The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy.
The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy.
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DOI：
10.1016/j.neuropharm.2021.108907
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发表时间：
2022-03-01
影响因子：
4.7
通讯作者：
Taylor BK
中科院分区：
文献类型：
--
作者：
Santos DFS;Donahue RR;Laird DE;Oliveira MCG;Taylor BK
吡格列酮是一种过氧化物酶体增殖激活受体的激动剂，已被fda批准用于治疗2型糖尿病的胰岛素抵抗。在雄性啮齿动物的大量研究表明，吡格列酮抑制炎症和神经性疼痛，但很少包括女性受试者。为了弥补这一空白，我们比较了两性吡格列酮在化学疼痛和疼痛性糖尿病神经病变（PDN）足底甲基乙二醛模型（MG）、术后疼痛的足底切口模型（PIM）、外伤性神经损伤的保留神经损伤（SNI）模型以及PDN的ZDF大鼠和db/db小鼠模型中的作用。我们通过一次性鞘内或腹腔内注射吡格列酮或将其添加到食物中6周，随后测量对非有害机械、有害机械、热和/或冷刺激的超敏反应。在所有小鼠模型中，注射吡格列酮减少了雌性小鼠的类痛行为，与雄性相比，其效力和/或疗效更强：MG模型中的热和机械超敏反应（0.1-10 MG /kg）；PIM模型机械超敏反应（10 μg）；SNI模型的机械和冷超敏反应（100 mg/kg）；db/db模型热过敏（100mg /kg）。此外，低剂量吗啡（1 mg/kg）和吡格列酮（10 mg/kg）联合给药可降低sni诱导的雌性小鼠的机械和冷超敏反应，但对雄性小鼠没有作用。在ZDF大鼠中，吡格列酮（100 mg/kg）降低了热和机械超敏反应，无性别差异。在db/db模型中，吡格列酮以0.3、3或30 mg/kg的剂量给药给鼠6周后没有效果。我们得出结论，雌性小鼠在化学诱导的痛觉、术后疼痛、神经性疼痛和PDN模型中表现出更强的抗痛觉过敏反应。这些发现为临床试验奠定了基础，以确定吡格列酮是否在广泛的慢性疼痛条件下具有镇痛特性，特别是在女性中。
Pioglitazone, an agonist at peroxisome proliferator-activated receptor gamma, is FDA-approved for the treatment of insulin resistance in type 2 diabetes. Numerous studies in male rodents suggest that pioglitazone inhibits inflammatory and neuropathic pain, but few included female subjects. To address this gap, we compared the effects of pioglitazone in both sexes in the intraplantar methylglyoxal model (MG) model of chemical pain and painful diabetic neuropathy (PDN), the plantar incision model (PIM) of postoperative pain, the spared nerve injury (SNI) model of traumatic nerve injury, and the ZDF rat and db/db mouse models of PDN. We administered pioglitazone by one-time intrathecal or intraperitoneal injection or by adding it to chow for 6 weeks, followed by measurement of hypersensitivity to non-noxious mechanical, noxious mechanical, heat, and/or cold stimuli. In all mouse models, injection of pioglitazone decreased pain-like behaviors with greater potency and/or efficacy in females as compared to males: heat and mechanical hypersensitivity in the MG model (0.1–10 mg/kg); mechanical hypersensitivity in the PIM model (10 μg); mechanical and cold hypersensitivity in the SNI model (100 mg/kg); and heat hypersensitivity in the db/db model (100 mg/kg). Furthermore, co-administration of low doses of morphine (1 mg/kg) and pioglitazone (10 mg/kg) decreased SNI-induced mechanical and cold hypersensitivity in female but not male mice. In the ZDF rat, pioglitazone (100 mg/kg) decreased heat and mechanical hypersensitivity with no sex difference. In the db/db model, pioglitazone had no effect when given into chow for 6 weeks at 0.3, 3 or 30 mg/kg doses. We conclude that females exhibit greater anti-hyperalgesic responses to pioglitazone in mouse models of chemical-induced nociception, postsurgical pain, neuropathic pain, and PDN. These findings set the stage for clinical trials to determine whether pioglitazone has analgesic properties across a broad spectrum of chronic pain conditions, particularly in women.
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影响因子：
82.9
作者：
Gear, RW;Miaskowski, C;Levine, JD
通讯作者：
Levine, JD
影响因子：
81.5
作者：
Feldman, Eva L.;Callaghan, Brian C.;Viswanathan, Vijay
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Viswanathan, Vijay
影响因子：
--
作者：
Averbuch, M;Katzper, M
通讯作者：
Katzper, M
影响因子：
8.8
作者：
Aubrun, F;Salvi, N;Riou, B
通讯作者：
Riou, B
影响因子：
7.3
作者：
de Guglielmo, Giordano;Kallupi, Marsida;Ciccocioppo, Roberto
通讯作者：
Ciccocioppo, Roberto