Background & Aims
Chemotherapy-induced neuropathic pain (CINP) poses a significant challenge in clinical settings, commonly arising from the administration of agents such as platinum derivatives, vinca alkaloids, taxanes, etc. This condition manifests as a painful state, and in severe cases, can lead to the loss of sensory perceptions. Current therapeutic options for CINP often fall short in providing adequate relief, while their use is hindered by central nervous system (CNS) toxicities, including sedation, cognitive dysfunction, and addiction. In this study, we aimed to explore the impact of CB13, a peripherally restricted agonist of CB1/CB2 receptors, on alleviating chemotherapy-induced neuropathic pain in rats.
Methods
We utilized a diverse array of pain behavioral assays to assess the therapeutic effectiveness of intraplantar CB13 administration in a rat model of paclitaxel-induced neuropathic pain. Further biochemical and molecular biology studies were performed to investigate the alterations in oxidative stress markers, mRNA and protein levels of TRP channels, VGCCs, and various neuro-inflammatory mediators, using RT-PCR and western blotting.
Results
The intraplantar administration of CB13 exhibited a preference for modality-specific inhibition of evoked pain in paclitaxel-induced neuropathic rats. Specifically, it demonstrated the alleviation of allodynia-like behavior without affecting hyperalgesia. Molecular investigations unveiled an upregulation in the expression of nociceptors, including TRPA1, TRPM8, and voltage-gated calcium channels (VGCCs) such as Cav2.2 and Cav3.2, in the L4-L5 dorsal root ganglion (DRG) of rats injected with paclitaxel. Remarkably, treatment with CB13 significantly attenuated these elevated expressions. Furthermore, CB13 administration had a significant restorative effect on the paclitaxel-induced decrease of glutathione (GSH) in the sciatic nerve. Simultaneously, it exhibited a noteworthy attenuation of neuro-inflammatory signaling in both DRG and spinal cord tissues of the rats.
Conclusions
Our findings suggests that the activation of peripheral CB1/CB2 receptors effectively mitigates allodynia-like behavior in paclitaxel-induced neuropathic rats without producing CNS toxicities. This therapeutic effect is attributed to the downregulation of transient receptor potential (TRP) channels and voltage-gated calcium channels (VGCCs). Moreover, the observed suppression of neuroinflammatory and oxidative cascades further highlights the multifaceted impact of CB13.
References
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