Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan.
Mol Pain. 2020 Jan-Dec;16:1744806920969476. doi: 10.1177/1744806920969476.
The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.
内源性大麻素系统（ECS）不仅被认为可以调节食物摄入，还可以调节疼痛，特别是通过在中枢神经系统和外周组织中表达的大麻素 1 型受体（CB1R）。我们之前的研究表明，禁食会在成年雄性小鼠中产生镇痛作用，而腹腔内（i.p.）给予 CB1R 拮抗剂（SR 141716）则会逆转这种作用。在本研究中，我们进一步研究了外周组织中表达的 CB1R 的作用。在福尔马林诱导的炎症性疼痛模型中，腹腔内给予外周受限的 CB1R 拮抗剂（AM 6545）可逆转禁食引起的镇痛作用。然而，腹腔内给予 SR 141716 并不影响禁食引起的镇痛作用。此外，在背根神经节中，禁食并未改变福尔马林模型中 CB1R 的 mRNA 表达。禁食对脊髓水平福尔马林诱导的 c-Fos 表达没有影响，从腰椎脊髓的浅层背角记录显示，禁食不会影响福尔马林诱导的神经活动，这表明脊髓在禁食引起的镇痛作用中参与程度较低。最后，当我们进行膈下迷走神经切断术以阻断来自胃肠道（GI）系统的饥饿信号时，AM 6545 并不影响禁食引起的镇痛作用，但 SR 141716 仍可逆转禁食引起的镇痛作用。综上所述，我们的结果表明，外周和中枢 CB1R 均有助于禁食引起的镇痛作用，而将禁食信号传递到大脑的 GI 系统中的 CB1R，而不是外周感觉神经元中的 CB1R，可能有助于禁食引起的镇痛作用。
