Targeting AMPK for the Alleviation of Pathological Pain

Asiedu, Marina N.; Dussor, Gregory; Price, Theodore J.

doi:10.1007/978-3-319-43589-3_11

Cited by 41 publications

(45 citation statements)

References 191 publications

(271 reference statements)

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“…Our in vitro experiments on DRG neurons indicate the combination of resveratrol and metformin activate AMPK in at least an additive fashion. These data add to a growing body of evidence that AMPK activation can inhibit the development of acute mechanical hypersensitivity resulting from injury (Melemedjian et al, 2011, Tillu et al, 2012a, Russe et al, 2013, Bullon et al, 2015, Ma et al, 2015, Song et al, 2015, Maixner et al, 2016, Ling et al, 2017), reduce the excitability of nociceptors (Melemedjian et al, 2011, Tillu et al, 2012a, Melemedjian et al, 2013, Asiedu et al, 2017) and prevent the development of hyperalgesic priming (Price and Dussor, 2013, Price et al, 2015, Asiedu et al, 2016, Mejia et al, 2016). We conclude that topical resveratrol and co-treatment of various AMPK activators such as metformin are clinically relevant and could show utility as pain therapeutics in humans.…”

Section: Discussionmentioning

confidence: 58%

Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

et al. 2017

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New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. Here we have used a variety of administration routes and combinations of AMPK activators to test this hypothesis. Topical administration of a resveratrol-based cream inhibited acute mechanical hypersensitivity evoked by incision and blocked the development of hyperalgesic priming. We also observed that systemic administration of metformin dose-dependently inhibited incision-evoked mechanical hypersensitivity and hyperalgesic priming. Interestingly, low doses of systemic metformin and local resveratrol that had no acute effect were able to mitigate development of hyperalgesic priming. Combined treatment with doses of systemic metformin and local resveratrol that were not effective on their own enhanced the acute efficacy of the individual AMPK activators for post-surgical mechanical pain alleviation and blocked the development of hyperalgesic priming. Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.

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Section: Discussionmentioning

confidence: 58%

Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

et al. 2017

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“…An additional promising strategy to normalize aberrant mRNA translation in persistent pain involves the activation of a cellular energy sensor, AMP-activated protein kinase (AMPK), using metformin or other compounds [61,62]. Metformin is a US Food and Drug Administration (FDA)-approved first-line anti-type 2 diabetic compound.…”

Section: Targeting Translation For Therapeutic Development Of Next-gementioning

confidence: 99%

Translational Control Mechanisms in Persistent Pain

Khoutorsky

Price

2018

Trends in Neurosciences

101

114

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Persistent pain, which is poorly treated and estimated to afflict one third of the world’s population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics.

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“…As noted in a recent review, (Asiedu et al, 2016) the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is a novel target for the alleviation of neuropathic pain. AMPK activators inhibit signaling pathways that are known to promote changes peripheral nociceptors that result in chronic pain.…”

Section: Perturbed Neuroinflammation-related Pathways Associated Withmentioning

confidence: 99%

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Miaskowski

Topp

Conley

et al. 2019

Journal of Neuroimmunology

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A B S T R A C TPaclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.

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Targeting AMPK for the Alleviation of Pathological Pain

Cited by 41 publications

References 191 publications

Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

Translational Control Mechanisms in Persistent Pain

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

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