The mammalian target of rapamycin complex 1 (mTORC1)
and the regulation of opioid efficacy

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.