Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis.
Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis.
复制标题
DOI：
10.1002/art.40118
复制
发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Malfait AM
中科院分区：
文献类型：
--
作者：
Miller RE;Ishihara S;Bhattacharyya B;Delaney A;Menichella DM;Miller RJ;Malfait AM
本研究的目的是确定激活外周 NaV1.8 阳性感觉神经元中表达的抑制性 G 蛋白偶联受体 (GPCR) 的药物控制骨关节炎相关疼痛的能力。因此，我们使用了由设计药物独家激活的设计受体 (DREADD) 技术，该技术利用工程 GPCR 在与合成配体氯氮平-N-氧化物结合后激活或抑制神经元。 NaV1.8-Pdi C57BL/6 小鼠被创建为在表达 NaV1.8 的感觉神经元中表达抑制性 DREADD 受体 Pdi。在 10 周大的雄性小鼠中进行内侧半月板 (DMM) 失稳。手术后 4、8、12 或 16 周，测试膝关节痛觉过敏或后爪机械异常性疼痛。随后，给予氯氮平-N-氧化物或媒介物，并由盲人观察者测量对行为的影响。使用吗啡作为对照。免疫组织化学和电生理学证实了 NaV1.8 阳性感觉神经元 Pdi 受体的功能表达。在接受氯氮平-N-氧化物治疗的小鼠中，急性抑制表达 NaV1.8 的神经元可减少 DMM 后 4 周的膝关节痛觉过敏和 DMM 后 8 周的机械异常性疼痛。抑制对 DMM 后 12 周和 16 周的行为没有影响。吗啡这种激活外周和中枢神经系统GPCR的药物，后期依然有效。对表达 NaV1.8 的神经元进行化学遗传学抑制可阻断早期实验性骨关节炎中的膝关节痛觉过敏和机械异常性疼痛，但在后期不再有效。这些数据表明仅位于中枢神经系统之外的抑制性 GPCR 的激活可能对治疗慢性骨关节炎疼痛无效。
The purpose of this study was to determine the ability of drugs that activate inhibitory G-protein coupled receptors (GPCRs) expressed in peripheral NaV1.8-positive sensory neurons to control osteoarthritis associated pain. Therefore, we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology, which utilizes engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand, clozapine-N-oxide. NaV1.8-Pdi C57BL/6 mice were created to express the inhibitory DREADD receptor, Pdi, in NaV1.8-expressing sensory neurons. Destabilization of the medial meniscus (DMM) was performed in 10-week old male mice. Four, 8, 12 or 16 weeks after surgery, knee hyperalgesia or hindpaw mechanical allodynia were tested. Subsequently, clozapine-N-oxide or vehicle was administered and the effect on behaviors was measured by a blinded observer. Morphine was used as a control. Immunohistochemistry and electrophysiology confirmed functional expression of the Pdi receptor by NaV1.8-positive sensory neurons. Acute inhibition of NaV1.8-expressing neurons in mice treated with clozapine-N-oxide reduced knee hyperalgesia 4 weeks after DMM and mechanical allodynia 8 weeks after DMM. Inhibition had no effect on behaviors 12 and 16 weeks after DMM. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage. Chemogenetic inhibition of NaV1.8-expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental osteoarthritis, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic osteoarthritis pain.
登录
查看更多内容
影响因子：
7.4
作者：
Ivanavicius, Stefan P.;Ball, Adrian D.;Read, Simon J.
通讯作者：
Read, Simon J.
影响因子：
13.3
作者：
Jackson, Miriam T.;Moradi, Babak;Little, Christopher B.
通讯作者：
Little, Christopher B.
DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
4
作者：
Ferreira-Gomes, Joana;Adaes, Sara;Castro-Lopes, Jose M.
通讯作者：
Castro-Lopes, Jose M.
影响因子：
7
作者：
Hawker, G. A.;Stewart, L.;Gooberman-Hill, R.
通讯作者：
Gooberman-Hill, R.