Developing nociceptor-selective treatments for acute and chronic pain.
Developing nociceptor-selective treatments for acute and chronic pain.
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DOI：
10.1126/scitranslmed.abj9837
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发表时间：
2021-11-10
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管大量的努力致力于开发新的，非成瘾性镇痛药，成功是有限的。临床上可用的药剂通常缺乏功效，产生抗药性，并且伴随着不期望的副作用。传统的基于靶点的药物发现工作虽然产生对单一靶点具有选择性的化合物，但由于临床疗效差而具有高的损耗率。在这里，我们研究了与当前的镇痛药物发现模型相关的问题，并审查了一种新方法的证据，用于识别不同形式的急性和慢性疼痛的镇痛靶点和化合物。使用人iPSC衍生的伤害感受器，可以鉴定在伤害感受器中选择性表达但不在其他可兴奋细胞类型中表达的基因，可以对疾病状态进行建模，表型筛选可以鉴定选择性降低伤害感受器兴奋性的化合物，并且可以鉴定个体患者对发展疼痛或对特定治疗作出响应的易感性。这种基于人类细胞/遗传学的方法可以识别调节多个靶点功能的伤害感受器特异性和疼痛疾病选择性化合物。这种多药理学方法将通过扩大药物对复杂疼痛机制的活性来增强镇痛功效，而对伤害感受器的选择性作用将抑制副作用。
Despite substantial efforts dedicated to the development of novel, non-addictive analgesics, success has been limited. Clinically available agents generally lack efficacy, creating pharmacoresistance, and are accompanied by undesirable side-effects. The traditional target-based drug discovery effort, while generating compounds with selectivity for single targets, has a high rate of attrition due to poor clinical efficacy. Here, we examine the problems associated with the current analgesic drug discovery model, and review evidence for a new approach for the identification of analgesic targets and compounds for the diverse forms of acute and chronic pain. Using human iPSC-derived nociceptors, genes selectively expressed in nociceptors, but not in other excitable cell types, can be identified, disease states can be modeled, phenotypic screens can identify compounds that selectively reduce nociceptor excitability and individual patient susceptibility to developing pain or responding to particular treatments can be identified. This human cell/genetics-based approach can identify nociceptor-specific and pain-disease selective compounds that modulate the function of multiple targets. This polypharmacology approach will enhance analgesic efficacy by broadening drug activity on complex pain mechanisms, while selective action on nociceptors will curb side-effects.
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影响因子：
25
作者：
Blanchard, Joel W.;Eade, Kevin T.;Szucs, Attila;Lo Sardo, Valentina;Tsunemoto, Rachel K.;Williams, Daniel;Sanna, Pietro Paolo;Baldwin, Kristin K.
通讯作者：
Baldwin, Kristin K.
影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
中枢神经系统靶标：镇痛的上脊髓机制。
DOI：
10.1007/s13311-020-00887-6
发表时间：
2020-07
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Bannister K;Dickenson AH
通讯作者：
Dickenson AH
影响因子：
5.9
作者：
Chanda, Soham;Ang, Cheen Euong;Davila, Jonathan;Pak, ChangHui;Mall, Moritz;Lee, Qian Yi;Ahlenius, Henrik;Jung, Seung Woo;Suedhof, Thomas C.;Wernig, Marius
通讯作者：
Wernig, Marius
影响因子：
64.8
作者：
Anzalone, Andrew V.;Randolph, Peyton B.;Liu, David R.
通讯作者：
Liu, David R.