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bioRxiv · 10.64898/2026.06.08.730909

Cannabidiol attenuates chemotherapy-induced peripheral neuropathic pain through a mechanism that requires the enzyme N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD)

Alves Jesus, C. H.·Li, A.·Luquet, S.·Mackie, K.·Hohmann, A. G.
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Abstract

Cannabidiol (CBD) is a non-psychoactive component of cannabis that has been studied as a potential therapy for chronic pain. CBD attenuates behavioral hypersensitivities in models of neuropathic pain, and promotes production of bioactive lipids (e.g., anandamide), altering lipid signaling. However, a lack of understanding of the mechanisms underlying the therapeutic effects of CBD has hindered development and application of CBD to mechanism-based therapies for pain in people. We asked whether the analgesics effects of CBD were dependent upon the enzyme NAPE-PLD. We used a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the acute and chronic antinociceptive effects of CBD and investigate its mechanisms. Pharmacological specificity was tested with antagonists targeting CB1, CB2, PPAR{gamma}, and PPAR receptors. Mechanisms were further examined using NAPE-PLD and GPR55 knockout mice. We also assessed repeated CBD dosing during both the development and maintenance of paclitaxel-induced CIPN in wild-type, GPR55 KO, and NAPE-PLD KO mice. CBD suppressed paclitaxel-induced behavioral hypersensitivities; these effects were attenuated by a PPAR and PPAR{gamma} antagonists, but not CB1 or CB2 antagonists. CBD reduced both the development and maintenance of neuropathic nociception in a model CIPN in wild-type mice, but these effects were absent in NAPE-PLD KO mice. By contrast, anti-allodynic efficacy of CBD was fully preserved in GPR55 KO mice. Pharmacological blockade of the PPAR receptor and genetic deletion of NAPE-PLD abolished the antinociceptive effects of CBD in a model of CIPN, suggesting a pivotal role for NAPE-PLD and PPAR receptors in CBD-mediated analgesia in chemotherapy-induced neuropathic pain.

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Alves Jesus, C. H., Li, A., Luquet, S., Mackie, K., Hohmann, A. G.. 2026-06-12. Cannabidiol attenuates chemotherapy-induced peripheral neuropathic pain through a mechanism that requires the enzyme N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). https://doi.org/10.64898/2026.06.08.730909

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