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首页> 外文期刊>Biochemical Pharmacology >Dual dose-related effects evoked by CCL4 on thermal nociception after gene delivery or exogenous administration in mice
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Dual dose-related effects evoked by CCL4 on thermal nociception after gene delivery or exogenous administration in mice

机译：CCL4在基因递送或小鼠外部给药后的热伤害诱捕的双剂量相关效果

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As recently described, the administration of extremely low doses (pg/kg) of CCL4 (Macrophage inflammatory protein 1 beta, MIP-1 beta) can induce antinociceptive effects in mice (Garcia-Dominguez et al., 2019b). We describe here that hydrodynamic delivery of a plasmid containing CCL4 cDNA provokes a biphasic response consisting in an initial thermal hyperalgesic reaction for 8 days followed by analgesia at days 10-12, being both responses blocked after the administration of the CCR5 antagonist DAPTA. Both the luminiscence evoked in liver after the administration of a plasmid containing CCL4 and luciferase cDNAs and the hepatic concentration of CCL4 measured by ELISA were maximal 4 days after plasmid administration and markedly diminished at day 10. A dose-effect curve including a wide dose range of exogenous CCL4 revealed thermal analgesia after the administration of 10-100 pg/kg whereas 1000 times higher doses (30-100 ng/kg) induced, instead, thermal hyperalgesia inhibited by DAPTA. This hyperalgesia was absent in mice with reduced white blood cells after cyclophosphamide treatment, thus supporting the involvement of circulating leukocytes. A multiarray bioluminescent assay revealed increased plasma levels of IL-1 alpha, CCL2, CXCL1, CXCL13, IL-16 and TIMP-1 in mice treated with 100 ng/kg of CCL4. The hyperalgesic response evoked by CCL4 was prevented by IL-1R, CXCR2 or CCR2 antagonists or by the neutralization of CXCL13 or IL-16, but not TIMP-1, with selective antibodies. The administration of the anti-IL-16 antibody was the unique treatment able to convert hyperalgesia evoked by 100 ng/kg of CCL4 in an analgesic effect. The ability of IL-16 to evoke hypernociception was confirmed by studying the response to its exogenous administration (10-30 ng/kg). In summary, the present results demonstrate that CCL4 induces a dual modulation of nociception and describe some mechanisms involved in the hyperalgesic response evoked by this chemokine.
机译：如最近所描述的，施用极低剂量（PG / kg）的CCL4（巨噬细胞炎症蛋白1β，MIP-1β）可以诱导小鼠的抗闭合性作用（Garcia-dominguez等，2019b）。在此描述含有CCl4 cDNA的质粒的流体动力学递送引起在初始热富级反应中的双相反应，其在第10-12天的镇痛后，镇痛，在给予CCR5拮抗剂DAPT后堵塞。在给予含Ccl4和荧光素酶CdNA的质粒后肝脏诱发的发光诱导和通过ELISA测量的CCL4的肝浓度在质粒给药后的最大4天，并在第10天显着减少。一种剂量效应曲线，包括宽剂量范围外源CCL4显示出10-100pg / kg后的热镇痛，而诱导的1000倍（30-100ng / kg）诱导的1000倍，而是由DAPTA抑制的热痛觉。在环磷酰胺处理后的白细胞减少的小鼠中，患有痛觉过敏症，从而支撑循环白细胞的参与。多射线生物发光测定显示用100ng / kg CCl4处理的小鼠IL-1α，CCl2，CXCL1，CXCL13，IL-16和TIMP-1的增加的血浆水平。通过IL-1R，CXCR2或CCR2拮抗剂或通过用选择性抗体中和，通过IL-1R，CXCR2或CCR2拮抗剂或通过中和CCL4引起的痛觉反应。抗IL-16抗体的给药是能够在镇痛作用中转化100ng / kg CCl4引起的痛觉过敏的独特处理。通过研究对其外源给药（10-30 ng / kg）的反应来确认IL-16引起高温皮肤的能力。总之，本结果表明，CCL4诱导伤害效果的双重调节，并描述该趋化因子引起的痛觉过敏反应中涉及的一些机制。

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