Cannabidiol prevents chemotherapy-induced neuropathic pain by modulating spinal TLR4 via endocannabinoid system activation

Abstract

Objectives This study aimed to investigate the effect of cannabidiol (CBD) on type 4 Toll-like receptors (TLR4), glial cells and pro-inflammatory cytokines during the neuropathic pain induced by the chemotherapy agent paclitaxel (PTX), as well as the involvement of the endocannabinoid system in this process. Methods Male C57BL6 mice were subjected to PTX-induced neuropathic pain. To evaluate the involvement of the TLR4, glial cells and cannabinoid CB2 receptor, specific inhibitors or antagonists were intrathecally administered. The western blotting and immunofluorescence assay was performed to evaluate the spinal expression of TLR4, microglia, astrocytes and cannabinoid CB2 receptor. The levels of spinal pro-inflammatory cytokines and endocannabinoids were determined by enzyme-linked immunosorbent assay and liquid chromatography-mass spectrometry analysis, respectively. Key findings CBD prevented PTX-induced neuropathic pain, and the cannabinoid CB2 receptor antagonist AM630 reversed this effect. In addition, CBD treatment inhibited the spinal expression of TLR4 and Iba1 in mice with neuropathic pain. CBD also increased spinal levels of endocannabinoids anandamide and 2-arachidonoylglycerol, and reduced levels of cytokines in mice with neuropathic pain. Conclusions CBD was efficient in preventing PTX-induced neuropathic pain, and this effect may involve inhibition of the TLR4 on microglia spinal with activation of the endocannabinoid system.

Novel Drug Targets and Emerging Pharmacotherapies in Neuropathic Pain

“…The results demonstrated a dose-dependent reduction in nociceptive behaviors, decreased lipid peroxidation levels, and increased GSH concentration, indicating the antioxidant effects of CBD [ 142 ]. The effects of cannabidiol (CBD) on neuropathic pain induced by paclitaxel were investigated using male C57BL6 mice [ 143 ]. CBD treatment effectively prevented paclitaxel-induced neuropathic pain and was associated with inhibition of type 4 Toll-like receptors (TLR4) and microglia activation [ 143 ].…”

“…The effects of cannabidiol (CBD) on neuropathic pain induced by paclitaxel were investigated using male C57BL6 mice [ 143 ]. CBD treatment effectively prevented paclitaxel-induced neuropathic pain and was associated with inhibition of type 4 Toll-like receptors (TLR4) and microglia activation [ 143 ]. CBD also increased the levels of endocannabinoids and reduced pro-inflammatory cytokine levels in the spinal cord [ 143 ].…”

“…CBD treatment effectively prevented paclitaxel-induced neuropathic pain and was associated with inhibition of type 4 Toll-like receptors (TLR4) and microglia activation [ 143 ]. CBD also increased the levels of endocannabinoids and reduced pro-inflammatory cytokine levels in the spinal cord [ 143 ]. The findings suggest that CBD’s effects on neuropathic pain may involve modulation of the TLR4 pathway and activation of the endocannabinoid system [ 143 ].…”

“…CBD also increased the levels of endocannabinoids and reduced pro-inflammatory cytokine levels in the spinal cord [ 143 ]. The findings suggest that CBD’s effects on neuropathic pain may involve modulation of the TLR4 pathway and activation of the endocannabinoid system [ 143 ]. CBD and β-caryophyllene, which are two cannabis constituents, when acting individually and in combination, showed analgesic effects in a rat model of chronic spinal cord injury pain [ 144 ].…”