Rationale
Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the ...KOR but may produce fewer or reduced side effects that are typical of KOR agonists.
Objectives
We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138,
1992
, Am J Primatol 46:213-227,
1998
) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157,
2018
).
Methods
Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032–0.1 mg/kg) and salvinorin A (0.00032–0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.01–0.32 mg/kg); the MOR agonist, oxycodone (0.0032–0.32 mg/kg); and as controls, cocaine (0.032–0.32 mg/kg) and ketamine (0.32–10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10–320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration.
Results
Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture.
Conclusions
Atypical “biased” KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.
Abstract Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT2A ) receptor neurotransmission in the brain, although no molecular mechanism has been identified. ...Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP55,940) or selective CB2 receptor agonists (JWH133 or GP1a) upregulate 5-HT2A receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT2A receptors was prevented in cells stably transfected with either CB2 or β-Arrestin 2 shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis also prevented the cannabinoid receptor-induced upregulation of 5-HT2A receptors. Our results indicate that cannabinoid agonists might upregulate 5-HT2A receptors by a mechanism that requires CB2 receptors and β-Arrestin 2 in cells that express both CB2 and 5-HT2A receptors. 5-HT2A receptors have been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to some cognitive and mood disorders in humans.
G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different mu-opioid ...receptor (muOR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a muOR with low affinity for beta-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors. Here, we evaluate muOR trafficking in response to activation by a novel mu-selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of beta-arrestin-2 to the muOR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced beta-arrestin interactions and muOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that beta-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.
Background
Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, ...addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse.
Methods
We evaluated SalA and the novel analogue β‐tetrahydropyran Salvinorin B (β‐THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail‐withdrawal assay, intradermal formalin‐induced inflammatory pain and paclitaxel‐induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry.
Results
β‐tetrahydropyran Salvinorin B produced a longer duration of action in the tail‐withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β‐THP SalB is a full agonist at the KOPr. In the formalin‐induced inflammatory pain model, β‐THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β‐THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel‐induced neuropathic pain model, in a dose‐dependent manner.
Conclusions
Structural modification of SalA at the C‐2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C‐2 produced potent analgesic and anti‐inflammatory effects, including a reduction in paclitaxel‐induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti‐inflammatory action and little risk of abuse.
Significance
Salvinorin A and the novel analogue β‐THP Salvinorin B show analgesic effects in the tail‐withdrawal and formalin assays. They reduce oedema and decrease neutrophil infiltration into inflamed tissue, and suppress mechanical and cold allodynia in paclitaxel‐induced neuropathic pain.
Background and rationale
Pain is a complex sensory experience, involving cognitive factors, environment (setting, society, and culture), experience, and gender and is modulated significantly by the ...central nervous system (CNS). The mechanisms by which opioid analgesics work are understood, but this class of drugs is not ideal as either an analgesic or anti-hyperalgesic. Accordingly, considerable effort continues to be directed at improved understanding of nociceptor function and development of selective analgesics that do not have the unwanted effects associated with opioid analgesics.
Objective
The purpose of this paper is to provide a review of the role of KOP receptors in the modulation of pain and highlight several chemotypes currently being explored as peripherally restricted KOP ligands.
Results
A growing body of literature has shown that KOP receptors are implicated in a variety of behavioral pain models. Several different classes of peripherally restricted peptidic and nonpeptidic KOP agonists have been identified and show utility in treating painful conditions.
Conclusion
The pharmacological profile of KOP agonists in visceral pain models suggest that peripherally restricted KOP agonists are potentially useful for a variety of peripheral pain states. Further, clinical investigation of peripherally restricted KOP agonists will help to clarify the painful conditions where KOP agonists will be most effective.
Background and Purpose
Acute activation of κ opioid (KOP) receptors results in anticocaine‐like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their ...clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi‐synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile.
Experimental Approach
We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine‐prime induced cocaine‐seeking behaviour in self‐administering rats to predict anti‐addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists.
Key Results
Mesyl Sal B had a longer duration of action than SalA, had anti‐addiction properties and increased DAT function in vitro in a KOP receptor‐dependent and Pertussis toxin‐sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell‐surface expression of DAT.
Conclusions and Implications
SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin‐based neoclerodane diterpene KOP receptor ligands produce both anti‐addiction and adverse side effects.
Linked Articles
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic ...method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORD-expressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.
At present, the Mexican mint
Salvia divinorum is an unregulated hallucinogen. This has resulted in various on-line botanical companies advertising and selling
S. divinorum as a legal alternative to ...other regulated plant hallucinogens. It is predictable that its misuse will increase rapidly. The active ingredient in
S. divinorum is the neoclerodane diterpene, salvinorin A (
1a), which has been shown to be a κ agonist both in vitro and in vivo. This review will cover the current state of research into the psychopharmacology of
S. divinorum.
•TV-5-249 and TV-6-41 function as neutral CB1R antagonists and full CB2R agonists.•Neither showed CB1R agonist effects; neither induced rimonabant-like scratching.•Rimonabant and TV-5-249 induced ...taste aversion, but TV-6-41 did not.•Rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not.•Combining neutral CB1R antagonism with CB2R agonism may be useful in drug dependence.
Cannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-related effects of ethanol in mice.
To further characterize these drugs, TV-5-249 and TV-6-41 were compared with the CB1R antagonist / inverse agonist rimonabant in assays relevant to adverse effects and cannabinoid withdrawal.
The cannabinoid tetrad confirmed that TV-5-249 and TV-6-41 were devoid of CB1R agonist effects at behaviorally-relevant doses, and neither of the novel drugs induced rimonabant-like scratching. Generalized aversive effects were assessed, and rimonabant and TV-5-249 induced taste aversion, but TV-6-41 did not. Schedule-controlled responding and observation of somatic signs were used to assess withdrawal-like effects precipitated by rimonabant or TV-6-41 in mice previously treated with the high-efficacy CB1R agonist JWH-018 or vehicle. Rimonabant and TV-6-41 dose-dependently suppressed response rates in all subjects, but TV-6-41 did so more potently in JWH-018-treated mice than in vehicle-treated mice, while rimonabant equally suppressed responding in both groups. Importantly, rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not.
These findings suggest differences in both direct adverse effects and withdrawal-related effects elicited by rimonabant, TV-5-249, and TV-6-41, which could relate to neutral CB1R antagonism, CB2R agonism, or a combination of both. Both mechanisms should be explored and exploited in future drug design efforts to develop pharmacotherapies for drug dependence.
Flavonoids have been recognized as the active ingredients of many medicinal plant extracts due to interactions with proteins via phenolic groups and low toxicity. Here, we report the investigation of ...the flavonoid core as a potential new scaffold for the development of opioid receptor ligands. Biological results suggest that stereochemistry of the C2 and C3 positions is important for antagonist activity and selectivity. Our results also suggest that the actions of Hypericum perforatum may be mediated in part by opioid receptors.
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