The role of endocannabinoid systems on the modulation of migraine
Molecular and Cellular Neurology and Neuropathology
Pharmacology
Final Report Abstract
Our main focus on this study was to assess the contribution of CB1 receptor-mediated endocannabinoid signaling to the chronic head-pain disease, migraine. As known, migraine is one of the most common chronic painful disease in the world. It is said that total number of migraineurs might reach up to 10 % of the whole population on the earth. Nevertheless the pathophysiological mechanisms is not completely clarified, which is demonstrated by the lack of holy grail medicines or treatments for the migraine. Cannabinoid is one of substance that is believed to improve migraine pain. Interestingly, some clinical reports showed that chronic migraine patients as well as medication overuse headache (MOH) patients has remarkably low serum endocannabinoid (eCB) content, suggesting that eCB activity is reduced in those patients. ECB activity is regulated by two G-protein coupled receptors CB1 and CB2, which is activated by two endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These ligands are produced by their production enzymes NAPE-PLD or DAGL, and rapidly degraded by degradation enzymes FAAH or MAGL. Thus, our eCB-mediated regulatory system, endocannabinoid system (ECS), is affected by these receptors together with enzymes that produce and degrade eCB ligands. Notably, enhancement of FAAH activity has been found in migraine patients which suggests that enhanced FAAH has been reduced eCB ligands, however there is no evidence that could connect “FAAH activity”, “eCB activity” and “migraine pain”.We therefore used genetically modified animals that lack either CB1 receptor, CB2 receptor, FAAH or MAGL, and induced acute migraine model or chronic MOH, to reveal the contribution of ECS particularly to the pain attack of those symptom. Our studies successfully added the scientific evidence to support several important aspects in context of endocannabinoid system contribution to migraine pain as follows: 1) Reduction of CB1 signalling drastically exacerbate the pain attack (now measured by the novel method = orofacial von-Frey test) in three different models of migraine, that was systemic NTG model, NTG-CGRP model and chronic triptan model. 2) Reduction of FAAH activity by either FAAH gene deletion or administration of FAAH inhibitor could abolish the orofacial hypersensitivity observed in three different models of migraine. 3) Female animals show stronger hypersensitivity to systemic NTG, however it only appeared when the NTG dose has been reduced to 3 mg/kg, which indicates that 10 mg/kg NTG gives plateau level of hypersensitivity to both males and females. Further, estrogen deficiency lead by ovariectomy (OVX) did not improve the greater hypersensitivity observed in female animals. 4) However, OVX improved the acute analgesic effect of FAAH inhibitor PF3845. Namely, 3 mg/kg of PF3845 could reverse the NTG-induced hyperalgesia in male and also in OVX-female animals, but not in normal female animals. Similar effect was also observed by c-Fos activity in trigeminal nuclei, therefore inhibitory effect of PF3845 administration to c-Fos upregulation was seen in males and PVX-females, but again not in normal females. We have also found that lack of CB1 receptor could modify the mitochondrial morphology from normal round shape to abnormal elongated shape, suggesting that without CB1 receptors cells can not maintain the mitochondrial function. This is found in any age of CB1 deficient animals, suggesting pathophysiological aspects observed in CB1 knockouts (e.g. enhanced migraine pain) might be at least partially due to this mitochondrial quality control impairment. We have not compared with actual migraine model yet, therefore to see whether CB1 deficiency-mediated mitochondrial disfunction will enhance the migraine symptom such as pain attack will be our next research target.
Publications
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CB2 receptor deletion on myeloid cells enhanced mechanical allodynia in a mouse model of neuropathic pain. Scientific Reports, 9(1).
Nent, Elisa; Nozaki, Chihiro; Schmöle, Anne-Caroline; Otte, David & Zimmer, Andreas
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Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 Receptor-deficient Mice. Brain Research Bulletin, 160, 40-49.
Kataoka, Kosuke; Bilkei-Gorzo, Andras; Nozaki, Chihiro; Togo, Akinobu; Nakamura, Keiichiro; Ohta, Keisuke; Zimmer, Andreas & Asahi, Toru
