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Journal of Molecular Neuroscience Copyright © 2002 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/02/18:143–149/$11.75

Venlafaxine and Mirtazapine Different Mechanisms of Antidepressant Action, Common Opioid-Mediated Antinociceptive Effects—A Possible Opioid Involvement in Severe Depression?

Shaul Schreiber,1 Avi Bleich,1 and Chaim G. Pick* ,2 1

Department of Psychiatry, Tel Aviv Sourasky Medical Center, and Tel-Aviv University Sackler School of Medicine, Tel-Aviv, Israel; and 2Department of Anatomy and Anthropology, Tel-Aviv University Sackler School of Medicine, Tel-Aviv, Israel Received May 6, 2001; Accepted July 1, 2001

Abstract 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 α2-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 (µ-, κ1- κ3- and δ-opioid receptor subtypes) combined with the α2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves µ- and κ3-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. Index Entries: Antidepressants; antinociception; delusional depression; hotplate; opioid receptor subtypes; noradrenaline; mirtazapine; refractory depression; serotonin; venlafaxine.

Introduction Delusional depression is a unique subtype of depressive illness, so far the only biologically characterized separate category of severe depression (Finlay et al., 1993; Coryell, 1997; Montgomery & Lecrubier, 1999). Psychotically depressed patients respond poorly to antidepressants alone, and remission is frequently achieved with combined

neuroleptic-antidepressants or electroconvulsive therapy (Dubovsky & Thomas, 1992; Coryell, 1996; Schreiber & Lerer, 1997). Although 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, it seems that some antidepressants are more effective than others in the treatment of severe types of depression, such as delusional

*Author to whom all correspondence and reprint requests should be addressed. E-mail: [email protected]

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144 depression (Dubovsky & Thomas, 1992; Coryell, 1996). In previous studies we evaluated the antinociceptive effects and the interaction of antidepressants with the opioid system in mice. We found that among the antidepressants of the newer generations, that involvement occurs with venlafaxine and mirtazapine, but neither with the post-synaptic serotonergic antidepressant nefazodone (Pick et al., 1992) nor with the pre-synaptic selective serotonin reuptake inhibitors (SSRIs) (Schreiber et al., 1996a,b), or with the reversible inhibitor of monoamine oxydase (RIMA) moclobemide (Schreiber et al., 1998). Venlafaxine is a structurally novel phentylethylamine antidepressant drug. In vitro, venlafaxine blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine (Lloyd et al., 1992). Venlafaxine has not been shown to inhibit MAO (Muth et al., 1986) and its monoamine-inhibitory properties differ from those of the serotonin selective reuptake inhibitors, which show high selectivity for serotonin reuptake only (Mendlewicz, 1995). Moreover, venlafaxine is inactive as a ligand in vitro to α1-, α2-adrenoreceptors, muscarinic and histaminergic receptors (Muth et al., 1986; Moyer et al., 1992; Ellingrod & Perry, 1994; Richelson, 1996). When studied in the mouse hot plate assay, venlafaxine was found to exert a clear, dose-dependent, opioid-mediated antinociceptive effect (Schreiber et al., 1999). Mirtazapine is a new antidepressant, one of a chemical series of compounds known as piperazinoazepines which is not related to any known class of psychotropic drugs. Mirtazapine enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central α2-auto- and hetero-adrenoreceptors (de Boer, 2000; Besson et al., 2000). Mirtazapine does not inhibit noradrenaline or serotonin uptake, but, it blocks specifically the 5-HT2 and 5-HT3 type receptors, failing to modulate monoamine reuptake. In these models mirtazapine manifested a very low affinity for dopaminergic receptors and high affinity for histamine H1 receptors (de Boer, 2000). However, it seems that mirtazapine’s intrinsic noradrenergic activity counteracts its histaminergic effects (de Boer, 2000). When studied in the mouse hot plate assay, mirtazapine was found to exert an opioid-mediated antinociceptive effect with a “therapeutic window” pattern (Schreiber et al., Submitted). Venlafaxine and mirtazapine act at different sides of the neuronal synapses: Venlafaxine, being a reuptake inhibitor of noradrenaline, serotonin, and


Schreiber, Bleich, and Pick dopamine, is a presynaptic drug, whereas mirtazapine exerts its pharmacological action at postsynaptic receptors. In common, these drugs seem to have only two characteristics: Both drugs are effective in the treatment of severe depression and both drugs have been found to involve opioid mechanisms of antinociception. Combining the findings of these two observations we speculate that the involvement of the opioid system in the antidepressant mechanism of action may be necessary, in order to prove effective in the treatment of severe depression.

Materials and Methods Subjects and Surgery Male ICR mice from Tel-Aviv University colony (Tel-Aviv, Israel), weight 25–35 g were used. The mice were maintained on 12 h light12 h dark cycles with Purina rodent chow and water available ad libitum. Animals were housed five per cage in a room maintained at 22°C ± 0.5°C until testing. Mice were used only once. Central injections in mice were made under light halothane anesthesia, using a Hamilton 10 µL syringe fitted to a 30-g needle with V1 tubing. Intrathecal (it) injections were introduced by lumbar puncture (Hylden & Wilcox, 1980). Agents Several agents were generously donated as follows: Venlafaxine HCl by Dexon (Hadera, Israel), Mirtazapine by N. V. Organon, (The Netherlands), Morphine by TEVA (Jerusalem, Israel), Naloxonazine by Dr. G. W. Pasternak from Memorial Sloan-Kettering Cancer Center, New York, USA, U50,488-H {trans-3,4-dchloro-N-methyl-N-[2(1-pyrrolindinyl)- cyclohexyl] - benzeneacetamide} by Upjohn Pharmaceutics (West Sussex, England), (D-Pen2,D-Pen5)enkephalin (DPDPE), β-funaltrexamine (β-FNA), Naltrindole HCl, Nalorphine HCl, Naloxone HCl and Norbinaltorphamine (Nor-BNI) were obtained from the Research Technology Branch of NIDA. Ethrane (Enflurane) was purchased from Abbott (Campoverde, Italy). Yohimbine HCl, Metergoline (N-CBZ[8b)-1,6dimethylergolin-8 yl] methylamine), Serotonin (5-Hydrotryptamine creatinine sulphate (5-HT)) and Clonidine HCl were purchased from Sigma (Israel). All other compounds were purchased from commercial sources. Yohimbine HCl was dissolved in distilled water. All other drugs were dissolved in saline; 5-HT contained 0.2 mg/mL ascorbic acid in addition to saline. Volume 18, 2002

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Venlafaxine and Mirtazapine Antinociception Assessment Mice were tested with the hotplate analgesimeter Model 35D (IITC Inc., Woodland Hills, CA), as previously described (Schreiber, et al., 1999). The device basically consists of a metal plate (40 × 35 cm) heated to a constant temperature, on which a plastic cylinder was placed. The analgesia meter was set to a plate temperature of 55.5 ± 0.5°C. The time of latency was recorded between the second the animal was placed on the hotplate surface until it licked its back paw or jerked it strongly or jumped out. Baseline latency was determined before experimental treatment for each mouse as the mean of two trials. Posttreatment latencies were determined after 30 min for opioids, which were subcutaneously (sc) administrated and for venlafaxine and mirtazapine, which were ip administrated. Posttreatment latencies were determinate after 15 min for DPDPE, which was administrated i.t. To minimize tissue damage a cutoff time of 30 s was adopted. Antinociception was defined quantitatively as doubling of baseline values for each mouse. Procedure The study was conducted in three experiments for each drug. Experiment 1 In the first stage of the study, groups of mice (n = 10) were injected ip with different doses of venlafaxine (from 1 mg/kg to 30 mg/kg) or mirtazapine (from 1 mg/kg to 12.5 mg/kg) to determine the effect of the drugs in eliciting antinociception. Normal motor behavior was observed following venlafaxine or mirtazapine injection. Experiment 2 The sensitivity of venlafaxine or mirtazapine to specific opioid, adrenoreceptor, and serotonin receptor antagonists was examined. Experiment 3 The sensitivity of venlafaxine or mirtazapine to specific opioid, adrenergic, and serotonin-receptor agonists was examined. Statistic Analysis Dose-response curves were analyzed, using a SPSS computer program. This program maximizes the log-likelihood function to fit a parallel set of Gaussian normal sigmoid curves to the dose-response data. Single dose antagonist studies were analyzed using the Fisher exact test. Journal of Molecular Neuroscience

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Fig. 1. Dose-response curve of the antinociceptive effect of venlafaxine and mirtazapine in the hotplate analgesia meter. Groups of mice (n = 10) were injected (ip) with various doses of mirtazapine or of venlafaxine. Posttreatment latencies were determined after 60 min.

Results Venlafaxine and Mirtazapine Antinociceptive Effects Both venlafaxine and mirtazapine demonstrated in mice efficacy as antinociceptive agents in the hotplate assay (Fig. 1). Venlafaxine induced a dosedependent analgesic effect following ip administration. The ED50 for mice in the hotplate assay for venlafaxine was 46.7 mg/kg (20.5; 146.5; 95% CL). Mirtazapine administered ip produced in doses from 1 to 7.5 mg/kg, an antinociceptive effect in the hotplate test in a dose dependent manner. As the mirtazapine dose increased beyond 10 mg/kg, hotplate latencies declined, yielding a biphasic dose-response curve. The Sensitivity of Venlafaxine and Mirtazapine Antinociception to Selective Opioid Receptor Antagonists The antinociceptive effect of venlafaxine (30 mg/kg) and of mirtazapine (7.5 mg/kg) were antagonized by naloxone (1 mg/kg s.c.; p < 0.05), implying that there is an opioid mechanism of action involved in both drugs induced antinociceptive effect (Fig. 2). At the next stage the involvement of the selective antagonists of µ, δ, and κ1 receptors was assessed to evaluate the potential involvement in venlafaxine or mirtazapine antinociception. We examined several selective antagonists (Fig. 2). Volume 18, 2002

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Schreiber, Bleich, and Pick onazine (at the same dose needed to reverse morphine analgesia) and naltrindole (at the same dose of that reversed DPDPE analgesia) reverse only partially venlafaxine antinociceptive effect. The doses of naltrindole and NorBNI that receptively reversed DPDPE and U50,488H analgesia reversed the antinociceptive effect of mirtazapine (p < 0.05; Fig. 2). β-FNA and naloxonazine given at a dose, which blocked morphine analgesia, failed to antagonized mirtazapine antinociceptive effects (Fig. 2). The activity of each of the antagonists was confirmed with its prototypic agonists (data not shown). None of the antagonists mediated antinociception by themselves, nor did they change the baseline latencies of the pretreated animals. The sensitivity of venlafaxine antinociceptive effect to selective antagonists implies κ1-mechanisms of action and to a lesser extent µ- and δ-opioid mechanisms whereas the sensitivity of mirtazapine antinociceptive effect to selective antagonists implies δ- and κ1-opioid mechanisms of action and to a lesser extent, a µ-mechanism.

Fig. 2. Effects of various opioid antagonists on mirtazapine or venlafaxine antinociception: naloxone (Nax; 1 mg/kg), β-FNA (40 mg/kg), nalaxonazine (NAZ; 35 mg/kg), naltrindole (NALT; 10 mg/kg), NOR- BNI (10 mg/kg), yohimbine (YOH; 4 mg/kg) and metergoline (MET; 2 mg/kg). Groups of mice (n = 10) were treated with venlafaxine (30 mg/kg) or with mirtazapine (7.5 mg/kg) each of them alone or were challenged in addition with one of the additional drugs. Naloxone, naltrindole, NOR- BNI, yohimbine and metergoline significantly antagonized mirtazapine antinociception (p < 0.05). All other drugs did not antagonized mirtazapine antinociception.

Administered 24 h prior to testing, β-FNA(40 mg/kg, sc) was found to be a selective µ1 and µ2 antagonist, while naloxonazine (35 mg/kg, sc) was found to be a selective µ1 antagonist (Paul & Pasternak, 1988). Similarly, the δ selective antagonist naltrindole (20 mg/kg, sc) blocks δ analgesia (Paul & Pasternak, 1988) and norBNI (10 mg/kg, sc) is a selective κ1 antagonist (Takemori et al., 1988). All these antagonists do not mediate antinociception by themselves and do not change the latencies of the baselines of the pretreated animals. NorBNI reversed venlafaxine antinociceptive effect at the same dose it reversed κ1 analgesia mediated by U50, 488H (p < .005; Fig. 2). β-FNA, nalox-


The Sensitivity of Venlafaxine and Mirtazapine Antinociceptive Effects to Selective Opioid Receptor Agonists In the next stage, multiple doses of the selective agonist of the µ subtype morphine were coadministrated with vehicle or with an inactive (subthreshold) dose of venlafaxine (2.5 mg/kg, ip) or inactive dose of mirtazapine (0.25 mg, ip Table 1). The ED50 of morphine alone was 5.4 mg/kg. A significant (p < .005) shift to the left in the dose-response curve was observed following venlafaxine administration with an ED50 of 2.4 mg/kg. Morphine, which was given in addition to mirtazapine, shifted significantly the dose-response to the left with an ED50 of 1.3 mg/kg (p < .005). Various doses of the selective agonist of the δ subtype DPDPE were injected with or without an inactive dose of venlafaxine (Table 1). Threefold shift to the left in the dose-response curve was detected (p < .005) ED50 of DPDPE without venlafaxine was 393 ng (it) and with venlafaxine was 130 ng, it. When we gave the selective agonists of the δ subtype DPDPE with or without an inactive dose of mirtazapine, no significant differences were found between the groups. The ED50 of DPDPE with mirtazapine was 276 ng, it. The selective agonist of the κ1 subtype U50, 488H was injected with or without an inactive dose of venlafaxine. A threefold shift to the left in the doseresponse curve (p < .005) was obtained. ED50 of U50, Volume 18, 2002

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Table 1 Receptor Selective Agonists, ED50 Alone and with Venlafaxine or with Mirtazapine

Morphine (µ) DPDPE (δ)

Alone

With Venlafaxine

With Mertazapine

5.4 (4.1; 7.3)

2.4 (1.0; 4.0) * 130 (96; 260) * 1.6 (0.2; 4.1) * 2.7 (6.7; 16.6) 0.1 (0.01; 0.3) * 645 (450; 910)

1.3 (0.4; 3.1) * 276 (142; 442)

393 (263; 549)

U50488H (κ1)

5.5 (3.4; 7.8)

Nalorphine (κ3) Clonidine (α)

31.1 (22.5; 51.2) 0.5 (0.3; 0.7)

Serotonin (5HT)

806 (504; 1130)

3.7 (1.2; 6.8) 9.5 (1.5; 24.1) 0.6 (0.4; 0.9) 519 (346; 759)

Each test group contained 10 mice. The numbers in parentheses are the 95% confidence limits of the ED50. *p < 0.05 for difference from the group without venlafaxine or without mirtazapine.

488H without venlafaxine was 5.5 mg/kg, sc and with venlafaxine was 1.6 mg/kg, sc. We gave the selective agonists of the κ1 subtype U50, 488H with or without an inactive dose of mirtazapine. We did not find any differences between the groups. The ED50 of U50, 488H with mirtazapine was 3.7 mg/kg, sc. The selective agonist of the κ3-subtype nalorphine was administered with or without an inactive dose of venlafaxine. A shift to the left of more then 11-fold of the dose-response curve was found (p < .005). ED50 of nalorphine without venlafaxine was 31.1 mg/kg, sc and with venlafaxine was 2.7 mg/kg, sc. We gave the selective agonists of the κ3 subtype nalorphine with or without an inactive dose of mirtazapine. We found a threefold shift to the left in the dose-response curve (p < 0.05). ED50 of nalorphine with mirtazapine was 9.5 mg/kg. These results suggest that venlafaxine when administered together with opiates, significantly potentates antinociception mediated by µ, δ, κ1, and κ3 opioid receptor subtypes. Mirtazapine significantly potentate’s antinociception mediated by µ and κ3 and to a lesser extent, by δ and κ1 opioid receptors.

The Sensitivity of Venlafaxine and Mirtazapine Antinociceptive Effects to Selective Opioid Receptor Antagonists In order to assess the involvement of the serotonergic and adrenergic systems in venlafaxine and mirtazapine antinociceptive effect, the effect of phentolamine (a α1-α2 adrenergic antagonist), yohimbine (a α2 adrenergic antagonist) and metergoline (a nonselective 5-HT receptor antagonist), were examined to establish their ability to block venlafaxine and mirtazapine antinociception (Fig. 2). The antinociJournal of Molecular Neuroscience

ception induced by venlafaxine was significantly inhibited only by yohimbine (at the same dose needed to reverse clonidine antinociception; p < 0.05), implying a α2 adrenergic mechanism of action in the venlafaxine induced antinociception. The antinociception induced by mirtazapine was significantly inhibited by phentolamine, yohimbine, and metergoline (p < 0.05), implying a combined serotonergic and adrenergic mechanism of action in the mirtazapine induced antinociception (Fig. 2).

Venlafaxine and Mirtazapine Action on Selected Opioid, Serotonergic and Adrenergic Receptor Subtypes Agonists Multiple doses of the selective agonist of the α2 adrenergic system (clonidine) or of the serotonergic system (serotonin) were coadministrated with vehicle or with an inactive (subthreshold) dose of venlafaxine (2.5 mg/kg, ip) or mirtazapine (0.25 mg/kg, ip; Table 1). When clonidine, was administered alone, a dosedependent antinociception was evident. Concomitant administration of clonidine with inactive dose of venlafaxine potentate clonidine antinociception effects and shifted its dose-response curve almost fivefold (p < 0.05) in to the left. ED50 value of clonidine alone was 0.5 mg/kg and with venlafaxine 0.1 mg/kg. We gave clonidine with or without an inactive dose of mirtazapine. We did not find any differences between the groups. The ED50 of clonidine with mirtazapine was 0.6 mg/kg, sc. We did not see any significant shift when we gave the nonselective 5-HT agonist serotonin with or without an inactive dose of venlafaxine or mirtazapine (Table 1). Volume 18, 2002

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Discussion Both venlafaxine and mirtazapine were found to induce a clear antinociceptive effect in the mouse hotplate assay. At doses from 1 to 30 mg/kg (venlafaxine) and 1 to 7.5 mg/kg (mirtazapine), both drugs administered ip induced antinociception in a dose-dependent manner (Fig. 1). However, although venlafaxine’s antinociception was linear, mirtazapine’s antinociception beyond 7.5 mg/kg was found to yield a biphasic dose-response curve, which implies a “therapeutic window effect.” Venlafaxine and mirtazapine induced antinociceptive effects were antagonized by naloxone (implying an involvement of the opioid system) and by the α2 adrenergic antagonist yohimbine (implying involvement of the noradrenergic system as well). However, only mirtazapine induced nociception was blocked by the nonselective serotonin antagonist metergoline, implying an involvement of 5-HT mechanisms as well. When administered together with various opioid receptor agonists, venlafaxine significantly potentates antinociception mediated by µ-, δ-, κ1-, and κ3-opioid receptor subtypes, whereas mirtazapine significantly potentates mainly antinociception mediated by µ-, and κ3-opioid receptors. Since most antidepressants of the new generation have not been found effective in the treatment of severe depression, and the few who do exert clear antinociceptive effects, we speculate that the involvement of the opioid system in the antidepressant 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 with venlafaxine and mirtazapine, but neither with nefazodone (Pick et al., 1992) nor with the SSRIs fluoxetine and fluvoxamine (Schreiber et al., 1996a,b), or with the RIMA moclobemide (Schreiber et al., 1998). Following our speculation that the opioid system is involved in the disregulation of neurotransmitters which underly the pathophysiology of severe depression, we successfully augmented SSRI-failed treatment of refractory depression with naltrexone (Amiaz et al., 1999). We used an opiate antagonist in order to prevent the hazads of prolonged opiateagonists treatment (e.g., tolerance, physical dependence). Naltrexone is a long acting, pure competitive opioid antagonist principally of µ-, but also of κ- and δ-opioid receptors in the central nervous system, used mainly for the treatment of alcohol and opiate dependence (O’Mara and Wesley 1994; Shufman et al. 1994; O’Brien et al. 1996), and for other conditions


Schreiber, Bleich, and Pick such as binge-eating and bulimia nervosa (Mitchell et al. 1993), Prader-Willi syndrome (Benjamin and Bout-Smith 1993), and augmentation of neuroleptics in schizophrenia (Rapaport et al. 1993). Interaction of the serotonergic and opioid systems has been documented in animal models, as far as the antinociceptive effects of various SSRIs are concerned (Schreiber et al. 1996 a,b). Furthermore, the activity of cerebral monoaminergic systems has been found in another animal model to be regulated to some degree by endogenous opioid input. When that input was chronically blocked, the basal metabolism of monoamines in the brain was not much altered but the system’s responsiveness to agonist challenge was increased (Ahee et al. 1990). Controlled clinical studies are needed in order to establish the efficacy in severe depression of opiate-augmentation of antidepressants, which lack opioid interactions technique, and the optimal dosage of drugs prescribed.

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149 nalmefene augmentation in neuroleptic-stabilized schizophrenic patients. Neuropsychopharmacology 9, 111–115. Richelson E. (1996) Synaptic effects of antidepressants. J. Clin. Psychopharmacol. 16 (Suppl. 2), 1S–9S. Schreiber S., Backer M. M., Weizman R., and Pick C. G. (1996a) The antinociceptive effects of fluoxetine. The Pain Clinic 9, 349–356. Schreiber S., Backer M. M., Yanai J., and Pick C. G. (1996b) The antinociceptive effect of fluvoxamine. Eur. Neuropsychopharmacol. 6, 281–284. Schreiber S. and Lerer B. (1997) Failure to thrive in elderly, depressed patients: a new concept or a different name for an old problem? Isr. J. Psychiatry Relat. Sci. 34, 108–114. Schreiber S., Getslev V., Weizman A., and Pick C. G. (1998) The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways. Neuroscience Letters 253, 183–186. Schreiber S., Backer M. M., and Pick C. G. (1999) The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms. Neuroscience Letters 273, 85–88. Schreiber S., Rigai T., Backer M. M., and Pick C. G. (Submitted) The antinociceptive effect of mirtazapine in mice is mediated through opioid and adrenergic mechanisms. Brain Research Bulletin (in press). Shufman E. N., Porat S., Witztum E., Gandaeu D., BarHamburger R., and Ginath Y. (1994) The efficacy of naltrexone in preventing reabuse of heroin after detoxication. Biol. Psychiatry 35, 935–945. Takemori A. E., Ho Y. H., Naeseth J. S., and Portoghase P. S. (1988) Nor-Binaltrophimine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J. Pharmacol. Exper. Ther. 246(1), 255–258.

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