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

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 (PKCε) plays an important role in nociceptor sensitization, in inflammatory and neuropathic pain. Here we investigated the effects of a novel small molecule that inhibits PKCε 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 PKCε inhibitor alters features of opioid withdrawal and opioid self-administration. This novel PKCε inhibitor attenuated paclitaxel-induced hyperalgesia, reversed hyperalgesia produced by opioid withdrawal, and reduced somatic signs of opioid withdrawal. This PKCε inhibitor did not modify opioid self-administration, nor produce self-administration. These findings suggest that PKCε 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.