A novel small molecule PKC epsilon inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal

Gregory-Flores, A.; Magayewski Bonet, I. J.; Desaivre, S.; Levine, J. D.; McHardy, S. F.; de Kraker, H.; Russell, N.; Fleischer, C.; Messing, R.; Marinelli, M.

doi:10.1101/2023.06.01.543325

bioRxiv · 10.1101/2023.06.01.543325

A novel small molecule PKC epsilon inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal

Gregory-Flores, A.·Magayewski Bonet, I. J.·Desaivre, S.·Levine, J. D.·McHardy, S. F.·de Kraker, H.·Russell, N.·Fleischer, C.·Messing, R.·Marinelli, M.

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Abstract

Aggressive marketing and increased prescribing of opioids for treating pain have fueled a prominent increase in opioid use disorder. This acute public health problem has led to calls for the development of non-opioid alternatives to treat chronic pain. The enzyme protein kinase C epsilon (PKC{varepsilon}) plays an important role in nociceptor sensitization, in inflammatory and neuropathic pain. Here we investigated the effects of a novel small molecule that inhibits PKC{varepsilon} in a rodent model of chemotherapy-induced neuropathic pain produced by administration of the cancer chemotherapy, paclitaxel. Because transition of opioid-dependent individuals to a non-opioid pain medication can increase pain due to opioid withdrawal, we also investigated if the PKC{varepsilon} inhibitor alters features of opioid withdrawal and opioid self-administration. This novel PKC{varepsilon} inhibitor attenuated paclitaxel-induced hyperalgesia, reversed hyperalgesia produced by opioid withdrawal, and reduced somatic signs of opioid withdrawal. This PKC{varepsilon} inhibitor did not modify opioid self-administration, nor produce self-administration. These findings suggest that PKC{varepsilon} inhibition is an effective, non-addictive strategy to treat chemotherapy-induced neuropathic pain with the added benefit of limiting hyperalgesia due to opioid withdrawal, which could facilitate switching treatment of chronic pain, in opioid-dependent individuals.

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Gregory-Flores, A., Magayewski Bonet, I. J., Desaivre, S., Levine, J. D., McHardy, S. F., de Kraker, H., Russell, N., Fleischer, C., Messing, R., Marinelli, M.. 2023-06-05. A novel small molecule PKC epsilon inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal. https://doi.org/10.1101/2023.06.01.543325

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