scholarly journals Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2602 ◽  
Author(s):  
Bronwyn Kivell ◽  
Kelly Paton ◽  
Nitin Kumar ◽  
Aashish Morani ◽  
Aimee Culverhouse ◽  
...  
Keyword(s):  
Side Effects ◽  
Learning And Memory ◽  
Behavioral Sensitization ◽  
Forced Swim Test ◽  
Salvinorin A ◽  
Self Administration ◽  
Kappa Opioid ◽  
Swim Test ◽  
Forced Swim ◽  
Antinociceptive Effects

The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.

scholarly journals Exploring the side effect profile of 16-Ethynyl Salvinorin A

2021 ◽  
Author(s):  
◽  
Stephen George Mathew
Keyword(s):  
Locomotor Activity ◽  
Side Effects ◽  
Dose Response ◽  
Forced Swim Test ◽  
Salvinorin A ◽  
Self Administration ◽  
Swim Test ◽  
Behavioural Sensitisation ◽  
Forced Swim ◽  
Sedative Effects

<p>Introduction: Drug addiction is a chronic and relapsing disorder that has widespread socioeconomic and health consequences. Globally, there are over 29.5 million people who are drug dependent, and New Zealand has one of the highest rates of drug use rates in the developed world. Currently, there are no Food and Drug Administration (FDA) approved pharmacotherapies that target psychostimulant addiction. Kappa opioid receptor (KOPr) agonists are being studied as a potential pharmacotherapy as it utilizes the brain’s own mechanism for controlling reward, however, KOPr agonists have unwanted side effects such as dysphoria and sedation. This thesis explores the KOPr agonists Salvinorin A (Sal A), a naturally-occurring, highly potent and short-acting non-nitrogenous KOPr agonist and a structural analogue, 16-Ethynyl Salvinorin A (16-Ethy). KOPr agonists, such as Sal A have known preclinical anti-addictive and anti-reward effects, therefore, this thesis focuses on evaluating Sal A and 16-Ethy in preclinical tests of reward and side effects.  Methods: Male Sprague-Dawley rats were used in preclinical tests to evaluate common KOPr-mediated side-effects including anxiety (elevated plus maze), depression (forced swim test) sedation (locomotor activity) and aversion (conditioned place aversion). The anti-cocaine effects were also examined using self-administration, dose-response and drug-behavioural sensitisation tests. 16-Ethy was tested at 2 mg/kg in all experiments.  Results: Acute pre-treatment of 16-Ethy induced sedative effects in non-habituated locomotor activity but when rats were habituated prior to administration, no sedation was observed. In contrast, Sal A (2 mg/kg) had sedative effects in habituated, but not in non-habituated locomotor activity (p = 0.0037). Compared to vehicle-treated rats, 16-Ethy and Sal A did not display pro-depressive effects in the forced swim test, show anxiogenic or aversive properties or modulate behavioural sensitisation to cocaine. Cocaine self-administration and dose-response tests were not successfully completed.  Conclusion: At 2 mg/kg, 16-Ethy was found to display sedative effects in non-habituated locomotor activity but not in a habituated paradigm. Compared to vehicle-treated rats, 16-Ethy did not display pro-depressive effects in the forced swim test, or display anxiogenic or aversive properties and did not show significant cocaine sensitisation. Cocaine self-administration and dose-response tests were not successfully completed and will need to be repeated to ascertain the effects of 16-Ethy on them. However, 16-Ethy has shown glimpses of promise as a potential pharmacotherapy against addiction.</p>

scholarly journals Exploring the side effect profile of 16-Ethynyl Salvinorin A

2021 ◽  
Author(s):  
◽  
Stephen George Mathew
Keyword(s):  
Locomotor Activity ◽  
Side Effects ◽  
Dose Response ◽  
Forced Swim Test ◽  
Salvinorin A ◽  
Self Administration ◽  
Swim Test ◽  
Behavioural Sensitisation ◽  
Forced Swim ◽  
Sedative Effects

<p>Introduction: Drug addiction is a chronic and relapsing disorder that has widespread socioeconomic and health consequences. Globally, there are over 29.5 million people who are drug dependent, and New Zealand has one of the highest rates of drug use rates in the developed world. Currently, there are no Food and Drug Administration (FDA) approved pharmacotherapies that target psychostimulant addiction. Kappa opioid receptor (KOPr) agonists are being studied as a potential pharmacotherapy as it utilizes the brain’s own mechanism for controlling reward, however, KOPr agonists have unwanted side effects such as dysphoria and sedation. This thesis explores the KOPr agonists Salvinorin A (Sal A), a naturally-occurring, highly potent and short-acting non-nitrogenous KOPr agonist and a structural analogue, 16-Ethynyl Salvinorin A (16-Ethy). KOPr agonists, such as Sal A have known preclinical anti-addictive and anti-reward effects, therefore, this thesis focuses on evaluating Sal A and 16-Ethy in preclinical tests of reward and side effects.  Methods: Male Sprague-Dawley rats were used in preclinical tests to evaluate common KOPr-mediated side-effects including anxiety (elevated plus maze), depression (forced swim test) sedation (locomotor activity) and aversion (conditioned place aversion). The anti-cocaine effects were also examined using self-administration, dose-response and drug-behavioural sensitisation tests. 16-Ethy was tested at 2 mg/kg in all experiments.  Results: Acute pre-treatment of 16-Ethy induced sedative effects in non-habituated locomotor activity but when rats were habituated prior to administration, no sedation was observed. In contrast, Sal A (2 mg/kg) had sedative effects in habituated, but not in non-habituated locomotor activity (p = 0.0037). Compared to vehicle-treated rats, 16-Ethy and Sal A did not display pro-depressive effects in the forced swim test, show anxiogenic or aversive properties or modulate behavioural sensitisation to cocaine. Cocaine self-administration and dose-response tests were not successfully completed.  Conclusion: At 2 mg/kg, 16-Ethy was found to display sedative effects in non-habituated locomotor activity but not in a habituated paradigm. Compared to vehicle-treated rats, 16-Ethy did not display pro-depressive effects in the forced swim test, or display anxiogenic or aversive properties and did not show significant cocaine sensitisation. Cocaine self-administration and dose-response tests were not successfully completed and will need to be repeated to ascertain the effects of 16-Ethy on them. However, 16-Ethy has shown glimpses of promise as a potential pharmacotherapy against addiction.</p>

Antidepressant-Like Effects of the Novel Kappa Opioid Antagonist MCL-144B in the Forced-Swim Test

Pharmacology ◽  
2008 ◽  
Vol 81 (3) ◽  
pp. 229-235 ◽  
Author(s):  
J.D. Reindl ◽  
K. Rowan ◽  
A.N. Carey ◽  
X. Peng ◽  
J.L. Neumeyer ◽  
...  
Keyword(s):  
Forced Swim Test ◽  
Opioid Antagonist ◽  
The Novel ◽  
Kappa Opioid ◽  
Swim Test ◽  
Forced Swim

scholarly journals Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test

2018 ◽  
Vol 9 ◽  
Author(s):  
Abigail Laman-Maharg ◽  
Alexia V. Williams ◽  
Mikaela D. Zufelt ◽  
Vanessa A. Minie ◽  
Stephanie Ramos-Maciel ◽  
...  
Keyword(s):  
Sex Differences ◽  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Forced Swim Test ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Swim Test ◽  
Opioid Receptor Antagonist ◽  
Forced Swim

scholarly journals UJI AKTIVITAS ANTIDEPRESAN PERASAN RIMPANG TEMULAWAK (Curcuma xanthorrhiza, Roxb) TERHADAP MENCIT PUTIH JANTAN (Mus musculus)

2019 ◽  
Vol 16 (01) ◽  
pp. 59
Author(s):  
Dian Kartikasari ◽  
Hairunisa Hairunisa ◽  
Emy Nadya Natasha
Keyword(s):  
Side Effects ◽  
Traditional Medicine ◽  
Mus Musculus ◽  
Forced Swim Test ◽  
Test Method ◽  
Antidepressant Effect ◽  
Swim Test ◽  
Forced Swim ◽  
Immobility Time ◽  
Ginger Rhizome

ABSTRACTPrevention and treatment with synthetic antidepressants has many side effects that affect the central nervous system and usage must be under the supervision of a doctor. Whereas prevention and traditional medicine relatively do not cause side effects, are inexpensive, and easy to obtain. One example of traditional medicine from natural ingredients, which can provide an antidepressant effect is ginger rhizome. This research aims to determine whether ginger rhizome have antidepressant effects on male white mice. Antidepressant effect testing was carried out on male white mice (Mus musculus) using the forced swim test method. The part of the plant used is the rhizome of the ginger plant. Curcuma rhizome is made with juice and given orally with a concentration of 20%, 40%, and 60%. The negative control used is Na CMC 0.5%, while the positive control used, namely amitriptilyn. The parameters observed were the duration of immobility time, swimming time and climibing time (in seconds) which were calculated from minutes 3-6 for 6 minutes, and statistical tests were carried out with a confidence level of 95%. The results showed that at a concentration of 40% the curcuma rhizome juice had a significant value (p> 0.05) which means that there was no significant difference in antidepressant effect (%) from the juice of temulawak 56.31% and amitriptylin 78.78%Keywords: ginger rhizome, antidepressants, the forced swim test

scholarly journals Pre-clinical Anti-Addictive and Side-Effect profiles of Novel Kappa-opioid Agonists

2021 ◽  
Author(s):  
◽  
David Young
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Salvinorin A ◽  
The Novel ◽  
Self Administration ◽  
Kappa Opioid ◽  
Drug Seeking ◽  
Hek 293 ◽  
293 Cells ◽  
Clinical Models

<p>Background: Drug addiction is a chronic, relapsing disorder with great socioeconomic and morbidity costs. An estimated 27 million people worldwide suffer from drug dependence, with over 180,000 drug abuse-related deaths reported annually (UNODC, 2015). Currently, there are no FDA-approved pharmacotherapies for psychostimulant addiction, limiting the efficacy of treatment for cocaine and amphetamine abuse. Kappa-opioid receptor (KOPr) agonists can act as inhibitors of reward, and have been investigated in pre-clinical models of drug abuse for potential anti-addictive properties, but display undesirable side-effects such as dysphoria and sedation. A naturally-occurring KOPr agonist, Salvinorin A (SalA), has been explored as a lead for new KOPr-based anti-addictive medications. SalA is a short-acting but potent non-nitrogenous KOPr agonist with known anti-cocaine effects, and chemical alterations to this structure have produced novel agonists with comparable or greater potency at the KOPr. This thesis compares two novel SalA analogues, 16-ethynyl Salvinorin A (Ethy-SalA) and 16-methyl Salvinorin A (Me-SalA), in pre-clinical models of addiction and side-effect tests.  Methods: Sprague-Dawley rats were used to model the behavioural effects of acute KOPr treatment upon cocaine self-administration and drug-seeking behaviour, natural reward-seeking, cocaine-induced and spontaneous locomotion, and pro-depressive forced-swim testing. Transiently co-transfected HEK-293 cells were used to model the influence of KOPr activation upon dopamine transporter (DAT) function in an in vitro model of dopamine uptake, using confocal microscopy to detect internalisation of the fluorescent DAT substrate ASP+.  Results: Acute pre-treatments of Ethy-SalA significantly attenuated cocaine-reinstatement of drug-seeking behaviour (at 0.1 and 0.3 mg/kg) and progressive ratio (PR) self-administration of cocaine (at 2.0 mg/kg). The less potent agonist Me-SalA did not attenuate cocaine-reinstatement or PR self-administration at the doses tested (0.3-2.0 mg/kg). Despite apparent anti-cocaine effects, Ethy-SalA (0.3 mg/kg) was not found to effectively reduce cocaine-induced locomotor hyperactivity or sensitisation in rats. Side-effect screens were carried out on the novel compounds using the doses tested in cocaine-primed reinstatement. Ethy-SalA (0.3 mg/kg) and Me-SalA (1.0 mg/kg) did not significantly affect spontaneous locomotor behaviour 0.3 mg/kg, or reduce self-administration of the natural reward sucrose at a dose of 0.3 mg/kg in rats. Depression-like effects caused by acute Ethy-SalA treatment (0.3 mg/kg) were also not detected in the Forced Swim Test. Treatment with Ethy-SalA (10 µM) significantly increased uptake of the fluorescent ASP+ in co-transfected DAT/KOPr HEK-293 cells.   Conclusions: A single treatment of the novel KOPr agonist Ethy-SalA, but not the novel agonist Me-SalA, was found to attenuate drug-seeking behaviours in models of cocaine administration with greater potency than SalA, and without detectable sedative or depression-like effects at a dose of 0.3 mg/kg. The cellular mechanism-of-action by which Ethy-SalA depresses cocaine reward is at least in part due to positive regulation of DAT, which would act to reduce extracellular dopamine within the brain. The lack of significant side-effects and the apparent improved potency of the compound support further exploration of Ethy-SalA as a lead for the development of an anti-addictive pharmacotherapy.</p>

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