A small molecule PKCε inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal
Adriana Gregory-Flores, … , Robert O. Messing, Michela Marinelli
Adriana Gregory-Flores, … , Robert O. Messing, Michela Marinelli
Published April 22, 2025
Citation Information: JCI Insight. 2025;10(8):e186805. https://doi.org/10.1172/jci.insight.186805.
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Research Article Neuroscience Therapeutics

A small molecule PKCε inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal

Abstract

The enzyme protein kinase C ε (PKCε) plays an important role in pain signaling and represents a promising therapeutic target for the treatment of chronic pain. We designed and generated a small molecule inhibitor of PKCε, CP612, and examined its effect in a rodent model of chemotherapy-induced neuropathic pain produced by paclitaxel, which does not respond well to current therapeutics. In addition, many patients with chronic pain use opiates, which over time can become ineffective, and attempts to discontinue them can increase pain thereby promoting sustained opioid use. Therefore, we also investigated if CP612 alters pain due to opioid withdrawal. We found that CP612 attenuated hyperalgesia produced by paclitaxel, and it both prevented and reversed hyperalgesia induced by opioid withdrawal. It was not self-administered and did not affect morphine self-administration. These findings suggest that inhibition of PKCε is an effective, nonaddictive strategy to treat chemotherapy-induced neuropathic pain, with the added benefit of preventing increases in pain that occur as opioid treatment is discontinued. This latter property could benefit individuals with chronic pain who find it difficult to discontinue opioids.

Authors

Adriana Gregory-Flores, Ivan J.M. Bonet, Stève Desaivre, Jon D. Levine, Stanton F. McHardy, Harmannus C. de Kraker, Nicholas A. Clanton, Peter M. LoCoco, Nicholas M. Russell, Caleb Fleischer, Robert O. Messing, Michela Marinelli

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Figure 11

Morphine withdrawal and conditioned place aversion (CPA) precipitated by naloxone.

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Morphine withdrawal and conditioned place aversion (CPA) precipitated by...
(A) Experimental timeline. (B) On conditioning day, naloxone (5 mg/kg, i.p.) evoked signs of withdrawal in male mice that received repeated administration of morphine (20–100 mg/kg, i.p.) and were treated with vehicle (n = 25) or a low dose of CP612 (10 mg/kg, i.p., n = 15), but this was decreased in mice treated with a high dose of CP612 (40 mg/kg, i.p., n = 10). (C) On test day, prior administration of naloxone produced CPA in mice that received repeated administration of morphine, and this occurred similarly in mice that were treated with vehicle (n = 30) or different doses of CP612 (5, 10, 20, 40 mg/kg, i.p., n = 6, 18, 7, 11, respectively). For B, box and whiskers are median and 25% interquartile intervals; dots are scores from individual mice. For C, Data are shown as mean ± SEM; dots are scores from individual mice. ##P < 0.01 and ###P < 0.001 compared with Saline + Vehicle: ***P < 0.001 compared with Morphine + Vehicle using Tukey’s post hoc test.