The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats

Zamarripa, C. Austin; Pareek, Tanya; Schrock, Hayley M.; Prisinzano, Thomas E.; Blough, Bruce E.; Sufka, Kenneth J.; Freeman, Kevin B.

doi:10.1007/s00213-021-05965-x

Cited by 12 publications

(7 citation statements)

References 60 publications

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“…In rhesus monkeys, triazole 1.1 (0.01–0.32 mg/kg) did not induce sedative or motor impairment effects ( Huskinson et al, 2020 ). Furthermore, in rats, triazole 1.1 reduced oxycodone self-administration, and co-administration of oxycodone and triazole 1.1 enhanced anti-nociceptive effects ( Zamarripa et al, 2021 ). Thus, trizole 1.1 demonstrates an improved therapeutic index in comparison to balanced KOR agonists such as U50,488.…”

Section: Diseases For Which the Kappa-opioid Receptors Has Therapeuti...mentioning

confidence: 99%

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

et al. 2022

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Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer’s disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein–biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

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Section: Diseases For Which the Kappa-opioid Receptors Has Therapeuti...mentioning

confidence: 99%

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

et al. 2022

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“…206 In male rats, triazole 1.1 reduced oxycodone self-administration while enhancing oxycodone-induced thermal antinociception. 207 In male rhesus monkeys, triazole 1.1 produced weak sedative-like effects and reduced oxycodoneinduced scratch. 208 Triazole 1.1 also had a reduced side-effect profile, both alone and in combination with oxycodone, in male rhesus monkeys.…”

Section: Iv3 Triazole 11mentioning

confidence: 99%

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

Khan

Sawyer

Akins

et al. 2022

European Journal of Medicinal Chemistry

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“…Indeed, this drug combination has been shown to result in an additive or supraadditive interaction in primates, which means smaller doses of each drug alone are needed to reduce drug-taking and may reduce the sideeffect profile and be more tolerable to treat substance use disorder in people (G. T. Collins and France, 2018). Other abuse-deterrent approaches have been proposed to create drug combinations (e.g., a mu opioid receptor agonist and a kappa opioid receptor agonist) that produce additive or supraadditive interactions with respect to one desired effect (e.g., antinociception), without enhancing an undesired effect (e.g., reinforcing effects; Townsend et al, 2017;Zamarripa et al, 2021). Thus, in addition to evaluating abuse-related effects of drug mixtures, dose-addition analyses can be applied to evaluate interactions between potentially therapeutic effects of drug combinations.…”

Section: Potential Treatment Applicationsmentioning

confidence: 99%

“…Though this article focused on the use of dose‐addition (and individual subject analyses) to understand the nature of the interactions between the discriminative stimulus, reinforcing, and relapse‐related effects of binary drug mixtures, these same concepts can be applied to polypharmacy approaches to reduce drug‐taking (e.g., G. T. Collins and France, 2018) or reduce the reinforcing effects (e.g., act as an abuse‐deterrent; Townsend et al, 2017; Zamarripa et al, 2021). For instance, lorcaserin (a serotonin 2C receptor agonist) and buspirone (a serotonin 1A receptor agonist and dopamine D 3 receptor partial agonist) are both FDA‐approved compounds that reduce drug‐taking on their own in preclinical studies.…”

Section: Figurementioning

confidence: 99%

Application of dose‐addition analyses to characterize the abuse‐related effects of drug mixtures

Doyle

Gannon

Mesmin

et al. 2022

J Exper Analysis Behavior

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Polysubstance use makes up a majority of drug use, yet relatively few studies investigate the abuse‐related effects of drug mixtures. Dose‐addition analyses provide a rigorous and quantitative method to determine the nature of the interaction (i.e., supraadditive, additive, or subadditive) between two or more drugs. As briefly reviewed here, studies in rhesus monkeys have applied dose‐addition analyses to group level data to characterize the nature of the interaction between the reinforcing effects of stimulants and opioids (e.g., mixtures of cocaine + heroin). Building upon these foundational studies, more recent work has applied dose‐addition analyses to better understand the nature of the interaction between caffeine and illicit stimulants such as MDPV and methamphetamine in rats. In addition to utilizing a variety of operant procedures, including drug discrimination, drug self‐administration, and drug‐primed reinstatement, these studies have incorporated potency and effectiveness ratios as a method for both statistical analysis and visualization of departures from additivity at both the group and individual subject level. As such, dose‐addition analyses represent a powerful and underutilized approach to quantify the nature of drug–drug interactions that can be applied to a variety of abuse‐related endpoints in order to better understand the behavioral pharmacology of polysubstance use.

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The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats

Cited by 12 publications

References 60 publications

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

Application of dose‐addition analyses to characterize the abuse‐related effects of drug mixtures

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