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首页> 外文期刊>The Open Drug Discovery Journal >Targeting TRPV1: Challenges and Issues in Pain Management
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Targeting TRPV1: Challenges and Issues in Pain Management

机译：针对TRPV1：疼痛管理中的挑战和问题

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Chronic neuropathic pain is notoriously difficult to treat. Standard pain drugs, even narcotic opioid analgesicagents, often provide unsatisfactory pain relief. The need for better drugs is universally recognized. However, despite asubstantial investment of resources by the pharmaceutical industry to identify alternative treatments, the effectivemanagement of chronic pain remains an unmet medical need. Recently, preclinical research has uncovered new molecularmechanisms underlying the generation and transduction of pain, many of which represent new targets for pharmacologicalintervention. This review focuses on Transient Receptor Potential (TRP) channel Vanilloid 1 (TRPV1) as a target fortreating chronic pain. TRPV1 is a multifunctional channel involved in thermosensation (heat) and taste perception (e.g.peppers and vinegar). Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seeminglyunrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that followsinflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has beenin clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Currently, site-specific capsaicinand resiniferatoxin (an ultrapotent capsaicin analog) injections are being evaluated as “molecular scalpels” to achievepermanent analgesia. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced intoclinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some ofthese antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in men, leadingto their withdrawal from the clinical trials. Clearly, the balance between the beneficial actions of drugs targeting TRPV1and the adverse effects must be carefully and pragmatically evaluated to determine if these drugs could emerge as the nextgeneration of pain killers.
机译：众所周知，慢性神经性疼痛难以治疗。标准止痛药，甚至麻醉性阿片类镇痛药，通常也不能令人满意地缓解疼痛。普遍需要更好的药物。然而，尽管制药业投入了大量资源来寻找替代疗法，但是对慢性疼痛的有效管理仍未满足医疗需求。最近，临床前研究发现了导致疼痛产生和转导的新分子机制，其中许多代表了药物干预的新目标。这篇综述集中在瞬态受体电位（TRP）通道香草酸1（TRPV1）作为治疗慢性疼痛的目标。 TRPV1是涉及热感（热）和味觉（例如胡椒和醋）的多功能通道。重要的是，TRPV1还可以充当各种看似无关的有害刺激的分子整合剂。实际上，TRPV1被认为是炎症和/或组织损伤后热痛觉过敏的主要转导者。对局部TRPV1激动剂（例如辣椒素乳膏和贴剂）脱敏已经在临床上使用了数十年，用于治疗慢性疼痛性疾病，如糖尿病性神经病。目前，特定部位的辣椒素和树脂毒素（超强辣椒素类似物）注射液已被评估为“分子手术刀”，以实现永久镇痛。最近，已将许多有效的小分子TRPV1拮抗剂用于减轻疼痛的临床试验。考虑到TRPV1在热敏中的突出作用，也许并不出人意料，其中一些拮抗剂对男性显示出令人担忧的不良反应（体温过高和有害的热感觉受损），导致他们退出临床试验。显然，必须仔细，务实地评估靶向TRPV1的药物的有益作用与不良反应之间的平衡，以确定这些药物是否可以作为下一代止痛药出现。

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