Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen A.

doi:10.1037/pha0000028

Cited by 13 publications

(4 citation statements)

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“…Morphine and oxycodone were also studied in C57/Bl/6 male and female mice trained to discriminate morphine from saline (Neelakantan et al, 2015) completely for morphine at equipotent doses in both sexes. Walentiny et al (2019) also trained C57Bl/6 mice to discriminate 1.3 mg/kg, s.c. oxycodone from vehicle using a fixed-ratio 10 schedule of food presentation.…”

Section: E Drug Discriminationmentioning

confidence: 99%

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

2023

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Oxycodone, a semi-synthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for over 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the μ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here which, in turn, have provided new information on opioid receptor pharmacology.

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Section: E Drug Discriminationmentioning

confidence: 99%

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

2023

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“…Multiple studies show that morphine is more efficacious in males in a variety of pre-clinical anti-nociception models. These include; inflammatory models (Loyd et al, 2008, visceral models (Ji et al, 2006, Neelakantan et al, 2015, tail-flick (Kepler et al, 1989, Kest et al, 1999, and hotplate assays (Cicero et al, 1997, Posillico et al, 2015. In humans, the existence of sex differences in μ receptor analgesia is controversial, with some reports stating no sex difference (Bijur et al, 2008, Niesters et al, 2010 and others show morphine is less efficacious in females than males (Cepeda et al, 2003).…”

Section: Kurkinol and Kurkinorin Have Reduced Duration Of Action In Supraspinal Thermally Mediated Anti-nociceptionmentioning

confidence: 99%

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Alder¹

2021

Preprint

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Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. <div> </div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain.

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“…Previous work suggests a role for sex hormones in opioid dependence and opioid reinforcing properties (Alexander et al, 1978;Bobzean et al, 2014;Cicero et al, 2003Cicero et al, , 2002bCicero et al, , 2002cHadaway et al, 1979;Harte-Hargrove et al, 2015;Serdarevic et al, 2017) , particularly in oral self-administration protocols (Stolerman and Kumar, 1972) . Sex differences are also apparent in the pharmacokinetic, metabolic, and analgesic effects of oxycodone (Chan et al, 2008;Holtman and Wala, 2006;Neelakantan et al, 2015) , and subtle differences have been observed in the liability for opioid abuse (Collins et al, 2016;Mavrikaki et al, 2017) . Therefore animal studies show that, relative to males, females self-administer more opioids, are more vulnerable to their reinforcing effects, and become more physically dependent, (Alexander et al, 1978;Boyer et al, 1998;Cicero et al, 2003Cicero et al, , 2002aGraziani and Nisticò, 2016b;Hadaway et al, 1979;Lofwall et al, 2012;Lynch, 2018;Lynch et al, 2002;Serdarevic et al, 2017) .…”

Section: Oxycodone 2-bottle Choice Highlights Sex Differences In Oxycmentioning

confidence: 99%

Female rats consume and prefer oxycodone more than males in a chronic two-bottle oral voluntary choice paradigm

Zanni

DeSalle

Deutsch

et al. 2019

Preprint

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The increased abuse of opioids -such as oxycodone -poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by continuous, voluntary, oral intake, and sex differences. Therefore the field would benefit from a preclinical in-depth characterization of sex differences in a chronic oral voluntary, free choice, and continuous access paradigm. Here we show in an oral oxycodone continuous access two-bottle choice paradigm sex-dependent voluntary drug intake, dependence, and motivation to take the drug . Adult female and male Long-Evans rats were given unlimited, continuous home cage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental).Most experimental rats voluntarily drank oxycodone (~10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater blood levels of oxycodone, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentration of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Thus, female rats consumed and preferred oxycodone more than males in this chronic two-bottle oral choice paradigm. Both sexes displayed many features of human oxycodone abuse, and behavioral pre-screening predicted parameters of intake and withdrawal. This model provides an additional paradigm for understanding mechanisms that mediate long-term voluntary drug use and for exploring potential treatment options.

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Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

Cited by 13 publications

References 56 publications

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Female rats consume and prefer oxycodone more than males in a chronic two-bottle oral voluntary choice paradigm

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