Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.783407
Title: The mammalian target of rapamycin complex 1 (mTORC1) and the regulation of opioid efficacy
Author: Alsubaiyel, Amal Mohammed
ISNI:       0000 0004 7968 9970
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2019
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Abstract:
Prolonged opioid administration leads to pharmacological tolerance that significantly restricts the clinical usefulness of opioids. In addition, the misuse of and addiction to opioids is a serious international crisis that affects public health as well as social and economic welfare. Thus, opioid-based treatments and research into understanding the mechanisms underlying the effects of opioids in chronic pain is warranted. Recently, there is growing evidence supporting the mammalian target of rapamycin complex 1 (mTORC1), a kinase which controls protein synthesis, as a regulator of opioid effectiveness, though the precise role of mTORC1 in the improvement of opioid-based treatments is uncertain. Therefore, this study aims to determine the extent to which alterations in mTORC1 activity within nociceptive pathways underlie the responsiveness to morphine. Specifically, by expanding upon studies investigating the role of mTORC1 in chronic pain, the goal was to define the importance of mTORC1 as a therapeutic target in mechanisms counteracting the analgesic effects of opioids in chronic pain leading to the development and maintenance of morphineinduced tolerance. By using a combination of in vivo models of tolerance and neuropathic pain as well as by behavioural testing and tools of molecular biology, it has been shown that inhibition of mTORC1 activity blocked the development and maintenance of morphine-induced analgesic tolerance in naïve mice and in animals subjected to neuropathic pain. This approach also potentiates the analgesic efficacy of morphine in neuropathic pain. Interestingly, improvement of morphine-mediated analgesia was observed after peripheral administration that could minimise the risk of side-effects associated with systemic administration of opioids. Moreover, mTORC1 inhibition did not regulate the motivational properties of morphine potentially offering safe pain control. The originality of this study shows that all these effects were produced by the anti-diabetic drug metformin which is known to inhibit in vivo mTORC1 activity via activation of the adenosine monophosphate-activated protein kinase (AMPK) and has safer therapeutic profile compared to direct mTORC1 inhibitors. To conclude, data presented here reveals that inhibition of mTORC1 activity improve morphine analgesic effectiveness and provided a novel insight into the complexity of the adaptive mechanisms that underlie opioid treatment and its side-effects in chronic pain. Importantly, this study shows that metformin may offer a novel and clinically relevant strategy for modulation of morphine efficacy in chronic pain, especially when prolonged opioid treatment is required.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.783407  DOI: Not available
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