Objective

Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms.

Background

The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective.

Methods

Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms.

Results

PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females.

Interpretation

We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

中文翻译：

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偏头痛慢性化的催乳素依赖性两性二态机制

客观的

确定促进偏头痛进展的机制中可能的性别差异以及催乳素和催乳素长 (PRLR-L) 和短 (PRLR-S) 受体亚型的贡献。

背景

大多数患有慢性偏头痛和药物过度使用性头痛的患者是女性。催乳素在女性中的含量较高，会增加偏头痛。PRLR-S 的催乳素信号选择性地使雌性啮齿动物的伤害感受器敏感，而 PRLR-L 的表达具有保护性。

方法

通过在雄性和雌性小鼠中反复施用舒马曲坦来模拟药物过度使用性头痛。眶周和后爪皮肤异常性疼痛可替代偏头痛样疼痛。用蛋白质印迹在三叉神经节中测量 PRLR-L 和 PRLR-S 同种型。用 RNAscope 确定 PRLR 与血清素 5HT1B 和 5HT1D 受体可能的共定位。卡麦角林是一种抑制循环催乳素的多巴胺受体激动剂，与舒马曲坦联合给药。CRISPR/Cas9 质粒的鼻腔给药用于编辑两种 PRLR 同种型的表达。

结果

PRLR与女性三叉神经节眼部区域的5HT1B或5HT1D受体共定位。单次注射舒马曲坦会增加雌性小鼠的血清 PRL 水平。重复舒马曲坦促进两性皮肤异常性疼痛，但下调三叉神经节 PRLR-L，而不改变 PRLR-S，仅在女性中。舒马曲坦与卡麦角林的共同给药仅在女性中预防异常性疼痛和 PRLR-L 的下调。三叉神经节中两种 PRLR 亚型的 CRISPR/Cas9 编辑可防止舒马曲坦诱导的女性眶周异常性疼痛。

解释

我们确定了偏头痛慢性化的性别二态机制，其涉及 PRLR-L 的下调和 PRLR-S 处循环催乳素的信号增加。这些研究揭示了一种以前未被认识的神经内分泌机制，该机制将下丘脑与伤害感受器致敏联系起来，这会增加女性偏头痛的风险，并为新的性别特异性疗法提供机会，包括通过鼻腔递送 CRISPR/Cas9 构建体进行基因编辑。