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Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.

ABSTRACT: Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprk1, Oprm1, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-1 antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/dark box, increased immobility in the FST and induced region-specific alterations in Oprk1, Oprm1, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant.

SUBMITTER: Falcon E

PROVIDER: S-EPMC4946065 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.

Falcon Edgardo E Browne Caroline A CA Leon Rosa M RM Fleites Vanessa C VC Sweeney Rachel R Kirby Lynn G LG Lucki Irwin I

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160316 9

Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice ...[more]

PMID: 26979295

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Project description:Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of mu-, delta- and kappa-opioid receptors.Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 microg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 microg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 microg), bremazocine (50 microg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20-80 microg), 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 microg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 microg) were also injected in the paw.The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the mu-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by kappa- and delta-opioid receptor agonists.

Project description:ObjectiveHomeostatic synaptic plasticity (HSP) serves as a gain control mechanism at central nervous system (CNS) synapses, including those between the dentate gyrus (DG) and CA3. Improper circuit control of DG-CA3 synapses is hypothesized to underlie epileptogenesis. Here, we sought to (1) identify compounds that preferentially modulate DG-CA3 synapses in primary neuronal culture and (2) determine if these compounds would delay or prevent epileptogenesis in vivo.MethodsWe previously developed and validated an in vitro assay to visualize the behavior of DG-CA3 synapses and predict functional changes. We used this "synapse-on-chip" assay (quantification of synapse size, number, and type using immunocytochemical markers) to dissect the mechanisms of HSP at DG-CA3 synapses. Using chemogenetic constructs and pharmacological agents we determined the signaling cascades necessary for gain control at DG-CA3 synapses. Finally, we tested the implicated cascades (using kappa opioid receptor (OR) agonists and antagonists) in two models of epileptogenesis: electrical amygdala kindling in the mouse and chemical (pentylenetetrazole) kindling in the rat.ResultsIn vitro, synapses between DG mossy fibers (MFs) and CA3 neurons are the primary homeostatic responders during sustained periods of activity change. Kappa OR signaling is both necessary and sufficient for the homeostatic elaboration of DG-CA3 synapses, induced by presynaptic DG activity levels. Blocking kappa OR signaling in vivo attenuates the development of seizures in both mouse and rat models of epilepsy.SignificanceThis study elucidates mechanisms by which synapses between DG granule cells and CA3 pyramidal neurons undergo activity-dependent homeostatic compensation, via OR signaling in vitro. Modulation of kappa OR signaling in vivo alters seizure progression, suggesting that breakdown of homeostatic closed-loop control at DG-CA3 synapses contributes to seizures, and that targeting endogenous homeostatic mechanisms at DG-CA3 synapses may prove useful in combating epileptogenesis.

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Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.

Publications

Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.

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