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.

Muscle injury caused by direct trauma to the skeletal muscle is among the main musculoskeletal disorders. Non-pharmacological treatments have been effective in controlling muscle injury–induced pain; however, there are just a few studies in the literature investigating this response. Thus, the present study aimed to evaluate the effect of a resistance exercise training protocol combined or not with whey protein supplementation on mechanical allodynia induced by muscle injury. In addition, we also investigated the involvement of spinal glial cells in this process. For this purpose, male Wistar rats underwent a muscle injury model induced by direct trauma to the gastrocnemius muscle. Mechanical allodynia was measured by a digital von Frey algesimeter test. To evaluate the effect of exercise and/or supplementation on mechanical allodynia, the animals practiced exercises three times a week for 14 days and received supplementation daily for 14 days, respectively. Moreover, the effect of both the participation of spinal glial cells in the muscle injury and the resistance exercise training and/or whey protein supplementation on these cells was also investigated by the Western blot assay. The results demonstrated that resistance exercise training and whey protein supplementation, combined or alone, reduced mechanical allodynia. These treatments also reduced the number of interstitial cells and pro-inflammatory cytokine IL-6 levels in the injured muscle. It was also found that spinal microglia and astrocytes are involved in muscle injury, and that resistance exercise training combined with whey protein supplementation inhibits spinal microglia activation. The results suggest that both resistance exercise training and whey protein supplementation may be effective non-pharmacological treatments to control pain in the muscle after injury induced by acute trauma.

Objectives Pain is the most common cause of seeking healthcare and the leading cause of disability worldwide. Although cannabidiol and transcutaneous electrical nerve stimulation (TENS) are effective and safe strategies for treating chronic pain, the combined effect of these interventions remains overlooked. To compare the isolated and combined effect of cannabidiol and TENS in the treatment of experimental neuropathic and inflammatory pain. Methods Swiss mice were subjected to chronic constriction injury (CCI)-induced neuropathic or carrageenan-induced inflammatory pain models. Cannabidiol or TENS alone and the combination of these therapies were administered once. The nociceptive threshold was measured by the von Frey test. IL-1β, TNF-α and IL-10 cytokine levels were measured by ELISA from spinal cord samples. Results Combined, cannabidiol and TENS potentiate antinociception only in neuropathic pain. IL-1β and TNF-α levels were similarly reduced when TENS or cannabidiol were administered alone or in combination. However, only cannabidiol and TENS combined increased IL-10 levels. Conclusions Our findings indicated TENS and cannabidiol combined were effective in potentiating antinociception in a neuropathic pain model, an effect potentially associated with spinal IL-10 upregulation.