PDF(Pubmed)
Abstract：
BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice.
METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR.
RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice.
CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR.
RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice.
CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
摘要：
背景：垂体腺苷酸环化酶激活肽（PACAP）是一种在偏头痛病理生理学中起关键作用的神经肽，被认为是一种有前途的新的偏头痛药物靶点。尽管静脉注射PACAP会引发偏头痛发作，最近一项使用PACAP抑制抗体的II期试验显示了预防偏头痛的功效，单独靶向PACAP受体PAC1没有成功。本研究调查了三种PACAP受体（PAC1，VPAC1和VPAC2）在诱导小鼠偏头痛相关超敏反应中的作用。
方法：反复注射PACAP38可诱发Hindpaw超敏反应。在三种敲除（KO）小鼠品系中使用vonFrey细丝定量触觉敏感性反应，每个都缺乏PACAP受体之一（Ntotal=160）。此外,体外线肌电图用于评估颈动脉的血管活性，通过qPCR检测PACAP受体的基因表达。
结果:PACAP38在WT对照中诱导超敏反应(p<0.01),其在VPAC1和VPAC2KO小鼠中降低(p<0.05)。相比之下,PAC1KO小鼠显示与WT对照相似的应答(p>0.05)。Myograph实验支持这些发现，表明VPAC1和VPAC2KO小鼠的血管活性降低。我们在KO小鼠中未发现未修饰的PACAP受体上调。
结论：这项研究评估了偏头痛小鼠模型中所有三种PACAP受体，并提示VPAC受体在偏头痛病理生理学中的重要作用。PAC1KO小鼠缺乏超敏反应性降低，提示其他PACAP受体或代偿机制的参与。结果表明，仅靶向单个PACAP受体可能不是有效的偏头痛治疗方法。
方法：反复注射PACAP38可诱发Hindpaw超敏反应。在三种敲除（KO）小鼠品系中使用vonFrey细丝定量触觉敏感性反应，每个都缺乏PACAP受体之一（Ntotal=160）。此外,体外线肌电图用于评估颈动脉的血管活性，通过qPCR检测PACAP受体的基因表达。
结果:PACAP38在WT对照中诱导超敏反应(p<0.01),其在VPAC1和VPAC2KO小鼠中降低(p<0.05)。相比之下,PAC1KO小鼠显示与WT对照相似的应答(p>0.05)。Myograph实验支持这些发现，表明VPAC1和VPAC2KO小鼠的血管活性降低。我们在KO小鼠中未发现未修饰的PACAP受体上调。
结论：这项研究评估了偏头痛小鼠模型中所有三种PACAP受体，并提示VPAC受体在偏头痛病理生理学中的重要作用。PAC1KO小鼠缺乏超敏反应性降低，提示其他PACAP受体或代偿机制的参与。结果表明，仅靶向单个PACAP受体可能不是有效的偏头痛治疗方法。
