Possible involvement of opiate receptors in the pharmacological profiles of antidepressant compounds

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 g/kg i.v., which selectively blocks the -opioid receptor, inhibited the antihyperalgesic effect of clomipramine and hence indicated that -opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH 2 (CTOP), ; naltrindole (NTI), ␦; and nor-binaltorphimine (nor-BNI), ] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: ␦-receptors at the supraspinal level and -receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evidence for an Involvement of Supraspinal δ- and Spinal μ-Opioid Receptors in the Antihyperalgesic Effect of Chronically Administered Clomipramine in Mononeuropathic Rats

Marchand

Ardid²,

Chapuy³

et al. 2003

“…TCAs have antagonistic action at N-methyl-D-aspartate (NMDA) receptors (Reynolds and Miller, 1988), and inhibit adenosine reuptake (Phillis and Wu, 1982). Furthermore, most TCAs have affinity for opioid (Isenberg and Cicero, 1984), NA, 5-HT, histamine, and muscarinic acetylcholine receptors (Hall and Ogren, 1981). In contrast, SNRIs selectively inhibit the reuptake of NA and 5-HT without relevant affinity for any other receptors or ion channels (Sindrup et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Monoamine-Dependent, Opioid-Independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats

Obata

Kimura²,

Nakajima³

et al. 2010

The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1-30 g) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-g injection. Doses of 30 g or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 g of milnacipran was blocked by intrathecal pretreatment with antagonists of the ␣ 2 -adrenoceptor (idazoxan; 30 g) or 5-HT receptors (methysergide; 30 g). Intrathecal pretreatment with 30 g of naloxone, a -opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.

“…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%

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Onali¹,

Dedoni²,

Olianas³

2009

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...