scholarly journals Exploring the Aversive and Anxiogenic Effects of Novel Kappa Opioid Receptor Agonists in Rats

2021 ◽  
Author(s):  
◽  
Aimee Culverhouse
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Prime Model ◽  
The Novel ◽  
Negative Consequences ◽  
Sprague Dawley ◽  
Initial Attempt ◽  
Kappa Opioid ◽  
Duration Of Action

<p>Drug addiction is characterised by uncontrolled, compulsive drug use despite negative consequences. As this disease has a high social and economic cost, greater attention is required in finding an effective treatment for individuals suffering addiction. Kappa opioid receptor (KOPr) agonists demonstrate anti-addiction effects in the rodent cocaine drug-prime model of reinstatement. Salvinorin A (Sal A), a novel non-nitrogenous KOPr agonist, has demonstrated reduced side-effects compared to traditional agonists. However, its short half-life and duration of action limit clinical development. The design of novel Sal A analogues with improved pharmacokinetics, anti-addiction effects, and reduced side-effects is an important step towards the pharmaceutical development of KOPr agonists. β-Tetrahydropyran Sal B (β-THP Sal B), Mesyl Sal B, ethoxymethyl salvinorin B ether (EOM Sal B), and Ethynyl Sal A (Ethy Sal A) have demonstrated anti-addiction effects by reducing cocaine-seeking behaviour in rats, but their aversive and anxiogenic properties have yet to be examined. Here the conditioned place aversion (CPA) paradigm is used to evaluate aversion and the elevated plus maze (EPM), light/dark test, and open field are utilised to measure anxiety in male Sprague-Dawley rats.  EOM Sal B (0.1 mg/kg, i.p) and Ethy Sal A (0.3 mg/kg, i.p) did not produce aversive effects, whereas the traditional KOPr agonist U50,488 (10 mg/kg, i.p), Sal A (0.3 mg/kg, i.p), and the novel analogue β-THP Sal B (1 mg/kg, i.p) produced significant aversion using the CPA protocol.  In the EPM all the novel analogues, β-THP Sal B, EOM Sal B, Mesyl Sal B, and Ethy Sal, A did not show a reduction in time spent on the open arm. In addition, EOM Sal B showed a significant increase in time spent on the open arm compared with Sal A (0.3 mg/kg, i.p). Sal A (0.3 and 1 mg/kg, i.p) showed significant anxiogenic effects, but the traditional agonist U50,488 did not. In the light/dark test Sal A (1 mg/kg, i.p) showed significant dose dependent anxiogenic effects with significant effects observed at 1 but not 0.3 mg/kg dose. This is in contrast to results observed in the EPM. The novel analogues EOM Sal B and β-THP Sal B demonstrated a non-significant trend toward anxiogenic behaviour in the light/dark test, but U50,488, Mesyl Sal B, and Ethy Sal A did not show significant reductions in time spent in the light box.  KOPr stimulation activates its associated G-proteins, allowing them to interact with several intracellular effectors. Activation of cAMP response element binding protein (CREB) can occur downstream of the KOPr signalling cascade. The phosphorylation of CREB is associated with dysphoria and stress-induced reinstatement of drug-seeking behaviour. An initial attempt to validate CREB assays was made.  The lack of behavioural anxiogenic and aversive side-effects with EOM Sal B, Mesyl Sal B and Ethy Sal A treatment demonstrates that the development of KOPr agonists with desirable effects and reduced side-effects is possible. These novel Sal A agonists provide promising candidates for pharmacotherapy development.</p>

scholarly journals Exploring the Aversive and Anxiogenic Effects of Novel Kappa Opioid Receptor Agonists in Rats

2021 ◽  
Author(s):  
◽  
Aimee Culverhouse
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Prime Model ◽  
The Novel ◽  
Negative Consequences ◽  
Sprague Dawley ◽  
Initial Attempt ◽  
Kappa Opioid ◽  
Duration Of Action

<p>Drug addiction is characterised by uncontrolled, compulsive drug use despite negative consequences. As this disease has a high social and economic cost, greater attention is required in finding an effective treatment for individuals suffering addiction. Kappa opioid receptor (KOPr) agonists demonstrate anti-addiction effects in the rodent cocaine drug-prime model of reinstatement. Salvinorin A (Sal A), a novel non-nitrogenous KOPr agonist, has demonstrated reduced side-effects compared to traditional agonists. However, its short half-life and duration of action limit clinical development. The design of novel Sal A analogues with improved pharmacokinetics, anti-addiction effects, and reduced side-effects is an important step towards the pharmaceutical development of KOPr agonists. β-Tetrahydropyran Sal B (β-THP Sal B), Mesyl Sal B, ethoxymethyl salvinorin B ether (EOM Sal B), and Ethynyl Sal A (Ethy Sal A) have demonstrated anti-addiction effects by reducing cocaine-seeking behaviour in rats, but their aversive and anxiogenic properties have yet to be examined. Here the conditioned place aversion (CPA) paradigm is used to evaluate aversion and the elevated plus maze (EPM), light/dark test, and open field are utilised to measure anxiety in male Sprague-Dawley rats.  EOM Sal B (0.1 mg/kg, i.p) and Ethy Sal A (0.3 mg/kg, i.p) did not produce aversive effects, whereas the traditional KOPr agonist U50,488 (10 mg/kg, i.p), Sal A (0.3 mg/kg, i.p), and the novel analogue β-THP Sal B (1 mg/kg, i.p) produced significant aversion using the CPA protocol.  In the EPM all the novel analogues, β-THP Sal B, EOM Sal B, Mesyl Sal B, and Ethy Sal, A did not show a reduction in time spent on the open arm. In addition, EOM Sal B showed a significant increase in time spent on the open arm compared with Sal A (0.3 mg/kg, i.p). Sal A (0.3 and 1 mg/kg, i.p) showed significant anxiogenic effects, but the traditional agonist U50,488 did not. In the light/dark test Sal A (1 mg/kg, i.p) showed significant dose dependent anxiogenic effects with significant effects observed at 1 but not 0.3 mg/kg dose. This is in contrast to results observed in the EPM. The novel analogues EOM Sal B and β-THP Sal B demonstrated a non-significant trend toward anxiogenic behaviour in the light/dark test, but U50,488, Mesyl Sal B, and Ethy Sal A did not show significant reductions in time spent in the light box.  KOPr stimulation activates its associated G-proteins, allowing them to interact with several intracellular effectors. Activation of cAMP response element binding protein (CREB) can occur downstream of the KOPr signalling cascade. The phosphorylation of CREB is associated with dysphoria and stress-induced reinstatement of drug-seeking behaviour. An initial attempt to validate CREB assays was made.  The lack of behavioural anxiogenic and aversive side-effects with EOM Sal B, Mesyl Sal B and Ethy Sal A treatment demonstrates that the development of KOPr agonists with desirable effects and reduced side-effects is possible. These novel Sal A agonists provide promising candidates for pharmacotherapy development.</p>

scholarly journals Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats

2019 ◽  
Author(s):  
Sarah Page ◽  
Maria M Mavrikaki ◽  
Tania Lintz ◽  
Daniel Puttick ◽  
Edward Roberts ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Time Course ◽  
Kappa Opioid Receptor ◽  
Tail Flick ◽  
Receptor Antagonists ◽  
Kappa Opioid ◽  
Duration Of Action ◽  
Opioid Receptor Antagonists ◽  
Opioid Receptor Agonists ◽  
Self Stimulation

Abstract Background New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. Methods We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). Results In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. Conclusions These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

scholarly journals Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

2021 ◽  
Author(s):  
◽  
Kelly Paton
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Mechanical Allodynia ◽  
Kappa Opioid Receptor ◽  
Nociceptive Pain ◽  
The Novel ◽  
Duration Of Action ◽  
Cold Allodynia ◽  
Antinociceptive Effects

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

scholarly journals Tackling the opioid crisis - development of kappa-opioid receptor peptide agonists for safer analgesic therapy

2021 ◽  
Author(s):  
Rink-Jan Lohman ◽  
Karnaker Reddy Tupally ◽  
Ajit Kandale ◽  
Peter Cabot ◽  
Harendra Parekh
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Specific Activity ◽  
Opioid Analgesic ◽  
Kappa Opioid Receptor ◽  
Metabolic Stability ◽  
Clinical Translation ◽  
Kappa Opioid

The kappa opioid receptor (KOPr) has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side effects have the limited their clinical translation. Here, we modify an active endogenous Dynorphin peptide with the aim of improving drug-likeness and developing safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from Dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, KOPr specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in Freund’s complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling. In vivo, KA305 and KA311 showed anti-nociception opioid receptor-specific activity comparable to morphine and U50 844. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide KOPr agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.

scholarly journals Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

2021 ◽  
Author(s):  
◽  
Kelly Paton
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Mechanical Allodynia ◽  
Kappa Opioid Receptor ◽  
Nociceptive Pain ◽  
The Novel ◽  
Duration Of Action ◽  
Cold Allodynia ◽  
Antinociceptive Effects

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

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