1612 Current Pharmaceutical Design, 2009, 15, 1612-1622

1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Opiates as Antidepressants

Esther Berrocoso1,2

, Pilar Sánchez-Blázquez2,3

, Javier Garzón2,3

and Juan A. Mico1,2,*

1Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry),

School of Medicine, University of Cádiz, Spain; 2Ciber of Mental Health (CIBERSAM), ISCIII, Madrid, Spain and

3Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, CSIC, Madrid, Spain

Abstract: The pathophysiology of mood disorders involves several genetic and social predisposing factors, as well as a

dysregulated response to a chronic stressor, i.e. chronic pain. Our present view that depression involves a dysfunction of

the monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. In fact, cur-

rent pharmacological treatment for depression is based on the use of drugs that act mainly by enhancing brain serotonin

and noradrenaline neurotransmission by the blockade of the active reuptake mechanism for these neurotransmitters. How-

ever, a substantial number of patients do not respond adequately to antidepressant drugs. In view of this, there is an in-

tense search to identify novel targets (receptors) for antidepressant therapy. Opioid peptides and their receptors are poten-

tial candidates for the development of novel antidepressant treatment. In this context, endogenous opioid peptides are co-

expressed in brain areas known to play a major role in affective disorders and in the action of antidepressant drugs. The

actions of endogenous opioids and opiates are mediated by three receptor subtypes ( , and ), which are coupled to dif-

ferent intracellular effector systems. Also, antidepressants which increase the availability of noradrenaline and serotonin

through the inhibition of the reuptake of both monoamines lead to the enhancement of the opioid pathway. Tricyclic anti-

depressants show an analgesic effect in neuropathic and inflammatory pain that is blocked by the opioid antagonist

naloxone. A compilation of the most significant studies will illustrate the actual and potential value of the opioid system

for clinical research and drug development.

Key Words: Opioid, opiate, (MOP receptor), (DOP receptor), (KOP receptor), antidepressant, depression, monoamines.

1. INTRODUCTION

Depression is a mental disorder characterized by a wide range of debilitating emotional and physical symptoms, such as a sad or blunted mood, loss of interest or pleasure that coexists with feelings of hopelessness, pessimism, worth-lessness or helplessness. Along with these basic symptoms, other disease characteristics include changes in appetite, a constant lethargic state or fatigue, restlessness, irritability, thoughts of death or suicide, as well as chronic pain [1].

Although the monoamine deficiency hypothesis, posited over 30 years ago, has proven to be a simplistic model of the complex pathophysiology of depression, it persists as a cen-tral heuristic, guiding the development of antidepressant agents. The monoamine hypothesis states that decreased ac-tivity of monoaminergic pathways leads to depression [2]. This is supported by the finding that compounds that in-crease monoaminergic activity through different mechanisms such as reuptake inhibition have antidepressant activity [3]. The clinical impact of monoamine-based antidepressant medication supports the view that alterations in both sero-tonin (5-HT) and norepinephrine (NE) function contribute to the syndrome of depression. In fact, a number of studies show that depression is associated with alterations in both

*Address correspondence to this author at the Pharmacology and Neurosci-

ence Research Group, Department of Neuroscience (Pharmacology and

Psychiatry), School of Medicine, University of Cádiz, Plaza Fragela 9,

11003 Cádiz, Spain; Tel: +34 956015247; Fax: +34 956015225;

E-mail: juanantonio.mico@uca.es

5-HT and NE neurotransmitters, 5-HT and NE receptors and transporters, and to a lesser degree the dopamine (DA) sys-tem. As a logical consequence, current antidepressant medi-cations are mechanistically based on this hypothesis, with most of them being able to inhibit the reuptake of mono-amines [4]. However, in spite of this, the etiopathogenesis of mood disorders is not fully explained by the monoaminergic theory and the complete resolution of depression is far from being achieved with current antidepressants. Remission of symptoms is at present the main goal of depression treatment but, today many patients fail to attain or maintain a long-term, symptom-free status. Recent findings indicate that ap-proximately 63% of patients with major depressive disorder fail to respond to suitable first-line monotherapy with a se-lective serotonin reuptake inhibitor (SSRI), the most used antidepressants. Furthermore, when more treatment steps

are

required, lower acute remission rates, and higher relapse rates during

the follow-up phase, are to be expected [5, 6].

These observations suggest that residual depressive symp-toms predispose and portend a subsequent relapse in depres-sion. This is especially relevant in long-term cases or when depression is co-morbid with another illness (psychiatric or not) [7]. Because of this, great interest has been taken in the improvement of treatment augmentation strategies or the development of innovative antidepressants, not necessarily or strictly based on the monoaminergic hypothesis of depres-sion. At the present time, overwhelming data suggest that depression is not only the cause or the consequence of a dis-turbance in monoamines [8]. Alternative drug targets for this disease are being investigated to find interventions with in-

Opiates as Antidepressants Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1613

creased efficacy, faster therapeutic onset and fewer side ef-fects [9].

The last few years have seen unprecedented advances in our knowledge about the neurobiology of depression. Sig-nificant breakthroughs have been made in genomics, imag-ing, and the identification of key neural systems involved in cognition, emotion and behaviour. In addition, novel targets have been identified for the development of new pharmacol-ogical and behavioural treatments. Besides the classical transmitter systems, both membrane-bound signal transduc-tion systems and intracellular signalling pathways seem to play an important role in the etiology of depression. Now it is well known that monoamines such as NE, 5-HT and DA produce their effect by inducing complex biochemical changes in postsynaptic neurons in the central nervous sys-tem by interacting with specific G protein subtypes inside the postsynaptic cell membrane. These G protein–linked receptors are stimulated by monoamines, as well as certain neuropeptides, and produce a change in the way postsynaptic neurons respond to glutamate, which binds to “ligand-gated” channels. These neurons send axonal branches throughout the brain forming an intrinsic modulatory system that acts via other G protein–linked receptors to alter the overall re-sponsiveness of the brain. Thus, it is not surprising that these modulatory neurotransmitters might be new targets for the pharmacotherapy of mental disorders such as depression.

Among the neuropeptidergic transmitters, opioids have been largely associated with mood regulation and conse-quently with depressive disorders [10]. Moreover, the opioid system has been proposed as a target for the treatment of depression [11]. The euphorogenic properties of opiates (and also endorphins) prompted questions such as the possibility that a defectively operating opioid system may represent a causative factor in the pathogenesis of endogenous depres-sion. Indeed, since the time of Emil Kraepelin the opium cure was recommended for the treatment of depressed pa-tients [12], employing slowly increasing and later decreasing dosages of tincture opii and of other opiates. Interestingly, according to reports of that time, although a standardized evaluation of its therapeutic efficacy was lacking, this treat-ment was effective and did not result in opiate addiction, possibly since the doses applied were comparatively low. It is interesting to note that the opium cure was used before the discovery of current antidepressant treatments or electrocon-vulsive therapy. Another circumstance that has suggested the implication of the opioid system in the ethiopathogenesis of depression is the fact that both traditional antidepressant compounds, in spite of not binding to any of the opioid re-ceptors, and electrotroconvulsive therapy seem to modulate indirectly opioid neurotransmissions. However, despite the numerous clues suggesting the implication of the opioid sys-tem in depressive illness and the potential utility of opiates, there is no opiate compound specifically designed at the pre-sent time with this purpose.

This review is intended to be a compilation of the clinical and preclinical evidence of the antidepressant or antidepres-sant-like effect of opioids and the interrelated mechanisms underlying this effect. These data highlight the need for both new research into the mechanisms producing depression and the development of novel mechanistic-based therapeutics.

2. DEPRESION AND OPIOID RECEPTORS

The opioid receptors were discovered and characterized in the mammalian brain in the 1970s, leading to the identifi-cation of endogenous opioid peptides (endorphins) in the brain. The discovery of endorphins, which are thought to function as neuromodulators in the human brain, sparked interest in the possible role of endorphins, and consequently of opioid receptors, in depressive illness. Perhaps, among the reasons behind this hypothesis was the fact that opioid recep-tors and endorphins are highly concentrated in the limbic and hypothalamic regions and they interact with the mono-aminergic system [13].

Most studies related with the antidepressant-like effects of opioids are associated with opioid receptors. Specific re-ceptors and endogenous peptide ligands mediating the di-verse actions of the opioid system were discovered a little over thirty years ago [14, 15]. Opioid receptors of three ma-jor types, (mu), (delta) and (kappa) (MOP, DOP and KOP: , and opioid receptors respectively), are distrib-uted throughout the CNS and periphery [16]. Each type has been cloned, and belongs to the G protein-coupled receptor (GPCR) superfamily having seven -helical transmembrane domains [16]. High sequence homology is conserved be-tween types, and across species. Effector mechanisms in-clude adenylate cyclase, ion channels, phospholipase C, and mitogen-activated protein kinase as well as less characterized signalling pathways related to cell death and survival [16, 17]. There have been several nomenclature conventions for opioid receptors (e.g., mu, μ, OP3, MOR, MOP). Current IUPHAR (International Union of Basic and Clinical Phar-macology) designations for the “big three” have returned to the original Greek letters ( , and ) or MOP/DOP/KOP respectively [18] (http://www.iuphar-db.org/GPCR/Chapter MenuForward?chapterID=1295). Despite pharmacological evidence suggesting subtypes for all opioid receptors [19], only few molecular entities have been cloned. This suggests that the notion of gene encoded subtypes might be artificial. In fact, opioid receptors are able to form homo- and het-erodimers among themselves, and heterodimers and oli-gomers with other GPCRs (adrenoceptors, somatostatin), and these associations modulate ligand binding, signaling and trafficking in vitro and in vivo [13, 20].

MOP Receptors, Depression and the Antidepressant Ef-

fect

As stated before, substantial evidence supports the belief that an impairment in the opioid system underlies the patho-physiology of depression. Most numerous clinical evidence points to the implication of MOP receptors in depression and stress states. This is thought to be, among other reasons, be-cause MOP receptors are densely distributed in several brain regions implicated in the response to stressors and emotion-ally salient stimuli. Indeed, it has been shown that there is such a pronounced reduction in MOP receptor availability in the posterior thalamus and anterior cingulate cortex of pa-tients with major depressive disorder that none responded to treatment with the SSRI fluoxetine [21]. On the other hand, some clinical reports describe the effectiveness of the MOP agonists, oxycodone and oxymorphone, and the partial ago-nist buprenorphine, in patients with refractory major depres-

1614 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Berrocoso et al.

sion [22, 23]. Moreover, patients with severe depression coupled with anxiety display decreased serum -endorphin levels [24, 25]. Also, in the learned helplessness model, morphine, the prototypical MOP agonist, showed an antide-pressant-like effect which was antagonized by naloxone, demonstrating opioid mediation [26, 27]. Other MOP ago-nists, like ( )-methadone and levorphanol, showed an anti-depressant effect in the learned helplessness test in rats [28]. These data make it clear that endogenous opioid neurotrans-mission is altered in patients diagnosed with major depres-sive disorder.

It has been shown very recently that the central admini-stration of the endogenous peptides, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which bind selectively to MOP receptors [29], de-creased the immobility time in the tail suspension test and forced swimming test in mice without affecting motor activ-ity [30]. These effects were blocked by the non-selective opioid antagonist, naloxone and the MOP selective antago-nist, -funaltrexamine. In contrast, this effect was not an-tagonized by the DOP and KOP selective antagonists, nal-trindole and nor-binaltorphimine (nor-BNI), respectively. This shows that the activation of MOP receptors underlies this antidepressant-like effect. However, Filliol and colabo-rators [31] showed that MOP-knockout mice showed slightly decreased immobility time in the forced swimming test. In addition, they increased locomotion after footshock exposure compared with wild-type controls in the conditioned sup-pression of motility paradigm, suggesting a depressive-like behaviour in these animals. Nevertheless, surprisingly, the attenuation of the conditioned suppression of motility in MOP-knockout mice was reversed by the DOP-antagonist naltrindole. The authors suggest a predominant activation of DOP receptors by endogenous peptides may be involved in the behavioural changes of MOP-knockout mice. Further important data is that the ensemble of phenotypic modifica-tions is observed for males only, opening the possibility of sexual dimorphism in the activity of opioid receptors for these behaviours.

The above mentioned data would suggest a possible role for opioid therapy in refractory depression. Furthermore, in addition to this per se effect of MOP agonists on these brain areas, a secondary mechanism has been suggested involving the serotoninergic system. In vivo microdialysis data have shown that systemic morphine administration in the dorsal raphe nucleus suppresses the GABAergic (gamma-amino- butyric acid) mediated inhibition of 5-HT release [32]. This results in a disinhibition of serotoninergic neurons and the release of an excess of central 5-HT in forebrain projection areas related with emotional integration, including the thalamus, nucleus accumbens, amygdala, frontal cortex, striatum, hypothalamus and ventral hippocampus [33]. Re-search in our group has shown a cooperative effect between sub-effective doses of the weak MOP agonist codeine and inhibitors of the reuptake of serotonin in the tail suspension test in mice (data not published). This would suggest that opiates indirectly stimulate 5-HT release in projection areas.

Concerning opioid-NE interaction, most studies suggest it to be unlikely. It has been shown that MOP agonists inhibit NE release in slices of the hippocampus, cerebellum, cere-

bral cortex and preoptic area [34-37]. Finally, it has also been demonstrated that morphine administered alone has no effect on NE release, but it attenuated GABA-augmented NE release in the hypothalamus and abolished it in the cortex [36, 38]. Therefore, a noradrenergic-MOP interaction seems unlikely.

Tramadol, an Atypical Opiate with Monoaminergic Proper-ties

Tramadol, (1RS,2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is a centrally-acting analgesic which is widely used in clinical practice. Tramadol is a synthetic opioid that binds weakly to MOP receptors [39]. Nevertheless, it is considered an atypical opioid because a non-opioid mechanism is also involved in its effects. It works by enhancing the extraneuronal concen-tration of NE and 5-HT by interfering with both their reup-take and release mechanisms [40, 41]. Tramadol, is an unique compound with both a weak MOP effect when com-pared to classical opioids, and a weak monoaminergic effect when compared to tricyclic antidepressants [40]. It has a different side-effect profile to tricyclic antidepressants or antiepileptics [42] and in contrast to classical MOP agonists, tolerance and dependence are uncommon complications of tramadol treatment [43, 44].

Tramadol is widely used in clinical pain practice, espe-cially for the treatment of neuropathic pain [45]. However, in addition to its well known analgesic effect, some evidence has suggested that it elicits antidepressant-like effects. Both clinical and preclinical data support this theory. In clinical practice, it has been used successfully in several psychiatric disorders such as refractory major depression [46], severe suicidal ideation [47] and antidepressant potentiation [48]. Tramadol has also been used with positive effects in anxiety and anxiety-like disorders such as obsessive-compulsive disorders (which respond effectively to antidepressants) and in the treatment of Tourette's syndrome [49, 50].

In behavioural studies, tramadol showed antidepressant-like effects in different models predictive of antidepressant activity, such as the forced swimming test [51], the chronic mild stress test in mice [52] and the learned helpessness test in rats [28], and is able to reverse reserpine-induced-hypo- thermia [53]. In addition, tramadol induces changes in the central nervous system similar to those induced with conven-tional antidepressants. It decreases the binding of frontocor-tical -adrenoceptors, 5-HT2A receptors [54] and 2-adreno- ceptors [55] but increases the binding of 1-adrenoceptors and dopamine D2/D3 receptors [56]. In addition, it inhibits locus coeruleus firing activity through 2-adrenoceptors mechanisms [57], like antidepressant compounds.

Considering all these preclinical and clinical data, it seems clear that tramadol, in addition to its analgesic effect, also demonstrates antidepressant-like effects. This could be important in refractory cases of depression when pain is pre-sent too.

DOP Receptors, Depression and the Antidepressant Effect

The DOP receptor was identified in the 1970s as having a high affinity for the endogenous opioid peptides met- and

Opiates as Antidepressants Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1615

leu-enkephalin. Instability and low bioavailability of delta peptides have been a drawback for the study and evaluation of DOP agonists. However, the development of selective non-peptidic DOP agonists has accelerated investigations into the physiological and behavioural changes produced by DOP receptor activation. Indeed, preclinical studies with DOP opiates, mainly in the last 15 years, have implicated them in a wide spectrum of conditions including analgesia [58], opiate craving [59], tolerance and dependence [60], neuropathic and inflammatory pain [61, 62], potentiation of MOP agonist analgesia [63], respiration [64], Parkinson's disease [65] and depression [66]. These possible therapeutic applications have intensified the search for DOP compounds. Unfortunately, seizures and/or convulsions have limited their therapeutic potential and clinical evidence is still lacking.

The association between the DOP system and depression, and also the antidepressant-like effects of opioid ligands, have been evaluated in preclinical assays. There is some evi-dence that DOP receptors may play a role in depressive states. For example, in recent studies knockout mice that lack DOP receptors [31] or preproenkephalin-derived pep-tides showed high anxiety levels and depressive-like re-sponses [67, 68], suggesting that the endogenous activity of DOP receptors may positively modulate mood states. In addition, DOP agonists such as delta-opioid peptides (Tyr- D - Ser - (O - tert - butyl) - Gly - Phe - Leu - Thr - (O - tert - butyl - OH) (BUBU), deltorphin II, [D-Pen2,D-Pen5]-enkephalin (DPD- PE), the systemically active DPDPE derivative JOM-13, and H-Dmt-Tic-NH-CH2-Bid all produced DOP-mediated anti-depressant-like effects in rodent models used to screen for antidepressant-like effects [69, 70]. The antidepressant-like effects observed with DPDPE, deltorphin II, H-Dmt-Tic-NH-CH2 and JOM-13 were blocked by the selective DOR antagonist naltrindole, demonstrating that these behaviours were mediated through the DOP receptors [70]. Similarly, treatment with enkephalinase inhibitors such as RB101 was associated with antidepressant-like effects in mice and rat models of depression [69, 71]. More recently, the non-peptidic delta-opioid agonists (+)-4-[ (R)- -[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] - (3 - hydroxyphenyl)- methyl]-N,N-diethylbenzamide ((+)BW373U86) and (+)-4-[(aR)-a-((2S,5R)-4 - allyl - 2,5 - dimethyl - 1piperazinyl) - 3 - meth- oxybenzyl]-N,N-diethylbenzamide (SNC80) have been shown to produce antidepressant- and anxiety-like effects in several rodent models [72-74]. Saitoh’s group has demon-strated that repeated administration of the DOP receptor agonist SNC80 showed an antidepressant-like effect in the olfactory bulbectomized rat model [75]. This point is very interesting because one of the major drawbacks of the model used to detect antidepressant activity is that both the model and the antidepressant drug administration is acute and in clinical practice several weeks of treatment are necessary to evidence the antidepressant effect. The olfactory bulbec-tomized rat model is one of the models that seem to correlate with the course of the clinical antidepressant effect and DOP agonists seem to be effective in this model.

The mechanism responsible for antidepressant-like ef-fects induced by DOP agonists remains unknown. However, an increase in monoaminergic activity seems to underlie the activation of DOP receptors. In this line, treatment with DOP

agonists generally increases swimming and climbing behav-iours in the forced swimming test in rats, implying a possible increase in 5-HT and NE/DA respectively. Regarding a pos-sible influence in the serotoninergic system, as mentioned above, sub-chronic treatment with SNC80 completely re-versed olfactory bulbectomized behavioural abnormalities. This antidepressant-like effect was accompanied by a rever-sal of the loss of tryptophane hydroxilase-positive cells in the dorsal raphe and the decrease of 5-HT and 5-HIAA (5-Hydroxyindoleacetic acid) in the frontal cortex, hippocam-pus and amygdala [75]. Furthermore, non-peptidic DOP an-tagonists (NTI, HS-378 and HS-459) suppressed the degra-dation of tryptophan [76]. These findings indicate that the activation of DOP receptors will impair serotoninergic dys-function in depressive states. Furthermore, DOP agonists increase locomotor activity in rodents, an effect blocked by dopaminergic antagonists, such as raclopride [72, 77]. This would suggest that these compounds increase dopaminergic pathway activity. However, the DOP agonists SNC80 and BW373U86 were not self-administered in monkeys and did not stimulate dopamine release in rats [78, 79]. Therefore it is not clear whether an interaction between the dopaminergic system and DOP exists.

The neurotrophic factor hypothesis is another possible mechanism of action for antidepressant-like effects induced by DOP agonists. Neurotrophins, such as brain derived neu-rotrophic factor (BDNF), play an important role in the thera-peutic actions of antidepressants [80]. BDNF regulates neu-ronal survival, differentiation, and plasticity. Human studies have linked BDNF with the pathophysiology of various mood disorders. For example, increased BDNF immunoreac-tivity has been found in patients with major depression that had been treated with antidepressants [81]. Animal studies also showed that chronic treatment with antidepressants could up-regulate BDNF mRNA expression in the hippo-campus of rats [82]. Regarding DOP receptors, it has been shown that acute treatment with DOP agonists (DPDPE) increases the expression of BDNF mRNA at doses that pro-duce an antidepressant effect and what it is more interesting, in a faster way than the antidepressants desipramine and bupropion [70, 83]. However, chronic treatment (21 days) with the DOP agonist (+)BW373U86 produced tolerance to the behavioural antidepressant effect and to the increase in the expression of BDNF mRNA [84].

The promising effects of DOP agonists as potential anti-depressant drugs has been limited by the existence of pro-seizure properties of non-peptidic DOP agonists such as SNC80 and (+)BW373U86. This effect was blocked by the selective DOP antagonist naltrindole, suggesting the direct mediation of DOP in the seizures [85]. The same profile has been found with various opioid peptides with affinity to DOP and with the enkephalinase inhibitor SCH 32615 [86-88]. However, Broom and collaborators showed that convul-sive activity is independent of the antidepressant-like effect because the convulsive effect of the DOP agonist (+)- BW373U86 was blocked by the benzodiazepine midazolan without altering its antidepressant-like profile [85]. There-fore, it seems possible to find DOP agonists which keep their antidepressant-like profile and are devoid of convulsive side effects.

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Collectively, all these data suggest that the activation of DOP could represent a highly useful therapeutic target for the treatment of mood disorders, but, in terms of therapeutic development, it is necessary to develop DOP receptor ago-nists devoid of convulsive properties. On that point, further pre-clinical and possibly clinical studies in which convulsive side effects are overcome will be required to firmly deter-mine the advantages and disadvantages of DOP receptor selective agonists as innovative antidepressant drugs.

KOP Receptors, Depression and the Antidepressant Effect

KOP opioid receptors participate in many physiological functions such as antinociception [89], diuresis [90], hormo-nal modulation [91] and neuroprotection [92]. In addition, several studies have indicated that KOP receptors are in-volved in mood regulation. In the same line, some preclinical studies, most of them in recent years, suggest that activation of the endogenous KOP system mediates depression- and anxiety-like behaviours [93] and that KOP antagonists could be new candidate compounds to treat depression.

Regarding clinical data, unfortunately, there is only one study providing evidence that the activation of the dynorphin receptor (KOP agonist) through the administration of an agonist causes dysphoria [94]. Data from behavioural models of depression showed that systemic administration of KOP receptor agonists, such as U-69593, increased the immobility time in the rat forced swimming test and reduced the reward-ing impact of the brain stimulation, indicating that KOP re-ceptor agonists elicit pro-depressant-like effects [95-97].

More interesting, central administration of KOP antago-nists, such as nor-BNI, produced antidepressant-like behav-ioural effects in animal models of depression including the forced swim test and learned helplessness paradigm [95, 98-101]. In addition, the novel KOP-antagonist/MOP-agonist MCL-144B decreased the immobility time in the forced-swim test in mice and produced antinociception in mice [102], probably through the activation and the blockade of MOP and KOP receptors respectively. Another recent paper shows that KOP antagonists, nor-BNI and JDTic, have anx-iolytic-like effects that accompany their antidepressant-like effects [93]. This could be especially relevant because KOP antagonists possess neither reward [96] nor sedative effects [95] that contribute to the abuse liability of benzodiazepines.

Regarding knock-out studies, it has been reported that disruption of the gene coding for the endogenous KOP re-ceptor agonist dynorphin, significantly reduced the time mice spent immobile in the repeated forced swimming stress test [103, 104], supporting the above findings about the anti-depressant effect of KOP antagonists. In contrast, previous data in KOP knock-out mice demonstrated similar responses to those of wild-type mice in the forced swimming test, dis-proving the idea that KOP receptors were not involved in depression states [31]. The neurobiological mechanisms by which KOP antagonists induce antidepressant-like effects and KOP agonists produce pro-depressant effects are not currently known. Concerning the antagonists of KOP, it has been suggested that the blockade of these receptors may pro-duce, similar to MOP and DOP, an increase in monoaminer-gic signalling pathways, producing a functionally similar

response to known antidepressants. Indeed, some lines of evidence suggest that KOP agonists decrease extracellular concentrations of DA within a key component of the mesolimbic system, the nucleus accumbens [97], which has been implicated in the pathophysiology of depressive condi-tions [105]. For instance, it has previously been shown that decreased dopaminergic function in the nucleus accumbens produces anhedonia [106]. It is interesting to note that im-mobilization and learned helplessness cause an increase of dinorphyn A and B in the hippocampus and nucleus accum-bens. Furthermore, the infusion of nor-BNI into the hippo-campus produced antidepressant-like effects in the learned helplessness model [101]. Likewise, Salvorin A, a KOP re-ceptor agonist isolated from Salvia divinorum, caused de-pressive-like effects in the forced swimming test in rats (in-creasing immobility and decreasing swimming behaviour) and decreased extracellular concentrations of DA within the nucleus accumbens, without affecting extracellular concen-trations of 5-HT [97]. This suggests that decreases in DA in the nucleus accumbens contributes to depressive-like behav-iours.

Furthermore, there is evidence that stressors can activate the transcription factor cAMP-response element binding pro-tein (CREB) in the nucleus accumbens. This selective eleva-tion of CREB function within the nucleus accumbens in-creases immobility behaviour in the forced swimming test [98] and the KOP antagonist nor-BNI attenuates the behav-ioural effects of elevated CREB expression within this nu-cleus [98]. This effect is the same as that caused by standard antidepressants [105]. In addition, Newton and collaborators showed that the blockade of CREB by overexpression of mCREB in transgenic mice or by viral expression of mCREB in the nucleus accumbens produced an antidepres-sant effect similar to that observed after the blockade of CREB [100]. In summary, it is hypothesized that KOP an-tagonists attenuate the behavioural effects of elevated CREB expression within the nucleus accumbens, most likely by blocking KOP receptors that normally inhibit neurotransmit-ter release from mesolimbic dopaminergic neurons, contrib-uting to an antidepressant-like effect.

Recently, it has been suggested that KOP receptors regu-late activity in the locus coeruleus, which is the primary source of forebrain NE and has therefore been implicated in the pathophysiology of depression. Locus coeruleus innerva-tion by the KOR ligand dynorphin has been identified [107] and KORs seem to be located in axon terminals in the locus coeruleus that also contain the vesicular glutamatergic trans-porter and corticotropin-releasing factor (CRF) [108]. A re-cent study by Valentino’s group suggests that the activation of KOP in the locus coeruleus will diminish neural discharge evoked by engaging either excitatory amino acid or CRF inputs. That is, KOP in the locus coeruleus are poised to pre-synaptically inhibit diverse afferent signalling, which would alleviate symptoms of stress-related disorders [108]. All these data together, suggest that KOP activation in the locus coeruleus may decrease noradrenergic innervations in fore-brain areas, which could contribute to the pro-depressive effect.

Moreover, recent data suggest the mediation of CRF in the dysphoric effect of KOP in other brain areas like the ba-

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solateral amygdala, nucleus accumbens, dorsal raphe and hippocampus, areas implicated with negative affective states [109]. This study suggests that stress will cause the release of CRF which binds to and activates CRF2 receptors elicit-ing a subsequent release of dynorphin and the activation of KOP receptors, ultimately producing aversion. The neu-rotrophic factor hypothesis is another possible mechanism of action for KOP agonist-induced antidepressant-like effects. The intra-cerebro-ventricular (i.c.v.) administered KOP an-tagonist nor-BNI up-regulated BDNF mRNA expression in some sub-regions of the hippocampus and increased the du-ration of nor-BNI-induced antidepressant-like behavioural effects (forced swimming test) synchronized with a nor-BNI-mediated increase in BDNF mRNA expression [99]. These findings further demonstrate that central KOP receptors me-diate the antidepressant-like effects of nor-BNI measured by both behaviour and BDNF gene expression.

3. IMPLICATION OF RECEPTOR SIGNALING

PATHWAYS IN THE ANTIDEPRESSANT EFFECT

OF OPIOID COMPOUNDS

It is becoming increasingly clear that signaling via G protein-coupled receptors is a diverse phenomenon involving receptor interaction with a variety of signaling partners. Strategies that are gaining considerable attention are those that take advantage of the allosteric properties of GPCRs and their ability to adopt active conformations that differ in their pharmacological, signaling and regulatory properties [110, 111]. As previously stated, this conformational diversity may be explained at least in part by organization of GPCRs into multiprotein arrays where the conformational state of the receptor is dictated by its interactions with different complex components. Opioid receptors are pleiotropic receptors capa-ble of interacting with and activating numerous G subtypes in brain and heterologous expression systems [112-114]. Results obtained in glioma, HEK and CHO cells indicate that within each specific expression system the profile of acti-vation is similar for all agonists. However, results obtained following i.c.v. administration of [D-Ala

2,N-Me-Phe

4,Gly

5-

ol]-enkephalin (DAMGO) or morphine suggest that these agonists might differ in their ability to promote GTP S bind-ing by different G subunits[115]. Experiments in which different G subunits were selectively inactivated within the periaqueductal gray (using knockdown by antisense oli-godesoxynucleotides) may also lend some support to the idea that MOP receptors activate G subunits in a ligand specific manner [112]. In addition to studies with G proteins, bio-chemical and genetic knockout analyses have convincingly demonstrated that RGS proteins act as essential regulatory elements in the GPCR-mediated signal transduction path-ways. Numerous studies have shown the selectivity of RGS proteins in regulating GPCRs. These research data show that some RGS proteins regulate certain subtypes of signaling molecules, but have no effect on other subtypes, while dif-ferent RGS proteins display significant differences in the effectiveness in regulating a given signalling molecule. In that sense, it has been demonstrated in stable cell lines ex-pressing 5-HT1A, 5-HT2A, or D2 receptors, all involved in the pathophysiology of depression, that adenovirus-delivered expressions of RGS4, RGS10, and RGSZ1 effectively at-tenuate G i-mediated 5-HT1A receptor signaling, but have no

effect on that of D2 receptors. In contrast, RGS2 and RGS7 decrease G q-mediated 5-HT2A receptor signaling signifi-cantly, but have little effect on 5-HT1A and D2 receptors. [116]. In addition, RGS9 is an excellent example in elucidat-ing the selectivity and specificity of an RGS protein. There are two RGS9 variants, RGS9-1 and RGS9-2, derived from an alternative splicing of the same RGS9 gene. RGS9-1 is expressed primarily in the retina, as it is needed for a prompt recovery of the photoresponse of the photoreceptor rhodop-sin. RGS9-2, however, is highly enriched in the striatum and certain other brain areas have been shown to specifically regulate D2 and MOP receptors [117]. Particularly, RGS9-2 is shown to selectively accelerate the kinetics of dopamine D2-activated GIRK channels, while RGS4 is known to selec-tively accelerate the deactivation of MOP and KOP-linked GIRK channels. Thus, the antidepressant-like action of opioids might involve the regulation of monoaninergic re-ceptors at the level of the G proteins and/or RGS proteins.

Recent evidence has indicated that the N-methyl-D-aspartate (NMDA) receptor complex is also involved in the pathogenesis of depression, since NMDA receptor antago-nists exert antidepressant-like effects in both preclinical and clinical tests. Similarly, it has been claimed that the l-arginine–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signaling pathway may be involved [118, 119]. In fact, some studies have also shown that NOS (nitric oxide synthase) inhibitors display an antidepressant-like behavioral profile in mice [120, 121] and NO donors and inhibitors have been shown to affect 5-HT release in a dose-dependent manner in rodents [122, 123]. Recent studies have shown the possibility that the inhibition of NOS could be used as a strategy to enhance the clinical efficacy of serotonergic anti-depressants [120].

In nervous tissue, the MOP receptor is associated to a signaling module that helps control the activity of agonist-activated G z subunits. The C terminus of this opioid recep-tor binds to the protein kinase C-interacting protein (PKCI or HINT1), which connects the C terminus of this receptor with the N-terminal cysteine rich domain (CRD) of RGSZ1 and RGSZ2 proteins [124]. The association of HINT1/RGSZ with the MOP receptors appears to control (reduce) the activ-ity of morphine and to prevent profound desensitization of the MOP receptors. I.c.v. administration of morphine to mice recruits PKC isoforms, mostly PKC , to the MOP receptor via the HINT1/RGSZ complex [124]. This MOP-PKC asso-ciation involves the CRDs in the regulatory C1 region of PKC, as well as requiring free zinc ions, HINT1 and RGSZ proteins. Increasing the availability of this metal ion recruits inactive PKC to the MOP, while phorbol esters prevent this binding and even disrupt it. Moreover, the nitric oxide donor (S)-Nitroso-N-acetylpenicillamine (SNAP) foments the asso-ciation of PKC with the MOP receptors, an effect that is prevented by the heavy metal chelator N,N,N ,N -tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), suggesting a role for endogenous zinc and neural nitric oxide synthase (nNOS). Interestingly, the NMDA receptor antagonist MK801 pre-vented PKC recruitment to MOP receptors and serine phos-phorylation of the receptors following i.c.v. morphine [124]. Thus the NMDA receptor/nNOS cascade, activated via MOP receptors, might be involved in the antidepressant-like effect of MOP agonists. Moreover, this molecular mechanism

1618 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Berrocoso et al.

might explain the important role of zinc homeostasis in the psychopathology and therapy of depression.

The knowledge of the specific mechanisms that regulate the activity of the MOP receptors in the nervous system has greatly expanded. Recent work has demonstrated that MOP signaling can be modulated by the NMDA-nNOS cascade and that opioids may promote the facilitation of NMDA re-ceptors [124], suggesting cross-talk between MOP receptors and NMDA/nNOS systems. An enormous amount of data supports a role for the excitatory amino acid glutamate and its receptors in depression and antidepressant activity. In view of the fact that an intimate relationship exists between MOP and NMDA receptors, opioids might produce their antidepressant-like activity, modulating the subcellular sig-naling systems linked to these receptors.

4. CURRENT ANTIDEPRESSANTS AND THE OPIOID

SYSTEM

Antidepressants drugs, in addition to their well known effect on mood, are widely use for the treatment of several pain conditions, mainly headache, neuropathic and cancer pain. The analgesic mechanism of action of antidepressants has been extensively studied (for review see [125]) and sev-eral mechanisms of action have been implicated, mainly re-lated with the monoaminergic pathways (5-HT, NE and DA). Furthermore, an enhancement of the opioid system seems to underlie the analgesic effect of antidepressants. For instance, tryciclic antidepressants such as clomipramine, amitriptyline, clomipramine, desmethylclomipramine, imipramine, de-sipramine, maprotiline, nortriptyline, amoxapine and dothie-pin showed a naloxone-sentive analgesic effect in neuro-pathic, inflammatory and/or acute pain conditions [126-130]. In the same line, the antinociceptive effect of other classes of antidepressants like the 5-HT/NA reuptake inhibitor ven-lafaxine [131] and the SSRI paroxetine [128] has been re-lated to the modulation of the opioid system. Therefore, an-tidepressants mainly increase monoaminergic and opioid neurotransmission which seem to enhance endogenous pain control which is compromised in chronic pain conditions.

Regarding the implication of the opioid system in the antidepressant effect of antidepressant compounds, there are less data available. In a behavioural model of depression, naloxone blocked the antidepressant-like effect of clomi-pramine, desipramine and venlafaxine in the forced swim-ming test in mice [132, 133]. However, at least in the case of venlafaxine, when specific MOP, DOP or KOP antagonists were tested to determine the specific subtype of receptor implicated, all of them were ineffective [132]. In addition, in the learned helplessness test in rats the antidepressant-like effect of the tricyclic imipramine was antagonized by naloxone [27]. The mechanisms through which antidepres-sants enhance the opioid system still remain to be elucidated. However, an indirect mechanism that implies multiple intra-cellular signaling events has been suggested, because antide-pressant compounds do not bind to any opioid receptors. Indeed, chronic treatment with amoxapine or amitriptyline markedly enhanced the levels of leu-enkephalin in the hypo-thalamus and cerebral cortex [134]. Also, nefazodone treat-ment increased the density of neural cells immunostained for MOP receptors in the frontal and cingulate cortices, dorsal

raphe nucleus and periaqueductal gray [135]. In rats, chronic treatment with the antidepressant agent fluoxetine induced a two hundred-fold increase in amygdala enkephalin mRNA, relative to saline-treated animals [136]. The propensity of fluoxetine to increase enkephalin levels in the amygdala was dependent upon normal 5-HT levels and function per se [136]. However, met-enkephalin levels were decreased in the striatum, hippocampus, hypothalamus and adrenal gland, yet significantly increased in the hippocampus, under these iden-tical experimental treatments [137]. It has recently been demonstrated that acute administration of a sub-threshold dose of fluoxetine (2.5 mg/kg) in rats potentiated condi-tioned place preference when administered with a sub-threshold dose of the MOP agonist morphine [138] and po-tentiated the analgesic effect of morphine in the rat tail jerk assay [139], presumably via opioid mechanisms. Chronic imipramine treatment promotes the expression of the MOP receptors in the hippocampus and frontal cortex of the rat [140], and chronic imipramine and desipramine inhibit the enkephalin-degrading aminopeptidase in a concentration-dependent manner in rat brains [141, 142]. Furthermore, endogenous opioids have been implicated in the mechanism of action of antidepressant therapies [143, 144]. It should be considered that acute and chronic imipramine administration affects neurochemically distinct profiles of met- and leu-enkephalin release within the ventral tegmental area and nu-cleus accumbens [145]. Acute administration of imipramine (10 mg/kg, i.p.) decreased proenkephalin mRNA (20%) and prodynorphin mRNA (25%) in the nucleus accumbens and striatum while chronic administration (10 mg/kg i.p. twice daily for 10 days) increased nucleus accumbens prodynor-phin mRNA 24 h following the cessation of treatment [146]. Therefore, it could be suggested that the antidepressants which increase the availability of NE and 5-HT through the inhibition of the reuptake of both monoamines lead to the enhancement of opioid pathways. However, unfortunately, neither the molecular mechanism nor the specific opioid re-ceptor subtype implicated in the antidepressant-like effect of antidepressants is yet known.

5. CONCLUSION

Major depressive disorder is highly prevalent and re-mains inadequately treated. Decades of research have not permitted us to fully understand the molecular basis of mood disorders. The cellular mechanisms of action of many anti-depressants are still unknown, and many depressed patients do not respond to antidepressant therapy. MOP and DOP activation and/or KOP blockade produce antidepressant-like effects in a number of preclinical assays, suggesting that these may be other pharmacological targets for treating de-pression in humans. Furthermore, cellular adaptations that occur following chronic opioid treatment profoundly influ-ence synaptic plasticity in neural systems which are impor-tant for their effects. Alteration in presynaptic transmitter release together with the modulation of the intracellular sig-naling pathways described above might be responsible for their effects as antidepressants. Recent studies describing a direct connection between the MOP receptor subtype and the NMDA receptor raise the possibility that intracellular signal-ing pathways might represent new targets with great poten-tial that would enable the design of more efficacious thera-

Opiates as Antidepressants Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1619

peutic protocols and drugs. The understanding of the mo-lecular mechanisms involved in the genesis and maintenance of depression appears to be a major objective in this field.

ACKOWLEDGEMENTS

This study has been supported by the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM (CB07/09/ 0033), Fondo de Investigación Sanitaria" (PI070687 and PI080417) and "Plan Andaluz de Investigación (CTS-510 and CTS-4303).

ABBREVIATIONS

= Mu opioid

= Delta opioid

= Kappa opioid

5-HIAA = 5-Hydroxyindoleacetic acid

5-HT = Serotonin

BDNF = Brain derived neurotrophic factor

cGMP = Cyclic guanosine monophosphate

CNS = Central nervous system

CRD = Cysteine rich domain

CRF = Corticotropin-releasing factor

DA = Dopamine

DOP = Delta opioid

GABA = Gamma-aminobutyric acid

GPCR = G Protein-coupled receptor

i.c.v. = Intra-cerebro-ventricular

i.p. = Intraperitoneal

IUPHAR = International Union of Basic and Clinical Pharmacology

KOP = Kappa opioid

MOP = Mu opioid

NE = Norepinephrine

NMDA = N-Methyl-D-aspartate

nNOS = Neural nitric oxide synthase

NO = Nitric oxide

Nor-BNI = Nor-Binaltorphimine

NOS = Nitric oxide synthase

PKCI = Protein kinase C-interacting protein

SNAP = (S)-Nitroso-N-acetylpenicillamine

TPEN = N,N,N ,N -Tetrakis(2-pyridylmethyl) ethylenediamine

REFERENCES

References 147-149 are related articles recently published.

[1] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia

LM. Neurobiology of depression. Neuron 2002; 34: 13-25. [2] Schildkraut JJ. The catecholamine hypothesis of affective disor-

ders: a review of supporting evidence. Am J Psychiatry 1965; 122: 509-22.

[3] Charney DS. Monoamine dysfunction and the pathophysiology and

treatment of depression. J Clin Psychiatry 1998; 59(Suppl 14): 11-4.

[4] Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69(Suppl E1): 4-

7. [5] Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart

JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D re-

port. Am J Psychiatry 2006; 163: 1905-17. [6] Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The

STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep 2007; 9: 449-59.

[7] Millan MJ. Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates,

drug discovery and therapeutic application. Pharmacol Ther 2006; 110: 135-370.

[8] Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008; 455: 894-902.

[9] Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F. Strategies for producing faster acting antidepressants. Drug Discov

Today 2005; 10: 578-85. [10] Extein I, Pottash ALC, Gold MS. In: Verebey K, Ed. Opioids in

mental illness: Theories, clinical observations and treatment possi-bilities, The New York Academy of Sciences: New York 1982; vol.

398, pp. 113-9. [11] Emrich HM, Vogt P, Herz A. In: Verebey K, Ed. Opioids in mental

illness: Theories, clinical observations and treatment possibilities, The New York Academy of Sciences: New York 1982; vol. 398:

pp. 108-12. [12] Kraepelin E. Einführung in die psychiatrische klinik. Ambrosius

Barth-Verlag: Leipzig 1901. [13] Milligan G, Murdoch H, Kellett E, White JH, Feng GJ. Interactions

between G-protein-coupled receptors and periplakin: a selective means to regulate G-protein activation. Biochem Soc Trans 2004;

32: 878-80. [14] Pert CB, Snyder SH. Opiate receptor: demonstration in nervous

tissue. Science 1973; 179: 1011-4. [15] Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of

opioid research: the exciting but vain quest for the Holy Grail. Br J Pharmacol 2006; 147(Suppl 1): S153-62.

[16] Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem 2004; 73: 953-90.

[17] Tegeder I, Geisslinger G. Opioids as modulators of cell death and survival--unraveling mechanisms and revealing new indications.

Pharmacol Rev 2004; 56: 351-69. [18] Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Por-

toghese PS, et al. International Union of Pharmacology. XII. Clas-sification of opioid receptors. Pharmacol Rev 1996; 48: 567-92.

[19] Sanchez-Blazquez P, Rodriguez-Diaz M, Frejo MT, Garzon J. Stimulation of mu- and delta-opioid receptors enhances phosphoi-

nositide metabolism in mouse spinal cord: evidence for subtypes of delta-receptors. Eur J Neurosci 1999; 11: 2059-64.

[20] Portoghese PS. From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J Med Chem

2001; 44: 2259-69. [21] Kennedy SE, Koeppe RA, Young EA, Zubieta JK. Dysregulation

of endogenous opioid emotion regulation circuitry in major depres-sion in women. Arch Gen Psychiatry 2006; 63: 1199-208.

[22] Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 1995;

15: 49-57. [23] Stoll AL, Rueter S. Treatment augmentation with opiates in severe

and refractory major depression. Am J Psychiatry 1999; 156: 2017. [24] Darko DF, Risch SC, Gillin JC, Golshan S. Association of beta-

endorphin with specific clinical symptoms of depression. Am J Psychiatry 1992; 149: 1162-7.

[25] Djurovic D, Milic-Askrabic J, Majkic-Singh N. Serum beta-endorphin level in patients with depression on fluvoxamine. Far-

maco 1999; 54: 130-3. [26] Besson A, Privat AM, Eschalier A, Fialip J. Effects of morphine,

naloxone and their interaction in the learned-helplessness paradigm in rats. Psychopharmacology (Berl) 1996; 123: 71-8.

[27] Tejedor-Real P, Mico JA, Maldonado R, Roques BP, Gibert-Rahola J. Implication of endogenous opioid system in the learned

1620 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Berrocoso et al.

helplessness model of depression. Pharmacol Biochem Behav

1995; 52: 145-52. [28] Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico JA. Anti-

depressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life Sci

2002; 72: 143-52. [29] Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective

endogenous agonist for the mu-opiate receptor. Nature 1997; 386: 499-502.

[30] Fichna J, Janecka A, Piestrzeniewicz M, Costentin J, do Rego JC. Antidepressant-like effect of endomorphin-1 and endomorphin-2 in

mice. Neuropsychopharmacology 2007; 32: 813-21. [31] Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin

F, et al. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 2000; 25:

195-200. [32] Tao R, Ma Z, Auerbach SB. Differential regulation of 5-

hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br J Pharmacol 1996;

119: 1375-84. [33] Tao R, Auerbach SB. Involvement of the dorsal raphe but not me-

dian raphe nucleus in morphine-induced increases in serotonin re-lease in the rat forebrain. Neuroscience 1995; 68: 553-61.

[34] Diez-Guerra FJ, Augood S, Emson PC, Dyer RG. Opioid peptides inhibit the release of noradrenaline from slices of rat medial preop-

tic area. Exp Brain Res 1987; 66: 378-84. [35] Hagan RM, Hughes IE. Opioid receptor sub-types involved in the

control of transmitter release in cortex of the brain of the rat. Neuropharmacology 1984; 23: 491-5.

[36] Peoples RW, Giridhar J, Isom GE. Gamma-aminobutyric acidA (GABAA) receptor modulation of morphine inhibition of norepi-

nephrine release. Biochem Pharmacol 1991; 42(Suppl): S121-6. [37] Werling LL, Brown SR, Cox BM. Opioid receptor regulation of the

release of norepinephrine in brain. Neuropharmacology 1987; 26: 987-96.

[38] Fiber JM, Etgen AM. Modulation of GABA-augmented norepi-nephrine release in female rat brain slices by opioids and adeno-

sine. Neurochem Res 2001; 26: 853-8. [39] Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic

and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung 1988; 38: 877-80.

[40] Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to

the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther 1992; 260: 275-85.

[41] Bamigbade TA, Davidson C, Langford RM, Stamford JA. Actions of tramadol, its enantiomers and principal metabolite, O-

desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997; 79: 352-6.

[42] Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, et al. Maintenance of the long-term effectiveness of tramadol in

treatment of the pain of diabetic neuropathy. J Diabetes Compl 2000; 14: 65-70.

[43] Flohe L, Arend I, Cogal A, Richter W, Simon W. [Clinical study on the development of dependency after long-term treatment with

tramadol (author's transl)]. Arzneimittelforschung 1978; 28: 213-7. [44] Richter W, Barth H, Flohe L, Giertz H. Clinical investigation on

the development of dependence during oral therapy with tramadol. Arzneimittelforschung 1985; 35: 1742-4.

[45] Hollingshead J, Duhmke RM, Cornblath DR. Tramadol for neuro-pathic pain. Cochrane Database Syst Rev 2006; 3: CD003726.

[46] Shapira NA, Verduin ML, DeGraw JD. Treatment of refractory major depression with tramadol monotherapy. J Clin Psychiatry

2001; 62: 205-6. [47] Spencer C. The efficacy of intramuscular tramadol as a rapid-onset

antidepressant. Aust N Z J Psychiatry 2000; 34: 1032-3. [48] Fanelli J, Montgomery C. Use of the analgesic tramadol in antide-

pressant potentiation. Psychopharmacology Bulletin 1998; 32: 442. [49] Shapira NA, Keck PE, Jr., Goldsmith TD, McConville BJ, Eis M,

McElroy SL. Open-label pilot study of tramadol hydrochloride in treatment-refractory obsessive-compulsive disorder. Depress

Anxiety 1997; 6: 170-3. [50] Shapira NA, McConville BJ, Pagnucco ML, Norman AB, Keck PE,

Jr. Novel use of tramadol hydrochloride in the treatment of Tourette's syndrome. J Clin Psychiatry 1997; 58: 174-5.

[51] Rojas-Corrales MO, Gibert-Rahola J, Mico JA. Tramadol induces

antidepressant-type effects in mice. Life Sci 1998; 63: PL175-80. [52] Yalcin I, Aksu F, Bodard S, Chalon S, Belzung C. Antidepressant-

like effect of tramadol in the unpredictable chronic mild stress pro-cedure: possible involvement of the noradrenergic system. Behav

Pharmacol 2007; 18: 623-31. [53] Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico JA. Anti-

depressant-like effect of tramadol and its enantiomers in reser-pinized mice: comparative study with desipramine, fluvoxamine,

venlafaxine and opiates. J Psychopharmacol 2004; 18: 404-11. [54] Hopwood SE, Owesson CA, Callado LF, McLaughlin DP,

Stamford JA. Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function. J Psychopharmacol 2001; 15:

147-53. [55] Faron-Gorecka A, Kusmider M, Inan SY, Siwanowicz J, Dzied-

zicka-Wasylewska M. Effects of tramadol on alpha2-adrenergic re-ceptors in the rat brain. Brain Res 2004; 1016: 263-7.

[56] Faron-Gorecka A, Kusmider M, Inan SY, Siwanowicz J, Piwowar-czyk T, Dziedzicka-Wasylewska M. Long-term exposure of rats to

tramadol alters brain dopamine and alpha 1-adrenoceptor function that may be related to antidepressant potency. Eur J Pharmacol

2004; 501: 103-10. [57] Berrocoso E, Mico JA, Ugedo L. In vivo effect of tramadol on

locus coeruleus neurons is mediated by alpha2-adrenoceptors and modulated by serotonin. Neuropharmacology 2006; 51: 146-53.

[58] Jiang Q, Takemori AE, Sultana M, Portoghese PS, Bowen WD, Mosberg HI, et al. Differential antagonism of opioid delta antinoci-

ception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol

Exp Ther 1991; 257: 1069-75. [59] Brandt MR, Furness MS, Rice KC, Fischer BD, Negus SS. Studies

of tolerance and dependence with the delta-opioid agonist SNC80 in rhesus monkeys responding under a schedule of food presenta-

tion. J Pharmacol Exp Ther 2001; 299: 629-37. [60] Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selec-

tive blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther

1991; 258: 299-303. [61] Nadal X, Banos JE, Kieffer BL, Maldonado R. Neuropathic pain is

enhanced in delta-opioid receptor knockout mice. Eur J Neurosci 2006; 23: 830-4.

[62] Fraser GL, Gaudreau GA, Clarke PB, Menard DP, Perkins MN. Antihyperalgesic effects of delta opioid agonists in a rat model of

chronic inflammation. Br J Pharmacol 2000; 129: 1668-72. [63] Porreca F, Takemori AE, Sultana M, Portoghese PS, Bowen WD,

Mosberg HI. Modulation of mu-mediated antinociception in the mouse involves opioid delta-2 receptors. J Pharmacol Exp Ther

1992; 263: 147-52. [64] Cheng PY, Wu D, Soong Y, McCabe S, Decena JA, Szeto HH.

Role of mu 1- and delta-opioid receptors in modulation of fetal EEG and respiratory activity. Am J Physiol 1993; 265: R433-8.

[65] Hudzik TJ, Howell A, Payza K, Cross AJ. Antiparkinson potential of delta-opioid receptor agonists. Eur J Pharmacol 2000; 396: 101-

7. [66] Jutkiewicz EM. The antidepressant -like effects of delta-opioid

receptor agonists. Mol Interv 2006; 6: 162-9. [67] Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN,

Brownstein MJ, et al. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 1996; 383: 535-8.

[68] Ragnauth A, Schuller A, Morgan M, Chan J, Ogawa S, Pintar J, et al. Female preproenkephalin-knockout mice display altered emo-

tional responses. Proc Natl Acad Sci USA 2001; 98: 1958-63. [69] Tejedor-Real P, Mico JA, Smadja C, Maldonado R, Roques BP,

Gilbert-Rahola J. Involvement of delta-opioid receptors in the ef-fects induced by endogenous enkephalins on learned helplessness

model. Eur J Pharmacol 1998; 354: 1-7. [70] Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson

SJ, Woods JH. Peptidic delta opioid receptor agonists produce an-tidepressant-like effects in the forced swim test and regulate BDNF

mRNA expression in rats. Brain Res 2006; 1069: 172-81. [71] Baamonde A, Dauge V, Ruiz-Gayo M, Fulga IG, Turcaud S,

Fournie-Zaluski MC, et al. Antidepressant-type effects of endoge-nous enkephalins protected by systemic RB 101 are mediated by

opioid delta and dopamine D1 receptor stimulation. Eur J Pharma-col 1992; 216: 157-66.

Opiates as Antidepressants Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1621

[72] Jutkiewicz EM, Eller EB, Folk JE, Rice KC, Traynor JR, Woods

JH. Delta-opioid agonists: differential efficacy and potency of SNC80, its 3-OH (SNC86) and 3-desoxy (SNC162) derivatives in

Sprague-Dawley rats. J Pharmacol Exp Ther 2004; 309: 173-81. [73] Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods

JH. Nonpeptidic delta-opioid receptor agonists reduce immobility in the forced swim assay in rats. Neuropsychopharmacology 2002;

26: 744-55. [74] Saitoh A, Kimura Y, Suzuki T, Kawai K, Nagase H, Kamei J.

Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents. J

Pharmacol Sci 2004; 95: 374-80. [75] Saitoh A, Yamada M, Yamada M, Takahashi K, Yamaguchi K,

Murasawa H, et al. Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-di-

methyl-4-(2-propenyl)-1-piperazinyl ]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model.

Brain Res 2008; 1208: 160-9. [76] Jenny M, Winkler C, Spetea M, Schennach H, Schmidhammer H,

Fuchs D. Non-peptidic delta-opioid receptor antagonists suppress mitogen-induced tryptophan degradation in peripheral blood

mononuclear cells in vitro. Immunol Lett 2008; 118: 82-7. [77] Spina L, Longoni R, Mulas A, Chang KJ, Di Chiara G. Dopamine-

dependent behavioural stimulation by non-peptide delta opioids BW373U86 and SNC 80: 1. Locomotion, rearing and stereotypies

in intact rats. Behav Pharmacol 1998; 9: 1-8. [78] Negus SS, Gatch MB, Mello NK. Discriminative stimulus effects

of a cocaine/heroin "speedball" combination in rhesus monkeys. J Pharmacol Exp Ther 1998; 285: 1123-36.

[79] Longoni R, Cadoni C, Mulas A, Di Chiara G, Spina L. Dopamine-dependent behavioural stimulation by non-peptide delta opioids

BW373U86 and SNC 80: 2. Place-preference and brain mi-crodialysis studies in rats. Behav Pharmacol 1998; 9: 9-14.

[80] Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity,

and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 2006; 58: 115-34.

[81] Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated

with antidepressant medication. Biol Psychiatry 2001; 50: 260-5. [82] Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ.

Hippocampal brain-derived neurotrophic factor expression follow-ing treatment with reboxetine, citalopram, and physical exercise.

Neuropsychopharmacology 2004; 29: 2189-99. [83] Torregrossa MM, Isgor C, Folk JE, Rice KC, Watson SJ, Woods

JH. The delta-opioid receptor agonist (+)BW373U86 regulates BDNF mRNA expression in rats. Neuropsychopharmacology 2004;

29: 649-59. [84] Torregrossa MM, Folk JE, Rice KC, Watson SJ, Woods JH.

Chronic administration of the delta opioid receptor agonist (+)BW373U86 and antidepressants on behavior in the forced swim

test and BDNF mRNA expression in rats. Psychopharmacology (Berl) 2005; 183: 31-40.

[85] Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH. Convulsant activity of a non-peptidic delta-opioid receptor

agonist is not required for its antidepressant-like effects in Sprague-Dawley rats. Psychopharmacology (Berl) 2002; 164: 42-8.

[86] Chipkin RE, Coffin VL. Analgesic and acute central nervous sys-tem side effects of the intravenously administered enkephalinase

inhibitor SCH 32615. Pharmacol Biochem Behav 1991; 38: 21-7. [87] Stutzmann JM, Bohme GA, Roques BP, Blanchard JC. Differential

electrographic patterns for specific mu- and delta-opioid peptides in rats. Eur J Pharmacol 1986; 123: 53-9.

[88] De Sarro GB, Marra R, Spagnolo C, Nistico G. Delta opioid recep-tors mediate seizures produced by intrahippocampal injection of

ala-deltorphin in rats. Funct Neurol 1992; 7: 235-8. [89] Millan MJ. Descending control of pain. Prog Neurobiol 2002; 66:

355-474. [90] Leander JD. A kappa opioid effect: increased urination in the rat. J

Pharmacol Exp Ther 1983; 224: 89-94. [91] Fjalland B, Christensen JD. Kappa-opioid receptor agonists differ-

entially affect the release of neurohypophysial hormones. Pharma-col Toxicol 1990; 66: 176-8.

[92] Birch PJ, Rogers H, Hayes AG, Hayward NJ, Tyers MB, Scopes DI, et al. Neuroprotective actions of GR89696, a highly potent and

selective kappa-opioid receptor agonist. Br J Pharmacol 1991; 103:

1819-23. [93] Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA, Jr.

Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther

2007; 323: 838-45. [94] Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis medi-

ated by kappa opiate receptors. Science 1986; 233: 774-6. [95] Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang

Y, Stevens WC, Jr., et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Phar-

macol Exp Ther 2003; 305: 323-30. [96] Todtenkopf MS, Marcus JF, Portoghese PS, Carlezon WA, Jr.

Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology (Berl) 2004; 172: 463-70.

[97] Carlezon WA, Jr., Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, et al. Depressive-like effects of the kappa-

opioid receptor agonist salvinorin A on behavior and neurochemis-try in rats. J Pharmacol Exp Ther 2006; 316: 440-7.

[98] Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carle-zon WA, Jr. Altered responsiveness to cocaine and increased im-

mobility in the forced swim test associated with elevated cAMP re-sponse element-binding protein expression in nucleus accumbens. J

Neurosci 2001; 21: 7397-403. [99] Zhang H, Shi YG, Woods JH, Watson SJ, Ko MC. Central kappa-

opioid receptor-mediated antidepressant-like effects of nor-Binaltorphimine: behavioral and BDNF mRNA expression studies.

Eur J Pharmacol 2007; 570: 89-96. [100] Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L,

Sakai N, et al. Inhibition of cAMP response element-binding pro-tein or dynorphin in the nucleus accumbens produces an antide-

pressant-like effect. J Neurosci 2002; 22: 10883-90. [101] Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman

RS. Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like ef-

fects. J Neurochem 2004; 90: 1258-68. [102] Reindl JD, Rowan K, Carey AN, Peng X, Neumeyer JL, McLaugh-

lin JP. Antidepressant-like effects of the novel kappa opioid an-tagonist MCL-144B in the forced-swim test. Pharmacology 2008;

81: 229-35. [103] McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid

receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 2003; 23: 5674-83.

[104] McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C. Prior activa-tion of kappa opioid receptors by U50,488 mimics repeated forced

swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 2006; 31: 787-94.

[105] Nestler EJ, Carlezon WA, Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006; 59: 1151-9.

[106] Wise RA, Bozarth MA. Action of drugs of abuse on brain reward systems: an update with specific attention to opiates. Pharmacol

Biochem Behav 1982; 17: 239-43. [107] Reyes BA, Johnson AD, Glaser JD, Commons KG, Van Bockstaele

EJ. Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neuroscience 2007;

145: 1077-86. [108] Kreibich A, Reyes BA, Curtis AL, Ecke L, Chavkin C, Van Bocks-

taele EJ, et al. Presynaptic inhibition of diverse afferents to the lo-cus ceruleus by kappa-opiate receptors: a novel mechanism for

regulating the central norepinephrine system. J Neurosci 2008; 28: 6516-25.

[109] Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C. The dysphoric component of stress is encoded by activation of the

dynorphin kappa-opioid system. J Neurosci 2008; 28: 407-14. [110] Garzon J, Rodriguez-Munoz M, de la Torre-Madrid E, Sanchez-

Blazquez P. Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid re-

ceptors in the CNS. Psychopharmacology (Berl) 2005; 180: 1-11. [111] Gilchrist A. Modulating G-protein-coupled receptors: from tradi-

tional pharmacology to allosterics. Trends Pharmacol Sci 2007; 28: 431-7.

[112] Garzon J, de Antonio I, Sanchez-Blazquez P. In vivo modulation of G proteins and opioid receptor function by antisense oligodeoxynu-

cleotides. Methods Enzymol 2000; 314: 3-20. [113] Robb S, Cheek TR, Hannan FL, Hall LM, Midgley JM, Evans PD.

Agonist-specific coupling of a cloned Drosophila octopa-

1622 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Berrocoso et al.

mine/tyramine receptor to multiple second messenger systems.

Embo J 1994; 13: 1325-30. [114] Sanchez-Blazquez P, Gomez-Serranillos P, Garzon J. Agonists

determine the pattern of G-protein activation in mu-opioid recep-tor-mediated supraspinal analgesia. Brain Res Bull 2001; 54: 229-

35. [115] Garzon J, Martinez-Pena Y, Sanchez-Blazquez P. Gx/z is regulated

by mu but not delta opioid receptors in the stimulation of the low Km GTPase activity in mouse periaqueductal grey matter. Eur J

Neurosci 1997; 9: 1194-200. [116] Ghavami A, Hunt RA, Olsen MA, Zhang J, Smith DL, Kalgaonkar

S, et al. Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2

receptor-mediated signaling and adenylyl cyclase activity. Cell Signal 2004; 16: 711-21.

[117] Garzon J, Rodriguez-Diaz M, Lopez-Fando A, Sanchez-Blazquez P. RGS9 proteins facilitate acute tolerance to mu-opioid effects.

Eur J Neurosci 2001; 13: 801-11. [118] Esplugues JV. NO as a signalling molecule in the nervous system.

Br J Pharmacol 2002; 135: 1079-95. [119] Mantovani M, Pertile R, Calixto JB, Santos AR, Rodrigues AL.

Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate re-

ceptors and the L-arginine-nitric oxide pathway. Neurosci Lett 2003; 343: 1-4.

[120] Harkin A, Connor TJ, Burns MP, Kelly JP. Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in

the forced swimming test. Eur Neuropsychopharmacol 2004; 14: 274-81.

[121] Harkin AJ, Bruce KH, Craft B, Paul IA. Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute

treatments are active in the forced swim test. Eur J Pharmacol 1999; 372: 207-13.

[122] Kaehler ST, Singewald N, Sinner C, Philippu A. Nitric oxide modulates the release of serotonin in the rat hypothalamus. Brain

Res 1999; 835: 346-9. [123] Lorrain DS, Hull EM. Nitric oxide increases dopamine and sero-

tonin release in the medial preoptic area. NeuroReport 1993; 5: 87-9.

[124] Rodriguez-Munoz M, de la Torre-Madrid E, Sanchez-Blazquez P, Wang JB, Garzon J. NMDAR-nNOS generated zinc recruits

PKCgamma to the HINT1-RGS17 complex bound to the C termi-nus of Mu-opioid receptors. Cell Signal 2008; 20: 1855-64.

[125] Mico JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. Trends Pharmacol Sci 2006; 27: 348-54.

[126] Valverde O, Mico JA, Maldonado R, Mellado M, Gibert-Rahola J. Participation of opioid and monoaminergic mechanisms on the an-

tinociceptive effect induced by tricyclic antidepressants in two be-havioural pain tests in mice. Prog Neuropsychopharmacol Biol

Psychiatry 1994; 18: 1073-92. [127] Marchand F, Ardid D, Chapuy E, Alloui A, Jourdan D, Eschalier

A. Evidence for an involvement of supraspinal delta- and spinal mu-opioid receptors in the antihyperalgesic effect of chronically

administered clomipramine in mononeuropathic rats. J Pharmacol Exp Ther 2003; 307: 268-74.

[128] Gray AM, Spencer PS, Sewell RD. The involvement of the opioi-dergic system in the antinociceptive mechanism of action of anti-

depressant compounds. Br J Pharmacol 1998; 124: 669-74. [129] Su X, Gebhart GF. Effects of tricyclic antidepressants on mecha-

nosensitive pelvic nerve afferent fibers innervating the rat colon. Pain 1998; 76: 105-14.

[130] Reichenberg K, Gaillard-Plaza G, Montastruc JL. Influence of naloxone on the antinociceptive effects of some antidepressant

drugs. Arch Int Pharmacodyn Ther 1985; 275: 78-85. [131] Schreiber S, Backer MM, Pick CG. The antinociceptive effect of

venlafaxine in mice is mediated through opioid and adrenergic mechanisms. Neurosci Lett 1999; 273: 85-8.

[132] Berrocoso E, Rojas-Corrales MO, Mico JA. Non-selective opioid

receptor antagonism of the antidepressant-like effect of venlafaxine in the forced swimming test in mice. Neurosci Lett 2004; 363: 25-

8. [133] Devoize JL, Rigal F, Eschalier A, Trolese JF, Renoux M. Influence

of naloxone on antidepressant drug effects in the forced swimming test in mice. Psychopharmacology (Berl) 1984; 84: 71-5.

[134] Hamon M, Gozlan H, Bourgoin S, Benoliel JJ, Mauborgne A, Taquet H, et al. Opioid receptors and neuropeptides in the CNS in

rats treated chronically with amoxapine or amitriptyline. Neurop-harmacology 1987; 26: 531-9.

[135] Ortega-Alvaro A, Acebes I, Saracibar G, Echevarria E, Casis L, Mico JA. Effect of the antidepressant nefazodone on the density of

cells expressing mu-opioid receptors in discrete brain areas proc-essing sensory and affective dimensions of pain. Psychopharma-

cology (Berl) 2004; 176: 305-11. [136] Rossby SP, Nalepa I, Huang M, Perrin C, Burt AM, Schmidt DE, et

al. Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant. Brain Res 1995; 687: 79-82.

[137] Dziedzicka-Wasylewska M, Dlaboga D, Pierzchala-Koziec K, Rogoz Z. Effect of tianeptine and fluoxetine on the levels of Met-

enkephalin and mRNA encoding proenkephalin in the rat. J Physiol Pharmacol 2002; 53: 117-25.

[138] Subhan F, Pache DM, Sewell RD. Potentiation of opioid-induced conditioned place preference by the selective serotonin reuptake

inhibitor fluoxetine. Eur J Pharmacol 2000; 390: 137-43. [139] Hynes MD, Lochner MA, Bemis KG, Hymson DL. Fluoxetine, a

selective inhibitor of serotonin uptake, potentiates morphine anal-gesia without altering its discriminative stimulus properties or af-

finity for opioid receptors. Life Sci 1985; 36: 2317-23. [140] de Gandarias JM, Echevarria E, Acebes I, Silio M, Casis L. Effects

of imipramine administration on mu-opioid receptor immunostain-ing in the rat forebrain. Arzneimittelforschung 1998; 48: 717-9.

[141] de Gandarias JM, Irazusta J, Fernandez D, Varona A, Gil J, Casis L. Effect of lidocaine administration on the enkephalin-degrading

aminopeptidase activities in discrete areas of the rat brain. Gen Pharmacol 1997; 29: 489-93.

[142] Gallego M, Casis L, Casis O. Imipramine inhibits soluble enkephalin-degrading aminopeptidase activity in vitro. Eur J Phar-

macol 1998; 360: 113-6. [143] De Felipe MC, De Ceballos ML, Gil C, Fuentes JA. Chronic anti-

depressant treatment increases enkephalin levels in n. accumbens and striatum of the rat. Eur J Pharmacol 1985; 112: 119-22.

[144] de Felipe MC, Jimenez I, Castro A, Fuentes JA. Antidepressant action of imipramine and iprindole in mice is enhanced by inhibi-

tors of enkephalin-degrading peptidases. Eur J Pharmacol 1989; 159: 175-80.

[145] Dziedzicka-Wasylewska M, Rogoz R. The effect of prolonged treatment with imipramine and electroconvulsive shock on the lev-

els of endogenous enkephalins in the nucleus accumbens and the ventral tegmentum of the rat. J Neural Transm Gen Sect 1995; 102:

221-28. [146] Przewlocki R, Lason W, Turchan J, Przewlocka B. Imipramine

induces alterations in proenkephalin and prodynorphin mRNAs level in the nucleus accumbens and striatum in the rat. Pol J Phar-

macol 1997; 49: 351-5. [147] Chen Z, Yang J, Tobak A. Designing new treatments for depres-

sion and anxiety. IDrugs 2008; 11(3): 189-97. [148] Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, Varella EA,

Nicolaides DN. Recent developments in the chemistry and in the biological applications of amidoximes. Curr Pharm Des 2008;

14(10): 1001-47. [149] Han TS, Teichert RW, Olivera BM, Bulaj G. Conus venoms - a

rich source of peptide-based therapeutics. Curr Pharm Des 2008; 14(24): 2462-79.