Background

Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats.

Methods

A “two-hit” priming model of medication overuse headache was used. Female Sprague-Dawley rats received six oral doses of sumatriptan 10 mg/kg over 2 weeks to induce latent sensitization (i.e. “priming”). Cutaneous allodynia was measured periodically over 20 days in the periorbital and hindpaw regions using von Frey filaments. The rats were then subjected to a 1-hour bright light stress challenge on two consecutive days. At the start of the second bright light stress exposure, oral sumatriptan 10 mg/kg, oral ubrogepant 25, 50, or 100 mg/kg, or vehicle was administered; thereafter, cephalic and hindpaw sensory thresholds were monitored hourly over 5 hours to determine the efficacy of ubrogepant in reversing bright light stress-induced cutaneous allodynia. A dose of ubrogepant effective in the medication overuse headache model (100 mg/kg) was then selected to determine if repeated administration would produce latent sensitization. Rats were administered six oral doses of ubrogepant 100 mg/kg, sumatriptan 10 mg/kg (positive control), or vehicle over 2 weeks, and cutaneous allodynia was evaluated regularly. Testing continued until mechanosensitivity returned to baseline levels. Rats were then challenged with bright light stress on days 20 and 21, and periorbital and hindpaw cutaneous allodynia was measured. On days 28 to 32, the same groups received a nitric oxide donor (sodium nitroprusside 3 mg/kg, i.p.), and cutaneous allodynia was assessed hourly over 5 hours.

Results

Sumatriptan elicited cutaneous allodynia in both cephalic and hindpaw regions; cutaneous allodynia resolved to baseline levels after cessation of drug administration (14 days). Sumatriptan priming resulted in generalized and delayed cutaneous allodynia, evoked by either bright light stress (day 21) or nitric oxide donor (day 28). Ubrogepant dose-dependently blocked both stress- and nitric oxide donor-induced cephalic and hindpaw allodynia in the sumatriptan-induced medication overuse headache model with a 50% effective dose of ∼50 mg/kg. Unlike sumatriptan, ubrogepant 100 mg/kg in repeated effective doses did not produce cutaneous allodynia or latent sensitization.

Conclusions

Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache.

Trial Registration Number: Not applicable

中文翻译：

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在药物过度使用性头痛的临床前模型中，Ubrogepant 不会诱发潜在致敏。

背景

Ubrogepant 是一种小分子降钙素基因相关肽受体拮抗剂，最近被批准用作急性偏头痛治疗的口服药物。本研究旨在确定 ubrogepant 是否在偏头痛样疼痛的临床前模型中显示出疗效，以及重复口服 ubrogepant 是否会诱导与大鼠药物过度使用性头痛相关的潜在致敏。

方法

使用了药物过度使用性头痛的“两次打击”启动模型。雌性 Sprague-Dawley 大鼠在 2 周内接受六次口服剂量的舒马曲坦 10 mg/kg 以诱导潜在致敏（即“引发”）。使用von Frey 细丝在20 天内定期测量眶周和后爪区域的皮肤异常性疼痛。然后连续两天对大鼠进行 1 小时的强光应激挑战。在第二次强光暴露开始时，口服舒马曲坦 10 mg/kg，口服 ubrogepant 25、50 或 100 mg/kg，或赋形剂；此后，在 5 小时内每小时监测一次头部和后爪感觉阈值，以确定 ubrogepant 在逆转强光应激引起的皮肤异常性疼痛方面的功效。然后选择在药物过度使用头痛模型中有效的 ubrogepant 剂量 (100 mg/kg) 以确定重复给药是否会产生潜在致敏作用。在 2 周内对大鼠给药 6 次口服剂量的 ubrogepant 100 mg/kg、舒马曲坦 10 mg/kg（阳性对照）或载体，并定期评估皮肤异常性疼痛。测试一直持续到机械敏感性恢复到基线水平。然后在第 20 天和第 21 天用强光刺激大鼠，并测量眶周和后爪皮肤异常性疼痛。在第 28 至 32 天，同一组接受一氧化氮供体（硝普钠 3 mg/kg，ip），并在 5 小时内每小时评估一次皮肤异常性疼痛。在 2 周内对大鼠给药 6 次口服剂量的 ubrogepant 100 mg/kg、舒马曲坦 10 mg/kg（阳性对照）或载体，并定期评估皮肤异常性疼痛。测试一直持续到机械敏感性恢复到基线水平。然后在第 20 天和第 21 天用强光刺激大鼠，并测量眶周和后爪皮肤异常性疼痛。在第 28 至 32 天，同一组接受一氧化氮供体（硝普钠 3 mg/kg，ip），并在 5 小时内每小时评估一次皮肤异常性疼痛。在 2 周内对大鼠给药 6 次口服剂量的 ubrogepant 100 mg/kg、舒马曲坦 10 mg/kg（阳性对照）或载体，并定期评估皮肤异常性疼痛。测试一直持续到机械敏感性恢复到基线水平。然后在第 20 天和第 21 天用强光刺激大鼠，并测量眶周和后爪皮肤异常性疼痛。在第 28 至 32 天，同一组接受一氧化氮供体（硝普钠 3 mg/kg，ip），并在 5 小时内每小时评估一次皮肤异常性疼痛。测量眶周和后爪皮肤异常性疼痛。在第 28 至 32 天，同一组接受一氧化氮供体（硝普钠 3 mg/kg，ip），并在 5 小时内每小时评估一次皮肤异常性疼痛。测量眶周和后爪皮肤异常性疼痛。在第 28 至 32 天，同一组接受一氧化氮供体（硝普钠 3 mg/kg，ip），并在 5 小时内每小时评估一次皮肤异常性疼痛。

结果

舒马曲坦引起头部和后爪区域的皮肤异常性疼痛；停止给药（14 天）后，皮肤异常性疼痛恢复到基线水平。舒马曲坦引发导致全身性和延迟性皮肤异常性疼痛，由强光应激（第 21 天）或一氧化氮供体（第 28 天）诱发。在舒马曲坦诱导的药物过度使用头痛模型中，Ubrogepant 剂量依赖性地阻断压力和一氧化氮供体诱导的头部和后爪异常性疼痛，50% 的有效剂量约为 50 mg/kg。与舒马曲坦不同，ubrogepant 100 mg/kg 重复有效剂量不会产生皮肤异常性疼痛或潜在致敏。

结论

在药物过度使用性头痛的临床前模型中，ubrogepant 和舒马曲坦均显示出作为急性药物治疗压力和一氧化氮供体诱发的头部异常性疼痛的疗效，这与它们在偏头痛急性治疗中的临床疗效一致。然而，与舒马曲坦相反，用 ubrogepant 重复治疗不会引起皮肤异常性疼痛或潜在致敏。这些研究表明 ubrogepant 可以提供一种有效的急性偏头痛治疗，而没有药物过度使用性头痛的风险。

试用注册号：不适用