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Strategies to reduce the impact of opioid‐induced adverse effects

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Paul, AK ORCID: 0000-0002-6090-2407 2018 , 'Strategies to reduce the impact of opioid‐induced adverse effects', PhD thesis, University of Tasmania.

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Abstract

Development of antinociceptive tolerance in the clinic after repeated administration of morphine limits its chronic use. Despite knowledge about the molecular mechanisms of morphine tolerance, we know little about the influence of dosage regimen (starting dose, follow-up dose, dosing and duration of treatment) for its development. I hypothesised that morphine dose, as well as dose increments, contribute to tolerance development. In addition, morphine-induced behavioural changes also might follow a similar pattern of antinociception and tolerance. Four groups of male Sprague Dawley rats received different daily doses of intermittent subcutaneous morphine for 14 days. After the development of antinociceptive tolerance, different increments of morphine doses were administered until tolerance redeveloped. Animals treated with lower starting-doses of morphine developed antinociceptive tolerance faster than those started on higher doses. Higher starting-doses and higher dose-increments after tolerance development resulted in more sustained antinociception and delayed the re-development of tolerance. These results were replicated in two anti-nociceptive assays and were therefore not assay-specific. The kinetics of morphineinduced motor suppression and desensitisation were similar to those of antinociception and antinociceptive-tolerance respectively. Overall, morphine dosing regimen in rats appears to significantly influence antinociceptive tolerance and total antinociception. My results also indicate that repetitive morphine dosing leads to desensitisation of motor suppression in all major motor behavioural parameters and manifests behavioural tolerance in conjunction with antinociceptive tolerance. Therefore, the results highlight that an optimised morphine dosing strategy can delay antinociceptive tolerance and reduce behavioural adverse effects.
Morphine and most other clinical opioids are MOP receptor agonists. The MOP receptor is responsible for both antinociception and generation of antinociceptive tolerance. Previous studies showed that an opioid ligand with mixed activity on multiple opioid receptor can reduce antinociceptive tolerance compared to morphine or other clinical opioids. Several novel opioids synthesised at the University of Tasmania were characterised for their in vitro specificity for major opioid receptors (MOP, DOP, KOP and NOP receptors) before one selected mixed activity opioid was tested for its antinociceptive effect, antinociceptive tolerance and motor behavioural effects in vivo. Collectively, UTA1003 acted as a MOP and KOP receptor agonist and a DOP receptor partial agonist. Therefore, I expected the ligand to reduce tolerance and motor suppression over a repeated treatment regimen. In rats, UTA1003 showed a mild antinociceptive effect with no noticeable motor suppression after subcutaneous administration. After repeated treatment over a period of eight days, UTA1003 displayed no tolerance and no motor behavioural adverse effect. In addition, the ligand maintained approximately 50% antinociception over the 8 days treatment without affecting morphineinduced motor suppression or hyper-excitation. Therefore, my study showed that coadministration of morphine and an opioid with mixed activity profile on multiple receptors can delay antinociceptive tolerance.
Worldwide, the elderly suffer from chronic pain while being the highest users of opioids. In current clinical practice, morphine is dosed in older patients based on patient-weight, with different calculations for adjustment. However, neither clinical experience nor the literature offers a clear evidence base for the relationship between antinociception, behavioural effects and morphine administration in older patients. In this study, I compared the nociceptive response of 8 and 24 week old rats after subcutaneous administration of morphine per body weight and analysed their motor behaviour. Residual morphine in all major tissues was determined. I observed prolonged morphine-induced antinociception in older rats compared to younger rats. Moreover, morphine significantly stimulated locomotor and rearing behaviour 180 min after injection, which was significantly higher in the 8-week compared to 24-week old rats. Tissue analysis from animals extracted during the stimulatory phase revealed a significantly higher concentration of residual morphine in the brain of older versus younger animals when standardised on tissue weight. Collectively, morphine exhibited higher antinociception and increased behavioural inhibition in older compared to younger animals, likely due to the significantly higher accumulation of morphine in the brain of older animals. Therefore, my findings would suggest that a lower dose of morphine is sufficient to provide sufficient pain-relief in older patients.
Diabetes patients increase worldwide and elderly people are highly susceptible for diabetes mellitus. Apart from pain-relief and behavioural effects, opioids also affect insulin secretion in pancreatic β-cells. Therefore, a pancreatic β-cell line (RIN-5F) was exposed to different selective agonists and antagonists of the major opioid receptors. My findings suggest that MOP and DOP receptors are mainly responsible for pancreatic insulin release. Therefore, my findings along with previous studies contribute to a better treatment strategy for the management of insulin homeostasis and diabetic neuropathy.
Overall, proper dosing of an opioid can show better analgesia, less tolerance and less behavioural adverse effects. My study identified “age of patient” as an important parameter for opioid dosing. The novel opioid UTA1003 could serve as an adjuvant with morphine to reduce morphine tolerance over a long-term treatment. Follow-up studies with structural modifications are required to increase its potency as a pain-killer as well as a pharmacokinetic study would help to understand its mechanism of action.

Item Type: Thesis - PhD
Authors/Creators:Paul, AK
Keywords: antinociception, antinociceptive tolerance, motor behaviour, morphine, mixed-activity opioid, chronic administration, motor suppression, age
Copyright Information:

Copyright 2018 the author

Additional Information:

Chapter 2 appears to be the equivalent of a post-print version of an article published as: Paul, A. K., Gueven, N. Dietis, N., 2017. Morphine dosing strategy plays a key role in the generation and duration of the produced antinociceptive tolerance, Neuropharmacology, 121, 158-166

Chapter 4 appears to be the equivalent of a post-print version of an article published as: Paul, A. K., Gueven, N. Dietis, N., 2018. Age-dependent antinociception and behavioral inhibition by morphine, Pharmacology, biochemistry and behavior, 168, 8-16

A published article contains supportive data related the research article that chapter 4 is the post-print equivalent of. The article is: Paul, A. K., Gueven, N. Dietis, N., 2018., Data on prolonged morphine-inducedantinociception and behavioralinhibition in older rats, Data in brief, 19, 193-188. Copyright 2018 The Authors. Published by Elsevier Inc. This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (http://creativecommons.org/licenses/by/4.0/)

Chapter 5 appears to be the equivalent of a post-print version of an article published as: Paul, A. K., Gueven, N. Dietis, N., 2014. Opioid receptor-dependent modulation of insulin-release in pancreatic beta-cells, UK journal of pharmaceutical and biosciences, 2(6), 22-31

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