Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

Obara, Go; Toyohira, Yumiko; Inagaki, Hirohide; Takahashi, Keita; Horishita, Takafumi; Kawasaki, Takashi; Ueno, S.; Tsutsui, Masato; Sata, Takeyoshi; Yanagihara, Nobuyuki

doi:10.1254/jphs.12164fp

Cited by 12 publications

(10 citation statements)

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“…Interestingly, a recent study indicates that pentazocine, a compound structurally similar to dezocine, inhibits NET function by reducing the amount of NET in cell surface membranes through an opioid receptor-independent pathway. (36) It is unclear whether dezocine could have similar properties as pentazocine in regards to indirect NET interaction. NET plays an important role in pain pathways and norepinephrine reuptake inhibition could be used for treating pain, (37) especially in neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Novel Molecular Targets of Dezocine and Their Clinical Implications

et al. 2014

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Background While dezocine is a partial mu opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and their implications. Methods A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human kappa opioid receptor to determine whether dezocine is a kappa antagonist. Data are presented as mean ± SE. Results The affinities for dezocine were 3.7±0.7 nM for the mu receptor, 527±70 nM for the delta receptor, and 31.9±1.9 nM for the kappa receptor. Dezocine failed to induce G protein activation with kappa opioid receptor and concentration dependently inhibited kappa agonist (salvinorin A and nalbuphine) induced receptor activation, indicating that dezocine is a kappa antagonist. Two novel molecular targets (norepinephrine transporter, NET; and serotonin transporter, SERT) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68±0.11 for NET and 5.86 ± 0.17 for SERT. Dezocine occupied the binding site for known NET and SERT inhibitors. Conclusions The unique molecular pharmacological profile of dezocine as a partial mu receptor agonist, a kappa receptor antagonist and a norepinephrine and serotonin reuptake inhibitor (via NET and SERT) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.

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Section: Discussionmentioning

confidence: 99%

Novel Molecular Targets of Dezocine and Their Clinical Implications

et al. 2014

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“…In mice, the addition of pentazocine (4.75 mg/kg-9.5 mg/kg s.c.) to morphine (0.69 mg/kg-1.38 mg/kg s.c.) yielded over-additive antinociceptive effects. Tentatively, inhibition of noradrenaline transporter by racemic pentazocine [34] may be causative for this over-additive effect. A similar synergism between pentazocine and morphine was also observed in the acetic acid writhing test.…”

Section: Pentazocinementioning

confidence: 99%

Efficacy of Full µ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists – Preclinical and Clinical Evidence

2016

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Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.

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“…Catecholamine secretion mediated by stimulation of these ion channels, and the mechanism underlying the stimulation of catecholamine synthesis in adrenal medullary cells, are both thought to be similar to those of noradrenaline in sympathetic neurons and brain noradrenergic neurons. Thus, adrenal medullary cells have provided a good model for the detailed analysis of cardiovascular (6) and analgesic (8) drugs that act on catecholamine synthesis, secretion, and reuptake.…”

Section: Introductionmentioning

confidence: 99%

New Insights Into the Pharmacological Potential of Plant Flavonoids in the Catecholamine System

et al. 2014

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Abstract. Flavonoids are biologically active polyphenolic compounds widely distributed in plants. Recent research has focused on high dietary intake of flavonoids because of their potential to reduce the risks of diseases such as cardiovascular diseases, diabetes, and cancers. We report here the effects of plant flavonoids on catecholamine signaling in cultured bovine adrenal medullary cells used as a model of central and peripheral sympathetic neurons. Daidzein (0.01 -1.0 mM), a soy isoflavone, stimulated 14 C-catecholamine synthesis through plasma membrane estrogen receptors. Nobiletin (1.0 -100 mM), a citrus polymethoxy flavone, enhanced 14 Ccatecholamine synthesis through the phosphorylation of Ser19 and Ser40 of tyrosine hydroxylase, which was associated with 45 Ca 2+ influx and catecholamine secretion. Treatment with genistein (0.01 -10 mM), another isoflavone, but not daidzein, enhanced [ 3 H]noradrenaline uptake by SK-N-SH cells, a human noradrenergic neuroblastoma cell line. Daidzein as well as nobiletin (≥ 1.0 mM) inhibited catecholamine synthesis and secretion induced by acetylcholine, a physiological secretagogue. The present review shows that plant flavonoids have various pharmacological potentials on the catecholamine system in adrenal medullary cells, and probably also in sympathetic neurons.

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Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

Abstract: Abstract. (±)-Pentazocine (PTZ), a non-narcotic analgesic, is used for the clinical management of moderate to severe pain. To study the effect of PTZ on the descending noradrenergic inhibitory system, in the present study we examined the effect of

Cited by 12 publications

References 32 publications

Novel Molecular Targets of Dezocine and Their Clinical Implications

Novel Molecular Targets of Dezocine and Their Clinical Implications

Efficacy of Full µ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists – Preclinical and Clinical Evidence

New Insights Into the Pharmacological Potential of Plant Flavonoids in the Catecholamine System

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