A novel, injury-free rodent model of vulnerability for assessment of acute and preventive therapies reveals temporal contributions of CGRP-receptor activation in migraine-like pain.
A novel, injury-free rodent model of vulnerability for assessment of acute and preventive therapies reveals temporal contributions of CGRP-receptor activation in migraine-like pain.
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一种新型、无损伤的易感性啮齿动物模型，用于评估急性治疗和预防性治疗，该模型揭示了降钙素基因相关肽（CGRP）受体激活在偏头痛样疼痛中的时间性作用。
DOI：
10.1177/0333102420959794
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Porreca F
中科院分区：
文献类型：
--
作者：
Kopruszinski CM;Navratilova E;Swiokla J;Dodick DW;Chessell IP;Porreca F
一种新型无损伤偏头痛样疼痛临床前模型的开发与特性研究，该模型可用于对急性和预防性治疗进行机制评估。
在未受伤的雌性和雄性C57BL/6小鼠中，采用“两次打击”的痛觉过敏启动策略，使其对伞形酮（UMB，一种TRPA1激活剂）这种通常为亚阈值的刺激产生易感性。启动（即第一次打击）通过连续三天每天一次的束缚应激（RS）诱导产生；同时也评估了重复使用UMB是否有潜在的启动效应。首次RS后的第16天，小鼠吸入UMB（即第二次打击）以引发偏头痛样疼痛。研究了目前用于急性或预防性偏头痛治疗的药物，包括普萘洛尔（一种β受体阻滞剂）和舒马曲坦（5HT1B/D激动剂），以及实验性降钙素基因相关肽（CGRP）受体拮抗剂奥尔塞吉泮和实验性长效κ阿片受体（KOR）拮抗剂去甲二氢吗啡酮（nor - BNI），在阻断启动以及预防或逆转已启动动物中UMB诱导的异常性疼痛方面的疗效。为评估偏头痛样疼痛，通过对眶周或后爪用von Frey细丝探查的反应来测定皮肤异常性疼痛（CA）。
重复的RS，而非UMB暴露，产生了在16天内消退的短暂性CA。RS产生了持续超过16天的长期启动效应，吸入UMB激发后CA的恢复证明了这一点。在RS之前用普萘洛尔或nor - BNI预处理，可预防短暂性CA和启动效应，表现为UMB不会诱导出CA。在RS启动效应建立后，奥尔塞吉泮可预防UMB诱导的CA，而普萘洛尔或nor - BNI则不能。在UMB给药1小时后给予舒马曲坦，可逆转RS启动大鼠中UMB诱导的CA，而奥尔塞吉泮则不能。
我们开发了一种具有转化相关性的新型无损伤模型，可用于研究与偏头痛样疼痛相关的机制，并评估新型急性或预防性治疗方法。RS启动诱导出一种对亚阈值刺激的易损状态，这被称为“潜伏致敏”（LS）。使用普萘洛尔或KOR拮抗剂阻断应激通路，可预防LS的发生。在LS建立后，UMB的亚阈值刺激可能通过激活脑膜表达TRPA1的伤害感受器而使CA恢复。因此，在RS启动的动物中，舒马曲坦可逆转UMB诱导的CA，这支持其外周作用位点，而普萘洛尔或nor - BNI则无效。令人惊讶的是，在LS小鼠中，奥尔塞吉泮在UMB激发前给药有效，但在激发后给药无效，这表明在该模型中CGRP受体信号传导在促进偏头痛样疼痛方面具有时间依赖性作用。CGRP受体的激活参与疼痛反应的起始，但在维持疼痛反应中的作用较为有限，这支持了小分子CGRP拮抗剂作为预防性药物的疗效。此外，舒马曲坦在逆转已发生疼痛方面的有效性表明，它还调节了其他非CGRP受体介导的伤害感受机制。KOR拮抗剂可能代表一种针对应激相关偏头痛的新型预防性疗法。
Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. A “two-hit” hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone (UMB), a TRPA1 activator, in uninjured female and male C57BL/6 mice. Priming (i.e., the first hit) was induced by three consecutive daily episodes of restraint stress (RS); repeated UMB was also evaluated for potential priming effects. Sixteen days after the first RS, mice received inhalational UMB (i.e., the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1B/D agonist), as well as olcegepant, an experimental CGRP receptor antagonist and nor-BNI, an experimental long-acting KOR antagonist, were investigated for their efficacy to block priming and prevent or reverse UMB-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia (CA) was determined by responses to periorbital or hindpaw probing with von Frey filaments. Repeated RS, but not UMB exposure, produced transient CA that resolved within 16 days. RS produced long-lasting priming that persisted beyond 16 days as demonstrated by reinstatement of CA following inhalational UMB challenge. Pretreatment with propranolol or nor-BNI prior to RS prevented both transient CA and priming demonstrated by a lack of UMB-induced CA. Following establishment of RS priming, olcegepant, but not propranolol or nor-BNI, prevented UMB-induced CA. When administered 1 hour after UMB, sumatriptan, but not olcegepant, reversed UMB-induced CA in RS primed rats. We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. RS priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as “latent sensitization” (LS). The development of LS could be prevented by blockade of stress-pathways with propranolol or with a KOR antagonist. Following establishment of LS, subthreshold stimulation with UMB reinstated CA likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in RS-primed animals, sumatriptan reversed UMB-induced CA supporting peripheral sites of action, while propranolol or nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with LS when given prior to, but not after, UMB challenge suggesting time-dependent contributions of CGRP receptor signaling in promoting migraine-like pain in this model. Activation of the CGRP receptor participates in initiating, but has a more limited role in maintaining, pain responses supporting the efficacy of small molecule CGRP antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-CGRP receptor-mediated nociceptive mechanisms. KOR antagonists may represent a novel preventive therapy for stress-related migraine.
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