The TRPA1 channel in migraine mechanism and treatment

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

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This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review

Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.     

鲑鱼降钙素联合低钙透析液治疗血透患者高磷血症的临床研究

目的：探讨低钙透析液联合鲑鱼降钙素对维持血透（Maintenance hemodialysis, MHD）患者高磷血症的影响。方法选取我院近期维持性血液透析患者中高磷血症患者40例,采用随机数字表法分为对照组21例,给予常规钙透析液＋活性维生素D3治疗;试验组19例,给予低钙透析液联合鲑鱼降钙素注射液治疗。观察两组患者治疗后第3、6个月时血清钙磷代谢等指标有无差别。结果对照组治疗后血清钙较治疗前无明显变化（P＞0.05）,但血磷和甲状旁腺激素（iPTH）较透析前明显增加（P〈0.05）;试验组治疗后血清钙、iPTH无明显变化（P＞0.05）,血磷显著降低（P〈0.05）。结论鲑鱼降钙素联合低钙透析液治疗MHD能有效降低患者血磷水平且不致影响iPTH。     

心肌及蛛网膜下腔NGF基因转染对1型糖尿病大鼠心脏损伤的保护作用

目的 探讨以重组腺相关病毒（rAAV）为载体,评价心肌点注射和蛛网膜下腔注射转导神经生长因子（NGF）基因对1型糖尿病大鼠心脏损伤的保护作用。方法 全实验包括两个子实验。实验一：将12只SPF级雄性SD大鼠采用随机数字表法分为2组（n=6）：对照组、糖尿病（DM）组,DM组大鼠通过注射链脲佐菌素（STZ）建立1型糖尿病模型,2组大鼠于注射STZ前1 d及后第1、2、4、6、8、9周测甩尾反射潜伏期,并在第9周时通过酶联免疫吸附试验（ELISA）检测各组织中的NGF、降钙素基因相关肽（CGRP）含量。实验二：24只SPF级雄性SD大鼠随机分为4组（n=6）：糖尿病心脏转染对照组（MC）组、糖尿病心脏转染（ME）组、糖尿病脊髓转染对照（SC）组、糖尿病脊髓转染（SE）组,采用2×2析因设计,4组糖尿病模型建模方法同DM组,成模后第4周,MC组和ME组以心脏点注射分别转染滴度为0.8×1013 μg/L携带绿色荧光蛋白（GFP）基因的重组腺相关病毒（rAAV9-GFP）和相同滴度的携带NGF基因的rAAV-GFP（rAAV9-NGF-GFP）,各100 μL;SC组和SE组以蛛网膜下腔注射分别转染滴度为0.8×1012 μg/L的rAAV2-GFP和相同滴度的rAAV2-NGF-GFP,各25 μL。5周后,测各组大鼠心功能指标。取心肌、T1-T5段脊髓及背根神经节组织,荧光显微镜下观察GFP的表达情况;采用ELISA测各组织中的NGF、CGRP含量。结果 实验一中,与对照组相比,DM组的甩尾反射潜伏期在第4周后明显延长（P＜0.05）,心肌组织中的NGF、CGRP明显下调（P＜0.05）。实验二中,心肌点注射法转染rAAV9-NGF-GFP可改善大鼠的各项心功能指标（P＜0.05）,上调心肌组织中NGF、CGRP蛋白含量（P＜0.05）;且实验过程中的转染物与转染途径之间存在交互效应,两者联用改善心功能和上调心肌组织中NGF、CGRP的效果更显著（P＜0.05）。结论 心肌点注射rAAV-NGF-GFP可以更有效地提高1型糖尿病大鼠心肌组织中NGF的表达,产生更有效的心脏保护作用。     

强骨胶囊联合鲑鱼降钙素针剂辅助治疗老年骨质疏松性压缩骨折临床观察

目的探讨强骨胶囊联合鲑鱼降钙素针剂辅助治疗老年骨质疏松性压缩骨折临床疗效及影响。方法 257例胸腰椎骨质疏松性骨折患者随机分为3组,观察组口服强骨胶囊同时肌肉注射鲑鱼降钙素注射液,对照I组口服强骨胶囊,对照Ⅱ组肌肉注射鲑鱼降钙素针剂。观察临床疗效,测定治疗前和治疗后骨密度(BMD),血骨钙素(BGP)、血钙、血磷浓度及碱性磷酸酶。尿液中尿钙,尿羟脯氨酸,尿肌酐的含量,并计算尿钙/尿肌酐与羟脯氨酸/尿肌酐比值。结果观察组总有效率明显优于对照I组和对照II组(P0.05)。治疗后,3组BMD明显升高,痛觉评分均明显降低(P0.01),尤其观察组更加明显(P0.05)。治疗后,3组骨钙素较治疗前有明显的升高(P0.05或0.01),碱性磷酸酶和羟脯氨酸/尿肌酐较治疗前有明显的下降(P0.05或0.01),尤其治疗组明显优于对照I组和对照II组。治疗后对照组I组和观察组血钙较治疗前有明显的下降(P0.05),但3组组间无差异性(P0.05)。治疗后,3组血磷和尿钙/尿肌酐较治疗前变化不明显,组间比较无差异性(P0.05)。结论骨胶囊和鲑鱼降钙素治疗老年骨质疏松性骨折疗效肯定,能缓解疼痛,促进愈合和降低骨折的再发生,无明显不良反应。     

The Headache Pipeline: Excitement and Uncertainty

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT_1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.     

The psychotomimetic drugs D-amphetamine and phencyclidine release calcitonin gene-related peptide in the limbic forebrain of the rat

Calcitonin gene-related peptide (CGRP) is the major product of the calcitonin gene in brain and exerts a number of actions in the central nervous system (CNS). In particular the finding that CGRP affects dopamine (DA) release and metabolism has raised the possibility that it may play a role in several neuropsychiatric disorders. Consequently, we have here studied the effects of two psychotomimetic drugs, namely, d-amphetamine (AMPH) and phencyclidine (PCP), on CGRP concentrations in brain microdialysates from freely moving rats. The animals were stereotaxically implanted with vertical concentric probes in the medial prefrontal cortex (mPFC), the ventral striatum (vSTR), or the hippocampus; and the experiments were performed 48 hr after surgery. The dialysis probes were perfused with a modified Ringer's solution at the rate of 5 μl/min. AMPH 1.5 mg/kg, PCP 2.5 mg/kg, or NaCl 0.9% were injected s.c.; and the perfusates were collected at 60 min intervals before and after the injections and used for CGRP-like immunoreactivity (-LI) determination by radioimmunoassay (RIA). In separate experiments, KCl (100 mM), veratridine (50 μM), or tetrodotoxin (2 μM), were added to the perfusate and infused in the vSTR. Baseline levels of CGRP-LI were detected in dialysates from all three regions. Both AMPH and PCP caused a significant and sustained increase (maximum about 300%) in CGRP-LI concentrations, in particular from the mPFC and vSTR, while saline had no effect. KCl and veratridine also increased CGRP-LI in dialysates during the first posttreatment period, while tetrodotoxin induced a significant but delayed decrease in CGRP-LI levels. Finally, cervical dislocation also elevated CGRP-LI in dialysates from the mPFC and the vSTR. Our findings demonstrate that 1) CGRP-LI can be measured in vivo in microdialysates from mPFC, vSTR, and hippocampus; 2) the release in vSTR is action potential-dependent; and 3) systemic administration of AMPH or PCP results in a long-lasting release of CGRP-LI in the mPFC and vSTR, thus demonstrating a novel action of these drugs in the brain. Since other studies have shown that major antipsychotic drugs appear to reduce CGRP release in brain, our study provides, in principle, support for a role of CGRP in psychotic disorders. © 1996 Wiley-Liss, Inc.