Naringenin relieves paclitaxel‐induced pain by suppressing calcitonin gene‐related peptide signalling and enhances the anti‐tumour action of paclitaxel

Background and Purpose Chemotherapy‐induced peripheral neuropathy (CIPN) commonly causes neuropathic pain, but its pathogenesis remains unclear, and effective therapies are lacking. Naringenin, a natural dihydroflavonoid compound, has anti‐inflammatory, anti‐nociceptive and anti‐tumour activities. However, the effects of naringenin on chemotherapy‐induced pain and chemotherapy effectiveness remain unexplored. Experimental Approach Female and male mouse models of chemotherapy‐induced pain were established using paclitaxel. Effects of naringenin were assessed on pain induced by paclitaxel or calcitonin gene‐related peptide (CGRP) and on CGRP expression in dorsal root ganglia (DRG) and spinal cord tissue. Additionally, we examined peripheral macrophage infiltration, glial activation, c‐fos expression, DRG neuron excitability, microglial M1/M2 polarization, and phosphorylation of spinal NF‐ κ B. Furthermore, we investigated the synergic effect and related mechanisms of naringenin and paclitaxel on cell survival of cancer cells in vitro. Key Results Systemic administration of naringenin attenuated paclitaxel‐induced pain in both sexes. Naringenin reduced paclitaxel‐enhanced CGRP expression in DRGs and the spinal cord, and alleviated CGRP‐induced pain in naïve mice of both sexes. Naringenin mitigated macrophage infiltration and reversed paclitaxel‐elevated c‐fos expression and DRG neuron excitability. Naringenin decreased spinal glial activation and NF‐ κ B phosphorylation in both sexes but influenced microglial M1/M2 polarization only in females. Co‐administration of naringenin with paclitaxel enhanced paclitaxel's anti‐tumour effect, impeded by an apoptosis inhibitor. Conclusion and Implications Naringenin's anti‐nociceptive mechanism involves CGRP signalling and neuroimmunoregulation. Furthermore, naringenin facilitates paclitaxel's anti‐tumour action, possibly involving apoptosis. This study demonstrates naringenin's potential as a supplementary treatment in cancer therapy by mitigating side effects and potentiating efficacy of chemotherapy.