Neurovascular Research Unit, Department of Neurology, Massachusetts General Hospital, 149 13th Street, Charlestown, Boston MA, 02129, USA.
J Headache Pain. 2024 Sep 17;25(1):152. doi: 10.1186/s10194-024-01855-7.
Migraine is among the most prevalent and burdensome neurological disorders in the United States based on disability-adjusted life years. Cortical spreading depolarization (SD) is the most likely electrophysiological cause of migraine aura and may be linked to trigeminal nociception. We previously demonstrated, using a minimally invasive optogenetic approach of SD induction (opto-SD), that opto-SD triggers acute periorbital mechanical allodynia that is reversed by 5HT receptor agonists, supporting SD-induced activation of migraine-relevant trigeminal pain pathways in mice. Recent data highlight hypothalamic neural circuits in migraine, and SD may activate hypothalamic neurons. Furthermore, neuroanatomical, electrophysiological, and behavioral data suggest a homeostatic analgesic function of hypothalamic neuropeptide hormone, oxytocin. We, therefore, examined the role of hypothalamic paraventricular nucleus (PVN) and oxytocinergic (OXT) signaling in opto-SD-induced trigeminal pain behavior.
We induced a single opto-SD in adult male and female Thy1-ChR2-YFP transgenic mice and quantified fos immunolabeling in the PVN and supraoptic nucleus (SON) compared with sham controls. Oxytocin expression was also measured in fos-positive neurons in the PVN. Periorbital mechanical allodynia was tested after treatment with selective OXT receptor antagonist L-368,899 (5 to 25 mg/kg i.p.) or vehicle at 1, 2, and 4 h after opto-SD or sham stimulation using von Frey monofilaments.
Opto-SD significantly increased the number of fos immunoreactive cells in the PVN and SON as compared to sham stimulation (p < 0.001, p = 0.018, respectively). A subpopulation of fos-positive neurons also stained positive for oxytocin. Opto-SD evoked periorbital mechanical allodynia 1 h after SD (p = 0.001 vs. sham), which recovered quickly within 2 h (p = 0.638). OXT receptor antagonist L-368,899 dose-dependently prolonged SD-induced periorbital allodynia (p < 0.001). L-368,899 did not affect mechanical thresholds in the absence of opto-SD.
These data support an SD-induced activation of PVN neurons and a role for endogenous OXT in alleviating acute SD-induced trigeminal allodynia by shortening its duration.
根据调整后的残疾生命年，偏头痛是美国最常见和负担最重的神经障碍之一。皮质扩散性去极化（SD）是偏头痛先兆最可能的电生理学原因，可能与三叉神经痛觉有关。我们之前使用 SD 诱导的微创光遗传学方法（光 SD）证明，光 SD 触发急性眶周机械性痛觉过敏，5HT 受体激动剂可逆转这种过敏，支持光 SD 在小鼠中激活与偏头痛相关的三叉神经痛觉通路。最近的数据突出了偏头痛中的下丘脑神经回路，SD 可能激活下丘脑神经元。此外，神经解剖学、电生理学和行为学数据表明下丘脑神经肽激素催产素具有稳态镇痛作用。因此，我们研究了下丘脑室旁核（PVN）和催产素能（OXT）信号在光 SD 诱导的三叉神经痛行为中的作用。
我们在成年雄性和雌性 Thy1-ChR2-YFP 转基因小鼠中诱导单次光 SD，并与假对照相比，在 PVN 和视上核（SON）中量化 fos 免疫标记。还测量了 fos 阳性神经元中的催产素表达。在光 SD 或假刺激后 1、2 和 4 小时，使用 von Frey 单丝纤维，用选择性 OXT 受体拮抗剂 L-368,899（5 至 25 mg/kg 腹腔内注射）或载体治疗后，测试眶周机械性痛觉过敏。
与假刺激相比，光 SD 显著增加了 PVN 和 SON 中的 fos 免疫反应细胞数量（p<0.001，p=0.018）。fos 阳性神经元的一个亚群也对催产素呈阳性染色。光 SD 在 SD 后 1 小时引起眶周机械性痛觉过敏（p=0.001 与假刺激相比），在 2 小时内迅速恢复（p=0.638）。OXT 受体拮抗剂 L-368,899 剂量依赖性地延长光 SD 诱导的眶周痛觉过敏（p<0.001）。L-368,899 对没有光 SD 的情况下的机械阈值没有影响。
这些数据支持 SD 诱导的 PVN 神经元激活，以及内源性 OXT 通过缩短其持续时间来缓解急性 SD 诱导的三叉神经痛觉过敏的作用。
