Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat

Smith, Karen; Cunningham, Jacobi I.; Eyerman, David J.; Dean, Reginald L.; Deaver, Daniel R.; Sanchéz, Connie

doi:10.1016/j.neuropharm.2018.11.015

Cited by 19 publications

(27 citation statements)

References 77 publications

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“…We found no effect of MOR activation, since neither the full agonist, morphine, nor the low intrinsic activity agonist, RDC 2944, had an effect on IFN-α-induced increase of immobility. These findings differ from previous FST data showing anti-immobility effects of the potent MOR agonist and KOR antagonist, buprenorphine, in the Wistar-Kyoto rat [33], possibly indicating that different biological pathways underpin the increased immobility behavior in IFN-α and Wistar-Kyoto rats subjected to the forced swim stress. Another possibility is that KOR antagonism possibly in combination with MOR agonism mediates the effect of buprenorphine [33].…”

Section: Discussioncontrasting

confidence: 99%

“…These findings differ from previous FST data showing anti-immobility effects of the potent MOR agonist and KOR antagonist, buprenorphine, in the Wistar-Kyoto rat [33], possibly indicating that different biological pathways underpin the increased immobility behavior in IFN-α and Wistar-Kyoto rats subjected to the forced swim stress. Another possibility is that KOR antagonism possibly in combination with MOR agonism mediates the effect of buprenorphine [33]. The lack of effect of morphine and RDC 2944 here may also be due to differences in the degree of MOR engagement produced by the doses applied, and the resulting activation of brain MORs.…”

Section: Discussioncontrasting

confidence: 99%

“…The lack of effect of morphine and RDC 2944 here may also be due to differences in the degree of MOR engagement produced by the doses applied, and the resulting activation of brain MORs. Further, both morphine and RDC 2944 were tested in the FST at 1hr following treatment, whereas buprenorphine was tested at 24hr following administration in the previous study [33], which may account for the different observations. We also report acute treatment with the KOR antagonist, DIPPA, had a n anti-immobility effect in the IFN-α-treated rats, with a correspondingly large effect size.…”

Section: Discussionmentioning

confidence: 99%

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Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model

Rouine

et al. 2019

Preprint

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Rationale: Many patients respond inadequately to antidepressant drug treatment; the search for alternate pharmacological treatment mechanisms is ongoing. Until the 1950's, opium was sometimes used to treat depression, but eventually abandoned due to addiction risk. Recent insights into opioid biology have sparked a renewed interest in the potential antidepressant properties of opioids. Objective: We studied how mu (MOR), kappa (KOR) and delta (DOR) opioid receptor ligands affect the dysregulation of motivated behavior (progressive ratio responding; PR), stresscoping behavior (forced swim test; FST) and hippocampal neurogenesis in rats, all induced by the back-translational interferon-alpha (IFN-α)-induced depression model. Methods: Male Wistar rats (3-months old, 8/group) were treated with recombinant human IFNα (170,000 IU/kg, 3 times/week) or saline. Ligands of the MOR, KOR and DOR receptors were administered as follows: a single subcutaneous dose, 30min before PR and 1h before FST, of the MOR agonist morphine (full agonist; 5mg/kg), the partial agonist RDC 2944 (0.1mg/kg) and the antagonist, cyprodime (10mg/kg); of the KOR agonist, U50 488 (5mg/kg), the antagonist, DIPPA (10mg/kg); and the DOR agonist, SNC 80 (20mg/kg) and antagonist naltrindole (10mg/kg). After 4 days of treatment with the mitotic BrdU marker, hippocampi were harvested and analysed for neurogenesis. Fluoxetine (10 mg/kg/day for 4 weeks, orally) served as control for assay sensitivity in the FST. Results: The KOR antagonist, DIPPA, the DOR agonist SNC 80 and fluoxetine reversed the IFN-αinduced immobility increase in the FST. The MOR agonist, morphine, the KOR antagonist DIPPA, and the KOR agonist U50 488 reduced the IFN-α-induced increase in the breakpoint in the PR. The DOR agonist SNC 80 recovered the IFN-α-induced decrease in BrdU+ hippocampal cells. Conclusion: Opioid receptors mediate different aspects of the IFN-α-induced dysregulation of motivational and stress-coping behaviors and hippocampal neurogenesis in a backtranslational model of depression. KORs and DORs appear to play more prominent roles in 3 torpor-inertia-type behaviors, whereas DORs appear more involved in the regulation of neurogenesis.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model

Rouine

et al. 2019

Preprint

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“…Yet, usage of any of the pain medication types shown in Table 2 (opioids, non-opioids, or NSAIDs) did not correlate with improved CIM. This is interesting, especially the lack of correlation with opioids, which are generally thought to modulate reward pathways that impact mood [54]. Non-opioids outperform opioids in terms of association with survival duration.…”

Section: Antidepressant Pain Sleeping Medication Correlate With Surmentioning

confidence: 99%

Associations of Patient Mood, Modulators of Quality of Life, and Pharmaceuticals with Amyotrophic Lateral Sclerosis Survival Duration

Bond

Bowen

Mertens

et al. 2020

Behavioral Sciences

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Associations of modulators of quality of life (QoL) and survival duration are assessed in the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. Major categories include clinical impression of mood (CIM); physical health; patient social support; and usage of interventions, pharmaceuticals, and supplements. Associations were assessed at p < 0.05 and p < 0.001 significance thresholds using applicable methods (Chi-square, t-test, ANOVA, logistical regression, random forests, Fisher’s exact test) within a retrospective cohort of 1585 patients. Factors significantly correlated with positive (happy or normal) mood included family support and usage of bi-level positive airway pressure (Bi-PAP) and/or cough assist. Decline in physical factors like presence of dysphagia, drooling, general pain, and decrease in ALSFRS-R total score or forced vital capacity (FVC) significantly correlated with negative (depressed or anxious) mood (p < 0.05). Use of antidepressants or pain medications had no association with ALS patient mood (p > 0.05), but were significantly associated with increased survival (p < 0.05). Positive patient mood, Bi-PAP, cough assist, percutaneous endoscopic gastrostomy (PEG), and accompaniment to clinic visits associated with increased survival duration (p < 0.001). Of the 47 most prevalent pharmaceutical and supplement categories, 17 associated with significant survival duration increases ranging +4.5 to +16.5 months. Tricyclic antidepressants, non-opioids, muscle relaxants, and vitamin E had the highest associative increases in survival duration (p < 0.05). Random forests, which examined complex interactions, identified the following pharmaceuticals and supplements as most predictive to survival duration: Vitamin A, multivitamin, PEG supplements, alternative herbs, antihistamines, muscle relaxants, stimulant laxatives, and antispastics. Statins, metformin, and thiazide diuretics had insignificant associations with decreased survival.

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“…Evidence from some (but not all) clinical studies suggests the combination of buprenorphine with samidorphan reduces depressive symptoms in patients with MDD and an inadequate response to their current therapy, when administered as an adjunct treatment to monoaminergic antidepressants (Ehrich et al, 2015;Fava et al, 2018;Peckham, De La Cruz, & Dufresne, 2018). In non-clinical studies, acute and subacute administration of buprenorphine with samidorphan induces behavioural changes indicative of antidepressant-like activity (Burke et al, 2019;Smith et al, 2019). It is unknown if the buprenorphine and samidorphan combination induces similar behavioural changes after chronic treatment in well-validated animal models.…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

Burke

Deaver

et al. 2019

J Psychopharmacol

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Background: The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined. Aims and methods: The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants. Results: Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing. Conclusion: Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.

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Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat

Cited by 19 publications

References 77 publications

Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model

Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model

Associations of Patient Mood, Modulators of Quality of Life, and Pharmaceuticals with Amyotrophic Lateral Sclerosis Survival Duration

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

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