Lee Grace J, Hode Veronica, Georgieva Teodora, Rau Jill, Dodick David W, Schwedt Todd J, Neugebauer Volker, Porreca Frank, Navratilova Edita
Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
GEMM Core, BIO5 Institute, University of Arizona College of Medicine, Tucson, AZ, USA.
Cephalalgia. 2025 Jan;45(1):3331024241313378. doi: 10.1177/03331024241313378.
Women with endometriosis are more likely to have migraine. The mechanisms underlying this co-morbidity are unknown. Prolactin, a neurohormone secreted and released into circulation from the anterior pituitary, can sensitize sensory neurons from female, but not male, rodents, monkeys and human donors.
We used a syngeneic model of endometriosis to determine whether elevated prolactin levels can sensitize trigeminal ganglion neurons and increase vulnerability to migraine pain.
Mice with endometriotic lesions showed increased serum prolactin levels and developed persistent abdominal, but not cephalic, allodynia. However, inhalation of a transient receptor potential ankyrin 1 agonist, umbellulone, a known environmental trigger of headache in some patients, elicited cephalic allodynia in mice with endometriosis but not sham controls, suggesting that endometriosis can promote sensitization of trigeminal neurons and migraine attacks. Endometriosis dysregulated the expression of prolactin receptor isoforms in trigeminal neurons and increased their excitability measured by patch clamp electrophysiology. Inhibition of pituitary prolactin following a 2-week treatment with a dopamine receptor agonist, cabergoline, prevented cephalic allodynia elicited by activation of trigeminal afferents with umbellulone. Cabergoline treatment also normalized the expression of prolactin receptor isoforms in trigeminal ganglia and the hyperexcitability of trigeminal neurons.
These data demonstrate that circulating prolactin in endometriosis promotes vulnerability to migraine through sensitization of trigeminal afferents. Clinically available dopamine receptor agonists or novel monoclonal antibodies targeting prolactin signaling may be effective for migraine prevention in women with endometriosis.
患有子宫内膜异位症的女性更易患偏头痛。这种共病的潜在机制尚不清楚。催乳素是一种从前脑垂体分泌并释放到循环系统中的神经激素，它能使雌性啮齿动物、猴子和人类供体的感觉神经元敏感化，但不能使雄性的敏感化。
我们使用子宫内膜异位症的同基因模型来确定催乳素水平升高是否会使三叉神经节神经元敏感化并增加偏头痛疼痛的易感性。
患有子宫内膜异位症病变的小鼠血清催乳素水平升高，并出现持续性腹部痛觉过敏，但无头部痛觉过敏。然而，吸入一种瞬时受体电位锚蛋白1激动剂伞形酮（一些患者已知的环境性头痛触发因素），在患有子宫内膜异位症的小鼠中引发了头部痛觉过敏，而假手术对照组则没有，这表明子宫内膜异位症可促进三叉神经神经元的敏感化和偏头痛发作。子宫内膜异位症使三叉神经神经元中催乳素受体亚型的表达失调，并通过膜片钳电生理学测量增加了它们的兴奋性。用多巴胺受体激动剂卡麦角林进行为期2周的治疗后，抑制垂体催乳素可预防由伞形酮激活三叉神经传入纤维引起的头部痛觉过敏。卡麦角林治疗还使三叉神经节中催乳素受体亚型的表达和三叉神经神经元的过度兴奋性恢复正常。
这些数据表明，子宫内膜异位症中循环的催乳素通过使三叉神经传入纤维敏感化而增加偏头痛的易感性。临床上可用的多巴胺受体激动剂或针对催乳素信号传导的新型单克隆抗体可能对预防子宫内膜异位症女性的偏头痛有效。
