Nav1.8、TRPV1、TRPA1作为氨溴索局部治疗神经性疼痛的可能靶点。

IF 4 2区医学 Q1 CLINICAL NEUROLOGY

Journal of Pain Pub Date : 2025-09-16 DOI:10.1016/j.jpain.2025.105563

Stefanie Hefner , George Oprita , Sebastian Pantke , Axel Hage , Andreas Leffler

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引用次数: 0

摘要

表皮感觉神经末梢的钠通道和辣椒素受体TRPV1是局部治疗神经性疼痛的既定靶点。氨溴索的促分泌作用可诱导有效的局部镇痛，这一特性可能涉及Nav1.8的优先阻断。我们在这里通过全细胞膜片钳记录检查了氨溴索抑制人和大鼠(r) Nav1.8的程度，以及刺激受体TRPV1和TRPA1的人类(h)同源物。氨溴索对rNav1.8通道（IC50为18µM）的强直抑制强于对hNav1.8通道（IC50为279µM）和ttx敏感Na+通道（IC50为76µM）的强直抑制。非灭活电流hNav1.8和rNav1.8对氨溴索的敏感性均高于瞬态电流。高浓度氨溴索对hTRPV1和hTRPA1的微弱但浓度依赖性激活超过了细胞内钙的非特异性增加。虽然hTRPV1的激活机制涉及香草素结合域，但hTRPA1对薄荷醇敏感性所需的残基似乎决定了氨溴索敏感性。氨溴索还以浓度依赖性和部分可逆的方式抑制辣椒素诱导的hTRPV1电流。这种抑制作用不依赖于细胞内钙，并在非脱敏突变体hTRPV1-Y672K上保持不变。芥末油或香芹酚对hTRPA1的诱导电流显示出氨溴索对hTRPA1的浓度依赖性降低，与向内电流相比，向外电流更强。我们得出结论，氨溴索对Nav1.8的抑制对rNav1.8 > hNav1.8具有明显的物种特异性。此外，高浓度氨溴索调节hTRPV1和hTRPA1的方式可能有助于局部镇痛。观点：局部应用氨溴索是一种众所周知的非标签治疗局灶性神经性疼痛的方法，但它仍然缺乏机制基础。本体外研究表明，人Nav1.8、TRPA1和TRPV1可能是氨溴索在感觉神经元中的药理靶点。

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Nav1.8, TRPV1 and TRPA1 as possible targets of ambroxol when used for topical treatment of neuropathic pain

Sodium channels and the capsaicin receptor TRPV1 in epidermal sensory nerve endings are established targets for topical treatment of neuropathic pain. The secretolytic ambroxol induces effective topically analgesia, a property that may involve a preferential block of Nav1.8. We here examined to what extent ambroxol inhibits human and rat (r) Nav1.8, but also the human (h) orthologues of the irritant receptors TRPV1 and TRPA1 by performing whole-cell patch clamp recordings. Ambroxol-induced tonic inhibition was stronger on rNav1.8 (IC₅₀ 18 µM) than on hNav1.8 (IC₅₀ 279 µM) and TTX-sensitive Na⁺ channels (IC₅₀ 76 µM). Non-inactivating currents of both hNav1.8 and rNav1.8 displayed a higher sensitivity to ambroxol than transient currents. A weak but concentration-dependent activation of hTRPV1 and hTRPA1 exceeded an unspecific increase in intracellular calcium by high concentrations of ambroxol. While the activation mechanism for hTRPV1 involves the vanilloid-binding domain, residues required for menthol-sensitivity of hTRPA1 seems to dictate ambroxol-sensitivity. Ambroxol also inhibited capsaicin-induced currents on hTRPV1 in a concentration-dependent and partly reversible manner. This inhibition was independent of intracellular calcium and preserved on the non-desensitizing mutant hTRPV1-Y672K. Currents induced by mustard oil or carvacrol on hTRPA1 exhibited a concentration-dependent reduction by ambroxol that was stronger on outward as compared to inward currents. We conclude that inhibition of Nav1.8 by ambroxol exhibits a pronounced species-specificity with rNav1.8 > hNav1.8. Furthermore, high concentrations of ambroxol modulate hTRPV1 and hTRPA1 in a manner that might contribute to topical analgesia.

Perspective

Topically applied ambroxol is a well-known off the label approach for treatment of focal neuropathic pain, but it still lacks a mechanistic foundation. This in vitro study presents human Nav1.8, TRPA1 and TRPV1 as possible pharmacological targets of ambroxol in sensory neurons.

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来源期刊

Journal of Pain 医学-临床神经学

CiteScore

6.30

自引率

7.50%

发文量

441

审稿时长

42 days

期刊介绍： The Journal of Pain publishes original articles related to all aspects of pain, including clinical and basic research, patient care, education, and health policy. Articles selected for publication in the Journal are most commonly reports of original clinical research or reports of original basic research. In addition, invited critical reviews, including meta analyses of drugs for pain management, invited commentaries on reviews, and exceptional case studies are published in the Journal. The mission of the Journal is to improve the care of patients in pain by providing a forum for clinical researchers, basic scientists, clinicians, and other health professionals to publish original research.