Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation

Wahlström, Agneta; Lenhammar, Lena; Ask, Birgitta; Rane, Anders

doi:10.1111/j.1600-0773.1994.tb00319.x

Cited by 39 publications

(22 citation statements)

References 25 publications

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“…The preferential activity of classic TCAs at -opioid receptors correlates with previous radioligand binding studies reporting a higher selectivity of these drugs for -over -and ␦-opioid binding sites in the human thalamic area (Wahlström et al, 1994).…”

Section: Discussionsupporting

confidence: 65%

“…For example, in vivo administration of TCAs has been found to cause a decrease, an increase, and no change in opioid receptor density in different brain areas (StengaardPedersen and Schou, 1986;Hamon et al, 1987;Chen and Lawrence, 2004). Moreover, TCAs have been reported to be either devoid of activity at brain opioid receptors (Hall and Ogren, 1981) or capable of inhibiting opioid receptor binding at pharmacologically relevant concentrations (Biegon and Samuel, 1980;Isenberg and Cicero, 1984;Wahlström et al, 1994). Thus, whether these drugs can directly act on opioid receptors and whether the distinct opioid receptor subtypes are differentially affected by TCAs still remain unresolved issues.…”

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confidence: 99%

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Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Onali¹,

Dedoni²,

Olianas³

2010

The Journal of Pharmacology and Experimental Therapeutics

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Tricyclic antidepressants (TCAs) have been reported to interact with the opioid system, but their pharmacological activity at opioid receptors has not yet been elucidated. In the present study, we investigated the actions of amoxapine, amitriptyline, nortriptyline, desipramine, and imipramine at distinct cloned and native opioid receptors. In Chinese hamster ovary (CHO) cells expressing ␦-opioid receptors (CHO/DOR), TCAs displaced [3H]naltrindole binding and stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding at micromolar concentrations with amoxapine displaying the highest potency and efficacy. Amoxapine and amitriptyline inhibited cyclic AMP formation and induced the phosphorylation of signaling molecules along the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase pathways. Amoxapine also activated ␦-opioid receptors in rat dorsal striatum and nucleus accumbens and human frontal cortex. In CHO cells expressing -opioid receptors (CHO/KOR), TCAs, but not amoxapine, exhibited higher receptor affinity and more potent stimulation of [35 S]GTP␥S binding than in CHO/DOR and effectively inhibited cyclic AMP accumulation. Amitriptyline regulated ERK1/2 phosphorylation and activity in CHO/KOR and C6 glioma cells endogenously expressing -opioid receptors, and this effect was attenuated by the -opioid antagonist nor-binaltorphimine. In rat nucleus accumbens, amitriptyline slightly inhibited adenylyl cyclase activity and counteracted the inhibitory effect of the full agonist trans-(Ϫ) -3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488). At the cloned -opioid receptor, TCAs showed low affinity and no significant agonist activity. These results show that TCAs differentially regulate opioid receptors with a preferential agonist activity on either ␦ or subtypes and suggest that this property may contribute to their therapeutic and/or side effects.Although the inhibition of presynaptic reuptake of monoamines is considered to be the primary mechanism of action of tricyclic antidepressants (TCAs), it is well established that these drugs can act on multiple molecular targets by affecting the activity of distinct neurotransmitter receptor systems and ion channels (Baldessarini, 2006). These secondary actions have been generally related to TCAs' adverse side effects, although some of them have been proposed to contribute to the therapeutic activity.An interaction with the opioid system has long been shown to be involved in the analgesic and mood-elevating effects of TCAs. A number of studies have reported that the antinociceptive effects of TCAs are reversed by opioid receptor antagonists (Biegon and Samuel, 1980;Gray et al., 1998;Marchand et al., 2003; Benbouzid et al., 2008a,b) and that TCAs potentiate morphine-induced analgesia both in animals (Hamon et al., 1987) and in humans (Micó et al., 2006). In animal behavioral tests predictive of antidepressant effects in humans, such as the forced swimming and learned helplessness tests, th...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Onali¹,

Dedoni²,

Olianas³

2010

The Journal of Pharmacology and Experimental Therapeutics

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“…Furthermore, these binding sites/isoforms are inhibited by methadone to different extents. Alteration of the M3G/M6G formation ratio has previously been observed after the inhibition of morphine glucuronidation by various drugs and metal ions in human liver microsome systems [38,42]. We have also observed an increase in the M3G/M6G ratio in methadone-maintained subjects administered morphine compared with non-opioid-dependent controls [43], suggesting that methadone differentially inhibits morphine glucuronidation to M3G and M6G in vivo in a stereoselective manner.…”

mentioning

confidence: 54%

“…In addition, further investigation showed that both (R)-and (S)-methadone noncompetitively inhibited the formation of both M3G and M6G. Noncompetitive inhibition of morphine metabolism by nortriptyline has previously been demonstrated [38]. However, this is the first time methadone has been shown to inhibit glucuronidation noncompetitively.…”

Section: Tablementioning

confidence: 72%

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Morrish

Foster

Somogyi

2005

Brit J Clinical Pharma

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Differential in vitro inhibition of M3G and M6G formation from morphine by (R)-and (S)-methadone and structurally related opioids Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia AimsTo determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. MethodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µ M ) and the mechanism of inhibition determined for (R)-and (S)-methadone (70-500 µ M ) using three microsomal samples. ResultsGlucuronide formation displayed single enzyme kinetics. The M3G V max (mean ± SD) was 4.8-fold greater than M6G V max (555 ± 110 vs. 115 ± 19 nmol mg − 1 protein h − 1 ; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg − 1 protein h − 1 ). K m values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 m M ; P = 0.89, 0.02; − 0.29, 0.32 m M ). M3G and M6G formation was inhibited ( P < 0.01) with a significant increase in the M3G/M6G ratio ( P < 0.01) for all compounds tested. Detailed analysis with (R)-and (S)-methadone revealed noncompetitive inhibition with (R)-methadone K i of 320 ± 42 µ M and 192 ± 12 µ M for M3G and M6G, respectively, and (S)-methadone K i of 226 ± 30 µ M and 152 ± 20 µ M for M3G and M6G, respectively. K i values for M3G inhibition were significantly greater than for M6G for (R)-methadone ( P = 0.017, 128; 55, 202 µ M ) and (S)-methadone ( P = 0.026, 75; 22, 128 µ M ). ConclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadonemaintained patients and reduced relative formation of the opioid active M6G compared with M3G. IntroductionMorphine is the gold standard opioid for the treatment of moderate to severe acute and chronic pain. Morphine is primarily cleared via glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17]. However, only UGT2B7 has been shown to form M6G [17,18]. The relative contribution of these isoforms to the overall glucuronidation of morphine is still unknown. Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h...

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“…A major reason for choosing the present sampling time is based on consideration that -opioid receptors may undergo a second adaptation (withdrawal effect) after long-term treatment with ATD, because we knew this receptor system showed a dynamic response to alcohol withdrawal in FH rats (Chen and Lawrence, 2000;Djouma and Lawrence, 2002). However, the interpretation of any alteration of -opioid receptor binding must be taken cautiously due to potential interactions between -opioid receptors and TCAs or SSRIs (Wahlstrom et al, 1994), even though such an interaction has been questioned (Wong et al, 1985). Lines of evidence do, however, support that the de- (Fig.…”

Section: Discussionmentioning

confidence: 99%

Chronic Antidepressant Treatment Causes a Selective Reduction of μ-Opioid Receptor Binding and Functional Coupling to G Proteins in the Amygdala of Fawn-Hooded Rats

Chen

Lawrence²

2004

The Journal of Pharmacology and Experimental Therapeutics

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We have previously documented that chronic alcohol consumption or alcohol withdrawal affects -opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether -opioid receptor binding and the receptormediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of . In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of -opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.

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Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation

Cited by 39 publications

References 25 publications

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Chronic Antidepressant Treatment Causes a Selective Reduction of μ-Opioid Receptor Binding and Functional Coupling to G Proteins in the Amygdala of Fawn-Hooded Rats

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