Anti-hyperalgesic and anti-inflammatory effects of 4R-tobacco cembranoid in a mouse model of inflammatory pain.
Anti-hyperalgesic and anti-inflammatory effects of 4R-tobacco cembranoid in a mouse model of inflammatory pain.
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DOI：
10.1186/s12950-023-00373-8
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发表时间：
2024-01-24
影响因子：
5.1
通讯作者：
Carrasquillo, Yarimar
中科院分区：
文献类型：
--
作者：
Rivera-Garcia, Luis G.;Francis-Malave, Adela M.;Castillo, Zachary W.;Uong, Calvin D.;Wilson, Torri D.;Ferchmin, P. A.;Eterovic, Vesna;Burton, Michael D.;Carrasquillo, Yarimar
关键词：
4 R是烟草西松烷类化合物，其结合并调节胆碱能受体，并表现出神经保护和抗炎活性。鉴于胆碱能系统在疼痛和炎症中的既定功能，我们建议4 R也是镇痛剂。在此，我们在炎症性疼痛小鼠模型中检验了全身4 R治疗通过调节α 7烟碱乙酰胆碱受体（α7 nAChR）减少疼痛相关行为和外周炎症的假设。我们通过将完全弗氏佐剂（CFA）注射到雄性和雌性小鼠的后爪中引发炎症。然后，我们分别在单次全身4 R（或溶媒）给药前和给药后不同时间点（2.5 h -8 d），使用丙酮、Hargreaves和von Frey试验评估炎症诱导的对冷、热和触觉刺激的超敏反应。我们评估了α7 nAChRs 4 R介导的镇痛作用，方法是在行为测试前用α7 nAChRs的选择性拮抗剂预处理小鼠，然后给予4 R（或溶剂）。我们通过测量爪厚度和使用苏木精和伊红染色定量注射后爪中的免疫细胞浸润来评估CFA诱导的爪水肿和炎症。最后，我们对α7 nAChR-cre：：Ai 9小鼠的爪皮肤进行免疫组织化学和流式细胞术分析，以测量α7 nAChR在免疫亚群上的表达。我们的实验表明，全身施用4 R降低雄性和雌性小鼠中炎症诱导的外周超敏反应和雄性但非雌性小鼠中炎症诱导的爪水肿。值得注意的是，在第1天单次全身给药后，4 R介导的镇痛和抗炎作用持续长达8天。用α7 nAChR选择性拮抗剂预处理阻止了4 R介导的镇痛和抗炎作用，表明4 R效应是通过调节α7 nAChR。我们进一步表明，后爪中的免疫细胞亚群表达α7 nAChR。然而，CFA或4 R处理未改变表达α7 nAChR的免疫细胞的数量，表明4 R效应不依赖于表达α7 nAChR的免疫细胞。总之，我们的研究结果确定了4 R烟草西松烷类化合物作为镇痛剂在雄性和雌性小鼠中的新功能，其以性别依赖性方式减少外周炎症，进一步支持胆碱能系统用于疼痛治疗的药理学靶向。在线版本包含补充材料，可通过10.1186/s12950-023-00373-8获取。
4R is a tobacco cembranoid that binds to and modulates cholinergic receptors and exhibits neuroprotective and anti-inflammatory activity. Given the established function of the cholinergic system in pain and inflammation, we propose that 4R is also analgesic. Here, we tested the hypothesis that systemic 4R treatment decreases pain-related behaviors and peripheral inflammation via modulation of the alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) in a mouse model of inflammatory pain. We elicited inflammation by injecting Complete Freund’s Adjuvant (CFA) into the hind paw of male and female mice. We then assessed inflammation-induced hypersensitivity to cold, heat, and tactile stimulation using the Acetone, Hargreaves, and von Frey tests, respectively, before and at different time points (2.5 h – 8d) after a single systemic 4R (or vehicle) administration. We evaluated the contribution of α7 nAChRs 4R-mediated analgesia by pre-treating mice with a selective antagonist of α7 nAChRs followed by 4R (or vehicle) administration prior to behavioral tests. We assessed CFA-induced paw edema and inflammation by measuring paw thickness and quantifying immune cell infiltration in the injected hind paw using hematoxylin and eosin staining. Lastly, we performed immunohistochemical and flow cytometric analyses of paw skin in α7 nAChR-cre::Ai9 mice to measure the expression of α7 nAChRs on immune subsets. Our experiments show that systemic administration of 4R decreases inflammation-induced peripheral hypersensitivity in male and female mice and inflammation-induced paw edema in male but not female mice. Notably, 4R-mediated analgesia and anti-inflammatory effects lasted up to 8d after a single systemic administration on day 1. Pretreatment with an α7 nAChR-selective antagonist prevented 4R-mediated analgesia and anti-inflammatory effects, demonstrating that 4R effects are via modulation of α7 nAChRs. We further show that a subset of immune cells in the hind paw expresses α7 nAChRs. However, the number of α7 nAChR-expressing immune cells is unaltered by CFA or 4R treatment, suggesting that 4R effects are independent of α7 nAChR-expressing immune cells. Together, our findings identify a novel function of the 4R tobacco cembranoid as an analgesic agent in both male and female mice that reduces peripheral inflammation in a sex-dependent manner, further supporting the pharmacological targeting of the cholinergic system for pain treatment. The online version contains supplementary material available at 10.1186/s12950-023-00373-8.
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影响因子：
4.8
作者：
de Lucas-Cerrillo, Ana M.;Constanza Maldifassi, M.;Montiel, Carmen
通讯作者：
Montiel, Carmen
影响因子：
5.6
作者：
Berlowitz I;Torres EG;Walt H;Wolf U;Maake C;Martin-Soelch C
通讯作者：
Martin-Soelch C
DOI：
10.1007/s11481-015-9601-5
发表时间：
2015-09
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Báez-Pagán CA;Delgado-Vélez M;Lasalde-Dominicci JA
通讯作者：
Lasalde-Dominicci JA
影响因子：
16.2
作者：
Colburn, Raymond W.;Lubin, Mary Lou;Qin, Ning
通讯作者：
Qin, Ning
影响因子：
6.7
作者：
Chan, Theresa W.;Langness, Simone;Costantini, Todd W.
通讯作者：
Costantini, Todd W.