors. Modulation of acoustic startle and its PPI by the alpha2A-AR subtype was investigated with mice lacking the alpha2A-AR (alpha2A-KO) and their wild-type (WT) controls, without drugs and after administration of the alpha2-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the alpha2-AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. alpha2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of alpha2A-KO mice were depleted by D-amph, revealing the alpha2A-AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated alpha2A-KO mice. alpha2A-AR also appeared to be responsible for the startle-modulating effects of alpha2-AR drugs, since the startle attenuation after the alpha2-AR agonist dexmedetomidine was absent in alpha2A-KO mice, and the alpha2-AR antagonist atipamezole had opposite effects on the startle reflex in alpha2A-KO and WT mice. Copyright 2004 Nature Publishing Group
PMID: 15039766 [PubMed - indexed for MEDLINE]
PMID: 209757 [PubMed - indexed for MEDLINE]
Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence.
Gold MS, Pottash AC, Sweeney D, Martin D, Extein I.
These clinical data may offer some support for the hypothesis that opiates have antidepressant, antimanic, and antipanic effects. This hypothesis should be studied directly by double-blind studies of the effects of exogenous and synthetic endogenous opioid peptides in patients with major depressive illness, panic and anxiety states, schizophrenia, and schizo-affective illness. These clinical data support our studies in nonhuman primates and man which suggest a common LC or NE hyperactivity may underly both drug withdrawal and spontaneous panic states. Whether endorphin deficiency or derangements account for the postulated NE hyperactivity needs additional study and we will discuss our preliminary work later. Failure of endorphins to terminate bursts in LC firing rate and NE release may be responsible for both of these types of panic states. In addicts, this mechanism could exist prior to opiate use, or abuse of potent exogenous endorphinomentic compound may cause an endorphin-abnormality. Both of these possibilities would be compensated by continuous opiate maintenance. Methadone maintenance is a complicated psychiatric, psychological, and social phenomenon. Further studies are necessary to evaluate the role of opiate maintenance in treating or suppressing the emergence of underlying psychopathology. Previous psychiatric hospitalization or treatment for a schizophrenic or affective illness may contraindicate absolutely the use of clonidine or other rapid detoxification methods. These data suggest the possibility of substituting a nonaddicting psychotropic medication for opiates in some patients who are self-medicators. The clinical data support other data suggesting the potential antipsychotic, antidepressant, and antianxiety/antipanic effects of the endogenous opioids, endorphins, and exogenous opioids, endorphins, and exogenous opiates. These and other data suggest potential utility for opioid agonists and endorphin testing in psychiatric treatment and diagnosis.
Publication Types:
· Case ReportsPMID: 6961853 [PubMed - indexed for MEDLINE]
Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat.Beique J, de Montigny C, Blier P, Debonnel G.
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, H3A 1A1, Quebec, Canada.
The effects of long-term administrations of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of the dual 5-HT and NE reuptake inhibitor venlafaxine (delivered s.c. by osmotic minipumps for 21 days) were assessed on the electrically-evoked release of tritium from hippocampal slices preloaded with either [(3)H]5-HT or [(3)H]NE, 48 h after the removal of the minipump. The high, but not the low, dose regimen of venlafaxine enhanced the electrically-evoked release of [(3)H]5-HT while treatment with the high dose of venlafaxine failed to alter the electrically-evoked release of [(3)H]NE. The inhibitory effect of the 5-HT(1B) agonist CP 93,129 on the electrically evoked release of [(3)H]5-HT was unaltered by the low dose regimen of venlafaxine while it was attenuated in rats treated with the high dose of venlafaxine, indicative of a functional desensitization of the terminal 5-HT(1B) autoreceptor. Unexpectedly, neither regimen of venlafaxine altered the inhibitory effect of UK 14,304 on the electrically evoked release of both [(3)H]5-HT and [(3)H]NE, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors were desensitized. Finally, the functions of the 5-HT and NE reuptake process were assessed. None of the treatment regimens altered the basal uptake of [(3)H]5-HT from hippocampal or mesencephalic slices nor that of [(3)H]NE from hippocampal slices. Finally, the enhancing effect of 1 microM of paroxetine in the perfusion medium on the electrical release of [(3)H]5-HT was unaltered in hippocampal slices prepared from rats that had been treated for 21 days with 40 mg/kg/day of venlafaxine. Taken together, these results indicate that, in terms of alteration of the sensitivity of the terminal 5-HT(1B) autoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of long-term administration of venlafaxine are no different than those observed with classical SSRI's.
Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.
Fawcett J, Barkin RL.
Department of Psychiatry, Rush-Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.
Publication Types:
· Review
· Review, TutorialPMID: 10333982 [PubMed - indexed for MEDLINE]
Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release.
Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ.
Institut de Recherches Servier, Psychopharmacology Department, Croissy-sur-Seine, France.
In the present study, a novel and exceptionally sensitive method of high-performance liquid chromatography coupled to coulometric detection, together with concentric dialysis probes, was exploited for an examination of the role of autoreceptors and heteroceptors in the modulation of dopamine, noradrenaline and serotonin levels in single samples of the frontal cortex of freely-moving rats. The selective D3/D2 receptor agonist, CGS 15855A [(+/-)-trans-1,3,4,4a,5,10b-hexahydro-4-propyl-2H-[1]benzopyrano[3 ,4-b]-pyridin-9-ol], and antagonist, raclopride, respectively decreased (-50%) and increased (+60%) levels of dopamine without significantly modifying those of serotonin and noradrenaline. The selective alpha2-adrenergic receptor agonist, dexmedetomidine, markedly decreased noradrenaline levels (-100%) and likewise suppressed those of serotonin and dopamine by -55 and -45%, respectively. This effect was mimicked by the preferential alpha2-adrenergic receptor agonist, guanabenz (-100%, -60% and -50%). Furthermore, the alpha2-adrenergic receptor antagonist, RX 821,002 [2(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline], and the preferential alpha2A-adrenergic receptor antagonist, BRL 44408 [2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidaz ole], both evoked a pronounced elevation in levels of noradrenaline (+212%, +109%) and dopamine (+73%, +85%). In contrast, the preferential alpha(2B/2C)-adrenergic receptor antagonist, prazosin, did not modify noradrenaline and dopamine levels. RX 821,002 and BRL 44408 did not significantly modify levels of serotonin, whereas prazosin decreased these levels markedly (-55%), likely due to its alpha1-adrenergic receptor antagonist properties. The selective serotonin-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), reduced serotonin levels (-65%) and increased those of dopamine and noradrenaline by +100%), and +175%, respectively. The selective serotonin-1A antagonist, WAY 100,635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo- hexanecarboxamide], which had little affect on monoamine levels alone, abolished the influence of 8-OH-DPAT upon serotonin and dopamine levels and significantly attenuated its influence upon noradrenaline levels. Finally, the selective serotonin-1B agonist, GR 46611 [3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamid e], decreased serotonin levels (-49%) and the serotonin-1B antagonist, GR 127,935 [N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide], which did not significantly modify serotonin levels alone, abolished this action of GR 46611. Levels of dopamine and noradrenaline were not affected by GR 46611 or GR 127,935. In conclusion, there is a complex pattern of reciprocal autoreceptor and heteroceptor control of monoamine release in the frontal cortex. Most notably, activation of alpha2-adrenergic receptors inhibits the release of noradrenaline, dopamine and serotonin in each case, while stimulation of serotonin-1A receptors suppresses serotonin, yet facilitates noradrenaline and dopamine release. In addition, dopamine D2/D3 autoreceptors restrain dopamine release while (terminal-localized) serotonin-1B receptors reduce serotonin release. Control of serotonin release is expressed phasically and that of noradrenaline and dopamine release tonically.
PMID: 9539213 [PubMed - indexed for MEDLINE]
The pharmacologic profile of mirtazapine.
de Boer T.
Neuropharmacology Department, Scientific Development Group, N.V. Organon, The Netherlands.
Mirtazapine (Org 3770) is a new antidepressant with prominent alpha 2-adrenergic auto- and heteroreceptor antagonistic properties and no effect on monoamine reuptake. Mirtazapine increases noradrenergic and serotonergic transmission, as measured by on-line microdialysis and by enhancement of noradrenergic locus ceruleus and serotonergic raphe nucleus cell firing. Mirtazapine has a low affinity for 5-HT1A receptors but shows 5-HT1A-agonistic-like effects in a conditioned taste aversion test and by causing lower lip retraction in rats. Mirtazapine therefore causes enhancement of 5-HT1-mediated transmission. Other studies show that both 5-HT2 and 5-HT3 receptors are specifically blocked. The enhancement of both noradrenergic and serotonergic transmission probably underlies the therapeutic activity of mirtazapine. Blockade of 5-HT2 and 5-HT3 receptors possibly prevents side effects associated with nonselective 5-HT activation and may also contribute to the anxiolytic and sleep-improving properties of mirtazapine.
Publication Types:
· Review
· Review, TutorialPMID: 8636062 [PubMed - indexed for MEDLINE]
Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine.Haddjeri N, Blier P, de Montigny C.
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Mirtazapine (Org 3770, Remeron) is a new alpha2-adrenoceptor antagonist which is an effective antidepressant drug. An in vivo electrophysiological paradigm in the rat was used to assess the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha2-adrenoceptors and to determine whether this drug can modulate serotonin (5-HT) neurotransmission. The acute administration of mirtazapine produced a rapid increase in both noradrenaline and 5-HT neurotransmission by blocking both alpha2-adrenergic auto- and heteroreceptors, resulting in an enhanced tonic activation of postsynaptic 5-HT receptors. Long-term administration showed that this tonic activation of postsynaptic 5-HT receptors was most likely enhanced after such a treatment, as a result of a sustained increase in 5-HT neuronal activity in the presence of and due to inactivated alpha2-adrenergic heteroreceptors.
Publication Types:
· Review
· Review, TutorialPMID: 8930005 [PubMed - indexed for MEDLINE]
Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist, (+)-S 14297: II. Both D2 and "silent" D3 autoreceptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways.Gobert A, Rivet JM, Audinot V, Cistarelli L, Spedding M, Vian J, Peglion JL, Millan MJ.
Department of Psychopharmacology, Centre de Recherches de Croissy, Paris, France.
The preferential dopamine (DA) D3 versus D2 receptor agonist, (+)-7-OH-DPAT, dose-dependently decreased DA synthesis in the nucleus accumbens, olfactory tubercles, striatum and frontal cortex. This action was potently mimicked by several other high-potency D3 agonists: CGS 15855A, (-)-quinpirole, quinelorane and N-0434. In contrast, piribedil, which displays a mild preference for D2 sites, was less active. Across eight agonists, potency for inhibition of DA synthesis correlated more potently to affinity at D3 (r = .82 +/- .04) than D2 receptors (r = .60 +/- .06, P < .05). Correlations were also marked to potency for induction of a further D3-mediated response, hypothermia (r = .93 +/- .02). The novel and selective D3 versus D2 antagonist, (+/-)-S 11556, attenuated the action of (+)-7-OH-DPAT in each structure. This action was shared by its active (+)-eutomer, (+)-S 14297, whereas its inactive (-)-distomer, (-)-S 17777, was ineffective. (+)-S 14297 similarly attenuated the inhibitory action of CGS 15855A and (-)-quinpirole upon DA synthesis, whereas it failed to modify inhibition of striatal DA synthesis by the alpha 2-adrenergic receptor agonist, clonidine. As compared with the D2/D3 receptor antagonist, haloperidol, neither (+/-)-S 11566 nor (+)-S 14297 modified DA turnover upon administration alone. Furthermore, across (nine) antagonists, potency in facilitating DA synthesis more powerfully correlated to affinity at D2 (r = .94 +/- .01) than D3 (r = .73 +/- .01) sites (P < .01). Correlations were also marked to potency for induction of catalepsy (r = .91 +/- .01) and prolactin secretion (r = .89 +/- .01) but not for antagonism of (+)-7-OH-DPAT-induced hypothermia (r = .60 +/- .01). In freely moving rats, (+)-7-OH-DPAT dose-dependently reduced dialysate concentrations of DA in the nucleus accumbens and contralateral striatum: this action was potently mimicked by CGS 15855A, but only weakly so by piribedil. (+)-S 14297 markedly attenuated the action of (+)-7-OH-DPAT, whereas (-)-S 17777 was inactive. In contrast, haloperidol completely blocked the action of (+)-7-OH-DPAT. Finally, in distinction to haloperidol, upon administration alone, (+)-S 14297 did not significantly enhance the release of DA. In conclusion, these data suggest that D3 (auto)receptors control synthesis and release of DA in dopaminergic pathways innervating the limbic system, cortex and striatum.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 7473181 [PubMed - indexed for MEDLINE]
The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission.
de Boer T.
Department of Neuropharmacology, Scientific Development Group, N.V. Organon, The Netherlands.
Mirtazapine is a new antidepressant with a unique mode of action: it preferentially blocks the noradrenergic alpha2-auto- and heteroreceptors held responsible for controlling noradrenaline and serotonin release. In addition, mirtazapine has a low affinity for serotonin (5-HT)1A receptors but potently blocks 5-HT2 and 5-HT3 receptors. It increases serotonergic cell-firing in the dorsal raphe and 5-HT release in the hippocampus as measured by microdialysis. These effects are explained by noradrenergic enhancement of 5-HT cell-firing and blockade of noradrenaline-mediated inhibition of hippocampal 5-HT release. Because mirtazapine blocks 5-HT2 and 5-HT3 receptors, only 5-HT1-mediated transmission is enhanced. The noradrenergic activation and the consequent indirect enhancement of serotonergic transmission most probably underlie the marked therapeutic activity of mirtazapine. The blockade of 5-HT2 and 5-HT3 receptors prevents development of the side effects associated with non-selective 5-HT activation and may contribute to the anxiolytic and sleep-improving properties of this new compound. Therefore mirtazapine can be described as a noradrenergic and specific serotonergic antidepressant (NaSSA).
Publication Types:
· Review
· Review, TutorialPMID: 8930006 [PubMed - indexed for MEDLINE]
Interactions between delta opioid receptors and alpha-adrenoceptors.
Rios C, Gomes I, Devi LA.
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York, USA.
1. Several studies have reported functional interactions between different subtypes of opioid and alpha2A-adrenoceptors in the induction of spinal cord analgesia. The mechanisms underlying this phenomenon are not well characterized. We propose that direct receptor-receptor associations could account for some of the observed functional interactions. In the present study, we examined the presence of delta opioid receptors and alpha2A-adrenoceptors in interacting complexes and the functional implications of such interactions on receptor activity. 2. Using the proximity based bioluminescence resonance energy transfer (BRET) assay, we found that the delta opioid receptors and alpha2A-adrenoceptors are in close enough proximity (< 100 A) in live cells that can foster physical interactions. 3. Using coimmunoprecipitation of differentially epitope-tagged receptors, we found that delta opiate receptors exist in interacting complexes with alpha2A-adrenoceptors in heterologous cells. 4. Finally, using receptor activity mediated neurite outgrowth in Neuro 2A cells as a physiological readout, we found that interactions between delta opiate receptors and alpha2A-adrenoceptors have functional consequences. The expression of alpha2A-adrenoceptors is sufficient to promote delta opiate receptor-mediated neurite outgrowth, suggesting that the presence of inactive alpha2A-adrenoceptors can enhance delta opiate receptor-mediated signalling. 5. Taken together, these findings suggest that modulation of receptor function as a result of physical associations between delta opiate receptors and alpha2A-adrenoceptors may account for the observed synergy between opiate and adrenergic agonists in spinal analgesia.
Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain.Haddjeri N, Blier P, de Montigny C.
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Mirtazapine ([(+/-)-MIR], Remeron, ORG 3770) is an alpha-2 adrenoceptor antagonist endowed with antidepressant activity in humans. The aim of the present study was to assess the effects of (+/-)-MIR and of its (-)enantiomer [(-)-MIR] on pre- and postsynaptic alpha-2 adrenoceptors and to characterize their putative modulation of 5-HT neurotransmission. (+/-)-MIR (25 micrograms/kg i.v.) enhanced the effectiveness of the electrical stimulation of the ascending 5-HT pathway by blocking both alpha-2 adrenergic auto- and heteroreceptors. (-)-MIR (10 micrograms/kg i.v.) enhanced the effectiveness of these stimulations due to a selective action of (-)-MIR on the alpha-2 heteroreceptors located on 5-HT terminals. Both (+/-)- and (-)-MIR (500 micrograms/kg i.v.) blocked the suppressant effect of microiontophoretically applied norepinephrine (NE) on the firing activity of CA3 dorsal hippocampus pyramidal neurons, indicating their antagonistic effects on postsynaptic alpha-2 adrenoceptors. (+/-)-MIR (10- 250 micrograms/kg i.v.) enhanced dose-dependently the firing activity of the 5-HT neurons in naive rats, but not in 6-hydroxydopamine-pretreated rats. (+/-)-MIR also significantly increased the firing activity of locus ceruleus NE neurons. In contrast, (-)-MIR (10-250 micrograms/kg i.v.) failed to change the firing rate of dorsal raphe 5-HT neurons. In conclusion, these results suggest that both (+/-)-MIR and (-)-MIR are antagonists at postsynaptic alpha-2 adrenergic receptors, that (+/-)-MIR is an antagonist of somatodendritic as well as terminal alpha-2 adrenergic auto- and heteroreceptors, whereas (-)-MIR is a selective antagonist at alpha-2 adrenergic heteroreceptors. Furthermore, the inhibitory effect of (-)-MIR on locus ceruleus NE neurons appears to be mediated via 5-HT neurons because it is abolished by a 5,7-dihydroxytryptamine pretreatment.
PMID: 8627568 [PubMed - indexed for MEDLINE]
The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice.
Sahraei H, Ghazzaghi H, Zarrindast MR, Ghoshooni H, Sepehri H, Haeri-Rohan A.
Department of Physiology and Biophysics, Baghyatallah (a.s.) University of Medical Sciences and Behavioral Science Research Center, Tehran, Iran.
It has been shown that the alpha-adrenergic system is involved in some effects of opioids, including analgesia and reward. Gender differences also exist between males and females in response to alpha-adrenergic agents. This study was designed to determine the effects of alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) in female mice. The experiments showed that subcutaneous injections of morphine (0.5-8 mg/kg) induced CPP in a dose-dependent manner in mice. Intrapritoneal administration of the alpha-1-adrenoceptor agonist, phenylephrine (0.03, 0.1 and 0.3 mg/kg), and alpha-2 adrenoceptor agonist, clonidine (0.0001, 0.0005 and 0.001 mg/kg), as well as alpha-1-adrenoceptor antagonist, prazosin (0.01, 0.05 and 0.1 mg/kg) or alpha-2 adrenoceptor antagonist, yohimbine (0.005, 0.01 and 0.05 mg/kg) did not induce motivational effects and also did not alter locomotor activity in the animals. In the second set of experiments, the drugs were used before testing on Day 5, to test their effects on the expression of morphine-induced CPP. Intrapritoneal administration of phenylephrine and clonidine decreased the expression of morphine-induced CPP. In contrast, after application of prazosin or yohimbine, the expression of morphine-induced CPP was increased. Administration of lower (0.03 mg/kg) and higher doses of phenylephrine (0.1 and 0.3 mg/kg) during acquisition of morphine CPP decreased and increased the morphine CPP, respectively. Similarly, the administration of prazosin and clonidine decreased while yohimbine increased the morphine CPP. It may be concluded that alpha-adrenoceptor mechanism(s) influence morphine-induced CPP in female mice.
PMID: 15159143 [PubMed - indexed for MEDLINE]
Loss of amitriptyline analgesia in alpha 2A-adrenoceptor deficient mice.
Ozdogan UK, Lahdesmaki J, Mansikka H, Scheinin M.
MediCity Research Laboratory, Department of Pharmacology and Clinical Pharmacology, University of Turku, Tykistokatu 6A, FIN-20520 Turku, Finland.
Tricyclic antidepressants have analgesic and sedative effects in addition to their antidepressive properties. We tested the acute analgesic and locomotor inhibitory effects of the tricyclic antidepressant amitriptyline and the alpha(2)-adrenoceptor agonist clonidine in wild-type control and in alpha(2A)-adrenoceptor knockout mice in hot-plate and tail-flick tests. Amitriptyline-induced analgesia was lost in alpha(2A)-adrenoceptor knockout mice. The locomotor inhibitory effect of amitriptyline was reduced, but not fully abolished in alpha(2A)-adrenoceptor knockout mice. Similar results were obtained with clonidine. We conclude that alpha(2A)-adrenoceptors appear to have a significant role in amitriptyline-induced acute analgesia in mice, and that alpha(2A)-adrenoceptors also participate in the sedative effects of amitriptyline
Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue.
Binder W, Mousa SA, Sitte N, Kaiser M, Stein C, Schafer M.
Department of Anesthesiology and Critical Care Medicine, Klinikum Benjamin Franklin, Freie Universitat, Hindenburgdamm 30, D-12200 Berlin, Germany. [email protected]
Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose-dependent antinociception, reversible by alpha(1)-, alpha(2)- and beta(2)-antagonists. alpha(1)-, alpha(2)- and beta(2)-adrenergic receptors were demonstrated on beta-endorphin-containing immune cells and noradrenaline induced adrenergic receptor-specific release of beta-endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by micro - and delta-opioid antagonists as well as by anti-beta-endorphin. Stress-induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron-derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release beta-endorphin, which induces analgesia via activation of peripheral opioid receptors.
PMID: 15245482 [PubMed - indexed for MEDLINE]
Alpha2-adrenergic receptor subtype specificity of intrathecally administered tizanidine used for analgesia for neuropathic pain.Leiphart JW, Dills CV, Levy RM.
Division of Neurosurgery, University of California, Los Angeles, California, USA. [email protected]
OBJECT: Intrathecally administered alpha2-adrenergic receptor subtype-specific antagonists were used to determine which alpha2-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine in a chronic constriction injury (CCI) rat model of neuropathic pain. METHODS: Seven days after CCI and intrathecal catheter surgeries had been performed in Sprague-Dawley rats, baseline neuropathic pain tests including cold-floor ambulation and paw pinch were performed. Either the dimethyl sulfoxide vehicle (seven rats) or one of the antagonists--5, 23, or 46 microg yohimbine (22 rats); 5, 25, 50, or 100 microg prazosin (25 rats); or 5, 45, or 90 microg WB4101 (11 rats)--were intrathecally administered to the animals, followed in 30 minutes by 50 microg intrathecally administered tizanidine. The neuropathic pain tests were repeated 30 minutes later. The resulting profile showed a descending order of antagonist efficacy for yohimbine, prazosin, and WB4101 for the cold-floor ambulation test and for the paw-pinch test of the affected paw. As expected given tizanidine's lack of analgesic effect on the contralateral, normal paw, there were no effects of antagonists on contralateral paw responses. The results of the paw-pinch test on the affected side were compared with binding data cited in the existing literature for the three different alpha2-adrenergic receptor subtypes (alpha2A, alpha2B, and alpha2C) with yohimbine, prazosin, and WB4101. The antagonist response profile for the paw-pinch test of the affected paw most closely approximated the alpha2B receptor binding profile. CONCLUSIONS: The antagonist profile from the current study is most consistent with the theory that the alpha2B-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine on CCI-associated neuropathic pain.
PMID: 15481719 [PubMed - indexed for MEDLINE]
Central monoamines and their role in major depression.Elhwuegi AS.
Department of Pharmacology and Toxicology, Faculty of Pharmacy and Health Sciences, Ajman University of Science and Technology Network, Abu Dhabi Campus, Abu Dhabi, P.O. Box 5102, United Arab Emirates. [email protected]
The role of the monoamines serotonin and noradrenaline in mental illnesses including depression is well recognized. All antidepressant drugs in clinical use increase acutely the availability of these monoamines at the synapse either by inhibiting their neuronal reuptake, inhibiting their intraneuronal metabolism, or increasing their release by blocking the alpha(2) auto- and heteroreceptors on the monoaminergic neuron. This acute increase in the amount of the monoamines at the synapse has been found to induce long-term adaptive changes in the monoamine systems that end up in the desensitization of the inhibitory auto- and heteroreceptors including the presynaptic alpha(2) and 5-HT(1B) receptors and the somatodendritic 5-HT(1A) receptors located in certain brain regions. The desensitization of these inhibitory receptors would result in higher central monoaminergic activity that coincides with the appearance of the therapeutic response. These adaptive changes responsible for the therapeutic effect depend on the availability of the specific monoamine at the synapse, as depletion of the monoamines will either reverse the antidepressant effect or causes a relapse in the state of drug-free depressed patient previously treated with antidepressant drugs. Furthermore, blocking the somatodendritic 5-HT(1A) or nerve terminal alpha(2) receptors proved to increase the response rate in the treatment of major and treatment-resistant depression, providing further support to the assumption that the antidepressant effect results from the long-term adaptive changes in the monoamine auto- and heteroregulatory receptors. On the other hand, the chronic treatment with antidepressants resulted in D(2) receptors supersensitivity in the nucleus accumbens. This supersensitivity might play a role in the mechanisms underlying antidepressant induced mood switch and rapid cycling.
Publication Types:
· ReviewPMID: 15093950 [PubMed - indexed for MEDLINE]
Evidence for functional presynaptic alpha-2 adrenoceptors and their down-regulation in human heart failure.Aggarwal A, Esler MD, Socratous F, Kaye DM.
Cardiovascular Medicine, Alfred Hospital and Baker Medical Research Institute, Melbourne, Victoria, Australia.
OBJECTIVES: The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF). BACKGROUND: Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release. METHODS: Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 microg and 0.48 microg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics. RESULTS: Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004). CONCLUSIONS: Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.
Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties.Cordi AA, Berque-Bestel I, Persigand T, Lacoste JM, Newman-Tancredi A, Audinot V, Millan MJ.
Institut de Recherches Servier, 11, rue des Moulineaux, F-92150 Suresnes, France. [email protected]
Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-naphthalenyl)methyl]-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.
Presynaptic N-methyl-D-aspartate receptor activation inhibits neurotransmitter release through nitric oxide formation in rat hippocampal nerve terminals.Sequeira SM, Malva JO, Carvalho AP, Carvalho CM.
Center for Neuroscience of Coimbra, Department of Zoology, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
In brain synapses, nitric oxide synthase activation is coupled to N-methyl-D-aspartate-mediated calcium entry at postsynaptic densities through regulatory protein complexes, however a presynaptic equivalent to this signaling mechanism has not yet been identified. Novel evidence indicates that N-methyl-D-aspartate glutamate receptors may play a presynaptic role in synaptic plasticity. Thus, we investigated whether ionotropic glutamate receptor activation in isolated nerve terminals regulates neurotransmitter release, through nitric oxide formation. N-Methyl-D-aspartate dose-dependently inhibited the release of glutamate evoked by 4-aminopyridine (IC(50)=155 microM), and this effect was reversed by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphopentanoic acid and by the nitric oxide synthase inhibitor, L-nitroarginine, in synaptosomes isolated from whole hippocampus, CA3 and CA1 areas, but not from the dentate gyrus. In contrast, the 4-aminopyridine-evoked release of glutamate was reduced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate by a nitric oxide-independent mechanism, since it was not blocked by L-nitroarginine, and N-methyl-D-aspartate, but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate, significantly increased cGMP formation. Presynaptic N-methyl-D-aspartate receptors are probably involved since removing extracellular nitric oxide with the scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide did not block the depression of glutamate release by N-methyl-D-aspartate. The mechanism underlying this depression involves the inhibition of synaptic vesicle exocytosis since N-methyl-D-aspartate/nitric oxide inhibited the release of [3H]glutamate and [14C]GABA evoked by hypertonic sucrose. The results also suggest that presynaptic N-methyl-D-aspartate receptors may function as auto- and heteroreceptors.
PMID: 11311981 [PubMed - indexed for MEDLINE]
Pharmacological treatment of neuralgic and neuropathic pain.
McQuay HJ.
Nuffield Department of Anaesthetics, Oxford University, Abingdon.
The current pharmacological management of neuropathic pain with antidepressants, anticonvulsants, drugs with action on the autonomic nervous system, steroids, baclofen and naloxone is reviewed. The underlying clinical theme of relative opioid insensitivity of neuropathic pain is emphasized. Future pharmacological approaches in neuropathic pain are suggested on the basis of the mechanism of action of the current remedies. The problems of clinical trials in this area are discussed.
Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline.Hamon M, Gozlan H, Bourgoin S, Benoliel JJ, Mauborgne A, Taquet H, Cesselin F, Mico JA.
The central mechanism responsible for the potentiation by antidepressant drugs of analgesia induced by morphine, was explored by measuring the levels of various neuropeptides (met-enkephalin, leu-enkephalin, dynorphin, substance P and cholecystokinin-like materials) and the density of delta and mu opioid binding sites in the spinal cord of rats treated for 14 days with amoxapine (10 mg/kg i.p., daily) or amitriptyline (10 mg/kg i.p., daily). Similar measurements were made in the hypothalamus and cerebral cortex for comparison. Chronic treatment with amoxapine or amitriptyline did not affect the levels of dynorphin, substance P and cholecystokinin, but markedly enhanced the levels of leu-enkephalin in the three structures examined. The levels of met-enkephalin were also increased after treatment with amitriptyline but only in the spinal cord and hypothalamus. No changes in opioid receptors were found in the cerebral cortex, but the densities of delta and mu opioid binding sites were increased in the spinal cord, and decreased in the hypothalamus of rats treated with amoxapine or amitriptyline. These changes induced by antidepressants in opioidergic markers at the spinal level might account for the potentiation of the action of morphine in amoxapine- or amitriptyline-treated rats. In addition, the observed alterations in the same markers in the hypothalamus could be associated with changes induced by antidepressants in neuroendocrine regulation.
Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system.Botney M, Fields HL.
Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.
Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain.Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, Rondelli I, Chamiot-Clerc P, Simonato M, Barbieri M.
Research and Development Department, Chiesi Farmaceutici SpA, Parma, Italy. [email protected]
N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.
Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal.Maldonado C, Cauli O, Rodriguez-Arias M, Aguilar MA, Minarro J.
Area de Psicobiologia, Facultad de Psicologia, Universitat de Valencia, Aptdo. 22109, 46071 Valencia, Spain.
Adaptive changes in neural systems due to chronic opiate exposure are related to the neural plasticity phenomenon, NMDA receptors being implicated in these processes, e.g. tolerance, dependence or withdrawal. In this work, we investigated the effect of two non-competitive NMDA antagonists, memantine and MK-801, in motivational (Conditioned Place Aversion paradigm, CPA) and physical aspects of morphine withdrawal. After the induction of morphine dependence, animals in which the CPA was studied, received memantine (5 and 10 mg/kg) or MK-801 (0.3-0.006 mg/kg) either during the acquisition (conditioning) or expression (test) phase of this procedure. Both drugs were capable of inhibiting conditioned aversion when administered in any phase. In a second experiment, the effects of these drugs were evaluated in the intensity of the physical signs of withdrawal, only memantine administration being efficient. In addition to these studies, the intensity of morphine dependence was investigated under the blockade of NMDA receptors, i.e. morphine was co-administered with memantine or MK-801. These animals did not develop CPA and present less intensity in the physical signs of morphine withdrawal. Our results support the idea that NMDA receptors are involved in the behavioural changes and therefore in the neural adaptations produced by repeated morphine administration.
Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval.Belozertseva IV, Dravolina OA, Neznanova ON, Danysz W, Bespalov AY.
Laboratory of Behavioural Pharmacology, Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, 6/8 Leo Tolstoy St., 197089, St. Petersburg, Russia.
The actual time-course of morphine antinociception is shorter than what would be predicted from its elimination kinetics, suggesting the presence of an acute tolerance phenomenon. Since antagonists acting at NMDA subtype of glutamate receptors were repeatedly shown to prolong acute morphine antinociception, acute tolerance may be attributed to hyperactivity of NMDA receptors. The ability of various site-selective NMDA receptor antagonists to affect morphine antinociception (tail-flick test) was assessed in mice 30 and 120 min after acute morphine challenge. Competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene) (SDZ EAA 494; 0.1-1 mg/kg), low-affinity channel blockers 1-amino-3,5-dimethyl adamantane (memantine) (1-10 mg/kg) and 1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride (MRZ 2/579) (1-10 mg/kg), glycine site antagonists 5-nitro-6,7-dichloro-1, 4-dihydro-2,3-quinoxalinedione (ACEA-1021) (5 or 10 mg/kg) and 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaliono(4, 5-b)quinoline-5-oxide choline salt (MRZ 2/576) (1-10 mg/kg) were administered intraperitoneally (i.p.) 15 or 30 min prior to the tail-flick test (i.e., interval between injections of morphine and NMDA receptor antagonist was either 0-15 or 90-105 min). ACEA-1021, MRZ 2/576 and to the lesser extent, memantine and MRZ 2/579 enhanced morphine antinociception when tests were conducted 120 but not 30 min post-morphine. D-CPPene potentiated morphine antinociception irrespective of the interval between morphine administration and the tail-flick test. The results suggest that NMDA receptor antagonists may restore analgesic activity of morphine in acutely tolerant mice.
Non-selective opioid receptor antagonism of the antidepressant-like effect of venlafaxine in the forced swimming test in mice.
Berrocoso E, Rojas-Corrales MO, Mico JA.
Pharmacology and Neuroscience Research Group (PAI-510), Department of Neuroscience (Pharmacology and Psychiatry), Faculty of Medicine, University of Cadiz, Plaza Falla, 9, 11003 Cadiz, Spain.
The opioid system has been implicated in mood disorders as well as in the mechanism of action of antidepressants. Since the opioid component in venlafaxine (VLX) is still a matter of discussion, we investigated the role of opioid receptors in the antidepressant-like effect of VLX in the forced swimming test in mice. The non-selective opiate antagonist naloxone at high dose (2 mg/kg, s.c.) antagonized the effect of VLX. In contrast, beta-funaltrexamine (40 mg/kg, s.c.), which preferentially blocks mu(1)/mu(2) opioid receptors, naloxonazine (35 mg/kg, s.c.), a selective mu(1) opioid antagonist, naltrindole (10 mg/kg, s.c.), a selective delta opioid antagonist, and Nor-binaltorphimine (10 mg/kg, s.c.), which selectively blocks kappa-opioid receptors, were all ineffective. Thus, although apparently mediated by the opioid system, the behavioural effect of VLX does not involve specific opioid receptors.
[Pharmacotherapy for neuropathic pain caused by injury to the afferent nerve fibers][Article in Dutch]
Weber WE.
Academisch Ziekenhuis, afd. Neurologie, Postbus 5800, 6202 AZ Maastricht.
Phantom pain, a form of neuropathic pain, is caused by damage to somatosensible afferent nerve fibres in the peripheral or central nervous system. Often, the pain cannot be satisfactorily treated with nonsteroidal anti-inflammatory drugs. Dependent on the underlying mechanism the pain is treated with either antidepressants (for more or less continuous pain) or anti-epileptics (for paroxysmal pain). Of the antidepressants, the tricyclic antidepressants are the best studied and most prescribed. The activity of new drugs, such as the selective serotonin reuptake inhibitor paroxetine as well as venlafaxine, has yet to be clearly shown. Of the anti-epileptics, carbamazepine and phenytoin are the most prescribed. New drugs which provide greater pain relief than the placebo are oxcarbazepine, gabapentine and lamotrigine. Other effective drugs for phantom pain are: gamma-butyric acid agonists (baclofen), opiates (morphine preparations with a regulated release; phentanyl patch), the N-methyl-D-aspartate receptor antagonist amantadine, transdermally administered clonidine and locally applied lidocaine.
The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways.
Schreiber S, Getslev V, Weizman A, Pick CG.
Department of Psychiatry C, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
Moclobemide is an antidepressant which affects the monoaminergic neurotransmitter system through a reversible inhibition of monoamine oxidase (MAO), preferentially type A. We examined the antinociceptive effects of moclobemide alone and in conjunction with specific opioid, adrenergic and serotonergic antagonists, using the mouse-tail flick test. Intraperitoneal moclobemide produced a dose-dependent antinociceptive effect with an ED50 of 69.1 mg/kg. Tests with selective antagonists yielded positive results only for yohimbine (P < 0.001), implying a noradrenergic mechanism of action in the moclobemide antinociceptive effect. This was confirmed by the coadministration of moclobemide with inactive doses of prototype agonists of the opioid, adrenergic and serotonergic systems. Only clonidine, an alpha2 agonist, significantly shifted (8-fold) the dose response curve of moclobemide. We conclude that there is a selective involvement of the alpha2 adrenergic pathways in the moclobemide-induced antinociceptive effect and a lesser involvement (if any) of the opioid, serotonergic and alpha1 adrenergic mechanisms. More research is needed to establish a possible role for moclobemide in pain managemen
“Psychobiological Mechanisms of Resilience and Vulnerability: Inplications for Successful Adaptation to Extreme Stress” by Dennis S. Charney (Am J Pschiatry 161:195-216, February 2004Subjects with major depression are hyperresponsive to amphetamine such that the severity of depression in major depression was highly correlated with the rewarding effects of amphetamine. The mechanism may be depletion of synaptic dopamine with up-regulation of dopamine receptors (154, 155). Increasing dopamine function in the nucleus accumbens, the orbital frontal cortex, and the ventral tegmental area and NMDA receptor blockade in the nucleus accumbens and the medial prefrontal cortex may enhance sensitivity to reward. Therefore, psychostimulants, dopamine reuptake inhibitors, monoxamine oxidase-B inhibitors (selegiline), the dopamine receptor agonists (pramipexole), and NMDA receptor antagonists (memantine) may be useful for treating anhedonia and hopelessness resulting from traumatic stress exposure.
"Effects of Chronic Tramadol on Pre- and Post-Synaptic Measures of Monoamine Functionby Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA.
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and The Royal London School of Medicine and Dentistry,
Royal London Hospital, Whitechapel, UK.
J Psychopharmacol 2001 Sep;15(3):147-53
ABSTRACT
The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphe (DRN) or median raphe (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology. "
Venlafaxine-tramadol similarities
by
Markowitz JS, Patrick KS
Department of Pharmacy Practice,
Institute of Psychiatry,
Medical University of South Carolina,
Charleston 29425-0810, USA.
Med Hypotheses 1998 Aug; 51(2):167-8ABSTRACT
Venlafaxine and tramadol are relatively new compounds indicated for the treatment of depression and pain, respectively. These agents share a number of molecular and pharmacological features that may allow for broader and overlapping therapeutic indications for both drugs. Additionally, certain patient populations with coexisting depression and pain syndromes could potentially be treated with a single agent.
The antinociceptive effect of tramadol-venlafaxine combination on the paw withdrawal threshold in a rat model of neuropathic pain.Uyar M, Onal A, Uyar M, Dogru A, Soykan N.
Pain Clinic, Department of Anesthesiology, Bornova, Izmir, Turkey. [email protected]
The combination of venlafaxine and tramadol was compared with the single use of these agents to investigate the antinociceptive effect on paw withdrawal latency (PWL) to paw pressure in rats with neuropathic pain. Rats were divided into 4 groups: group 1 received saline (0.2 ml i.p.); group 2 received venlafaxine (22 mg/kg i.p.); group 3 received tramadol (20 mg/kg i.p.); and group 4 received venlafaxine + tramadol. No statistically significant changes were observed in the saline and venlafaxine groups with respect to PWL in the lesioned paw. However, tramadol produced a significant antinociceptive effect on the lesioned paw at 30 min compared with the saline and venlafaxine groups. A more potent antinociceptive effect was observed in the tramadol + venlafaxine group, beginning at 60 min and lasting for 1 h. The combination of venlafaxine + tramadol was more effective in increasing the pain threshold in this animal model of neuropathic pain than either of these drugs administered alone. (c) 2003 Prous Science. All rights reserved.
Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?Schreiber S, Bleich A, Pick CG.
Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Israel.
The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies as far as mild to moderate depression is involved. However, it seems that some antidepressants are more effective than others in the treatment of severe types of depression (i.e., delusional depression and refractory depression). Following studies regarding the antinociceptive mechanisms of various antidepressants, we speculate that the involvement of the opioid system in the antidepressants' mechanism of action may be necessary, in order to prove effective in the treatment of severe depression. Among the antidepressants of the newer generations, that involvement occurs only with venlafaxine (a presynaptic drug which blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine) and with mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-auto- and hetero-adrenoreceptors). When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.
Serotonin and noradrenaline reuptake inhibitors in animal models of pain.
Mochizucki D.
Asahi Kasei Pharma, Chiyoda-Ku, Tokyo, Japan. [email protected]
Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline and serotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathic pain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone. 2004 John Wiley & Sons, Ltd.
Treatment of pain syndromes with venlafaxine.
Grothe DR, Scheckner B, Albano D.
Global Medical Communications, Neuroscience, Wyeth Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.
Major depressive disorder (MDD) and anxiety disorders such as generalized anxiety disorder (GAD) are often accompanied by chronic painful symptoms. Examples of such symptoms are backache, headache, gastrointestinal pain, and joint pain. In addition, pain generally not associated with major depression or an anxiety disorder, such as peripheral neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia), cancer pain, and fibromyalgia, can be challenging for primary care providers to treat. Antidepressants that block reuptake of both serotonin and norepinephrine, such as the tricyclic antidepressants (e.g., amitriptyline), have been used to treat pain syndromes in patients with or without comorbid MDD or GAD. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has been safe and effective in animal models, healthy human volunteers, and patients for treatment of various pain syndromes. The use of venlafaxine for treatment of pain associated with MDD or GAD, neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome is reviewed. Currently, no antidepressants, including venlafaxine, are approved for the treatment of chronic pain syndromes. Additional randomized, controlled trials are necessary to fully elucidate the role of venlafaxine in the treatment of chronic pain.
Synergistic antinociceptive effect of amitriptyline and morphine in the rat orofacial formalin test.
Luccarini P, Perrier L, Degoulange C, Gaydier AM, Dallel R.
Institut Universitaire de Technologie Genie Biologique, Universie d' Auvergne-Clermont I, Les Cezeaux, Aubiere, France.
BACKGROUND: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats. METHODS: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline. RESULTS: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. CONCLUSIONS: The current study suggests that systemic amitriptyline and morphine synergistically inhibit cutaneous orofacial inflammatory pain in rats.
http://www.clinicaltrials.gov/show/NCT00040261
Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants.
Memantine (Akatinol memantine), an agent that is approved in Germany for dementia syndrome, Parkinson's disease has significant antiglutamatergic and neuroprotective properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential efficacy of memantine, an agent which reduces glutamatergic output via open-channel block of the NMDA receptor-associated ion channel. Most importantly, memantine only blocks the channel during periods of abnormal, excessive activity, and leaves relatively spared normal neurotransmission. This finding is the basis for the minimal side effect profile displayed by memantine.
Posted by JackD on February 22, 2006, at 23:33:11
In reply to Re: Please keep the memantine updates coming!, posted by JackD on February 22, 2006, at 23:23:02
Excuse the long post, I'm trying to show why I believe Namenda (Memantine hcl) may help with Effexor and Remeron (or both together's) poopout, not to mention tolerance to pain meds and certain other meds. This is probably a waste of time, but hopefully someone may see where I'm going with all this regurgitation and find it useful.
Also just for the record, I haven't personally found Namenda useful for ANYTHING just taken by itself.
I wish everyone well :)
Posted by JackD on February 22, 2006, at 23:37:33
In reply to Re: Please keep the memantine updates coming!, posted by JackD on February 22, 2006, at 23:33:11
Whoops, I totally forgot I've posted all this before... oh bother :)
Posted by KayeBaby on June 5, 2007, at 1:22:14
In reply to Please keep the memantine updates coming!, posted by mike99 on January 19, 2006, at 13:36:14
I have been on Namenda 5mg for 1 week, now into week 2 at day 5 on 10 mg. This was added to EMSAM 6mg/24hr patch that I have been on for 6 weeks that is working well for me other than just no motivation. My Dr thinks Namenda will round it all out for me.
My mood is good, wanting to socialize more, less anxiety and more patience. Hars to say how much is the Namenda and how much the EMSAM is doing.
Seems to be gentle but good stuff.
Kaye
Posted by KayeBaby on June 5, 2007, at 1:22:41
In reply to Please keep the memantine updates coming!, posted by mike99 on January 19, 2006, at 13:36:14
I have been on Namenda 5mg for 1 week, now into week 2 at day 5 on 10 mg. This was added to EMSAM 6mg/24hr patch that I have been on for 6 weeks that is working well for me other than just no motivation. My Dr thinks Namenda will round it all out for me.
My mood is good, wanting to socialize more, less anxiety and more patience. Hars to say how much is the Namenda and how much the EMSAM is doing.
Seems to be gentle but good stuff.
Kaye
Posted by KayeBaby on June 9, 2007, at 22:49:35
In reply to Re: Please keep the memantine updates coming! » mike99, posted by KayeBaby on June 5, 2007, at 1:22:14
My dr. told me that Namenda would kick in in about two weeks. At 2 weeks and one day something kicked in!
My motivation and happiness ratcheted up a couple notches Fri. I did some laundry and worked in the garden this weekend. Fri. night I felt some gentle euphoria. I don't feel manic-y at all just very well.
It could be the 6+ weeks of EMSAM really doing it's stuff too.
Whatever it is I am grateful.
I am on my 3rd day of 20mg Namenda. This stuff seems to wipe out anxiety without being sedating. I can see how terribly anxious I am now that it has been lifted.
I am enjoying some blessed relief right now-hope it lasts and I hope this info is helpful to someone out there.
Thanks!
Kaye
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