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.
RESUMEN | Aunque la estimulación nerviosa eléctrica transcutánea (TENS) ha sido propuesta para modular el dolor y los mecanismos subyacentes a la analgesia sigue siendo mal entendida, la evidencia del efecto antiinflamatorio es limitada.El propósito de este estudio fue examinar los mecanismos opioidérgicos de los efectos de la TENS en dos frecuencias diferentes sobre el dolor y el edema inflamatorio en un modelo de ratas con esguince de tobillo. Se utilizó el umbral a la estimulación mecánica para examinar los cambios producidos por inyección intraperitoneal del antagonista opiáceo no selectivo naloxona sobre el efecto antihiperalgésico inducido por un período de 20 minutos de 2Hz o 100Hz TENS en el modelo con esguince de tobillo, producido por sobrecarga manual de los ligamentos laterales. El esguince de tobillo indujo una reducción de larga duración en latencia de la pata retraída (PWL) después de 30 minutos por hasta 24 horas en simulación de la TENS (SH-TENS) para las ratas tratadas. El PWL reducido después de la inducción del esguince de tobillo fue restaurado parcialmente en 0,1,2,3 y 6, pero no por 24 horas, después de la terminación de 2 Hz-TENS (LF-TENS).La reducción en PWL fue menor que LF-TENS en 100Hz(HF-TENS) y tanto los efectos de LF como de HF fueron completamente bloqueados en ratas tratadas con naloxona.Las ratas tratadas con LF-y HF-TENS no alcanzaron la elevación del edema y presentaron una reducción progresiva del edema durante más de 24 horas en comparación con el grupo SH-TENS. Ambos efectos fueron reducidos por la naloxona. Efectos antihiperalgésicos y antiedematosos TENSinducidos observados en el modelo con esguince de tobillo fueron mediados por el sistema opioide endógeno.Palabras clave |
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