Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
Mayo Clinic, Scottsdale, AZ, USA.
Cephalalgia. 2022 Oct;42(11-12):1194-1206. doi: 10.1177/03331024221099841. Epub 2022 May 11.
Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache.
Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points.
After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14-67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia.
Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.
研究肉毒毒素 A 在急性和持续性创伤后头痛的小鼠模型中的作用。
采用重物坠落法诱导轻度创伤性脑损伤。测量眶周和后爪皮肤痛觉过敏 14 天。然后，将小鼠暴露于强光应激下，重新评估痛觉过敏。在不同的损伤后时间点，将肉毒毒素 A（0.5U）皮下注射到头骨缝线处。
轻度创伤性脑损伤后，小鼠出现眶周和后爪痛觉过敏，持续约 14 天。仅在先前受伤的小鼠中，在第 14-67 天暴露于应激下可重新诱发痛觉过敏。在轻度创伤性脑损伤后 2 小时给予肉毒毒素 A 治疗可完全阻断短暂的急性和应激诱导的痛觉过敏，直至第 67 天。在轻度创伤性脑损伤后 72 小时给予肉毒毒素 A 治疗可逆转急性痛觉过敏，但仅部分预防应激诱导的痛觉过敏。在初始痛觉过敏基本消退的第 12 天给予肉毒毒素 A 治疗，可部分且短暂地预防应激诱导的痛觉过敏。急性痛觉过敏的程度与随后的应激诱导的痛觉过敏呈正相关。
轻度创伤性脑损伤引起短暂的头痛样疼痛，随后是长时间的敏化和对通常无害的应激刺激的持续易感性，分别模拟急性和持续性创伤后头痛。在急性创伤后头痛消退后给予肉毒毒素 A 治疗可减轻持续性创伤后头痛，但效果是短暂的，表明潜在的持续性轻度创伤性脑损伤引起的适应性不良未得到逆转。相比之下，早期给予肉毒毒素 A 治疗可完全阻断急性创伤后头痛以及向持续性创伤后头痛的转变，提示预防促进头痛样疼痛易感性的神经适应性不良。此外，急性创伤后头痛的程度可预测持续性创伤后头痛的风险。
