Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Exp Neurol. 2018 Feb;300:87-99. doi: 10.1016/j.expneurol.2017.10.026. Epub 2017 Oct 26.
Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy. Mice with RTX neuropathy exhibited thermal hypoalgesia and mechanical allodynia, reduced skin innervation, and altered DRG expression profiles with decreased TrkA(+) neurons and increased Ret(+) neurons. RTX neuropathy induced the expression of activating transcription factor 3 (ATF3), and ATF3(+) neurons were colocalized with Ret but not with TrkA (P<0.001). As a neuroprotectant, 4-Methylcatechol (4MC) promoted skin reinnervation partially with correlated reversal of the neuropathic behaviors and altered neurochemical expression. Gambogic amide, a selective TrkA agonist, normalized thermal hypoalgesia, and GW441756, a TrkA kinase inhibitor, induced thermal hypoalgesia, which was already reversed by 4MC. Mechanical allodynia was reversed by a Ret kinase inhibitor, AST487, which induced thermal hyperalgesia in naïve mice. The activation of Ret signaling by XIB4035 induced mechanical allodynia and thermal hypoalgesia in RTX neuropathy mice in which the neuropathic behaviors were previously normalized by 4MC. Distinct neurotrophic factor receptors, TrkA and Ret, accounted for negative and positive neuropathic behaviors in RTX-induced small fiber neuropathy, respectively: TrkA for thermal hypoalgesia and Ret for mechanical allodynia and thermal hypoalgesia.
神经营养因子及其相应的受体在维持不同表型的背根神经节 (DRG) 神经元中发挥关键作用，其轴突在小纤维神经病中退化，导致各种神经病变表现。小纤维神经病的阳性和阴性症状的机制尚未系统探索。本研究根据辣椒素（RTX）诱导的小纤维神经病小鼠模型中 TrkA 和 Ret 的免疫组织化学和药理学干预，研究了这些看似矛盾的神经病变行为的分子基础。RTX 神经病小鼠表现出热痛觉减退和机械性痛觉过敏、皮肤神经支配减少以及 DRG 表达谱改变，表现为 TrkA(+)神经元减少和 Ret(+)神经元增加。RTX 神经病诱导激活转录因子 3 (ATF3)的表达，并且 ATF3(+)神经元与 Ret 共定位，但与 TrkA 不共定位 (P<0.001)。作为神经保护剂，4-甲基儿茶酚 (4MC) 部分促进皮肤再支配，与神经病变行为的相关逆转和神经化学表达的改变相关。Gambogic 酰胺，一种选择性 TrkA 激动剂，可使热痛觉减退正常化，TrkA 激酶抑制剂 GW441756 可诱导热痛觉减退，4MC 已将其逆转。Ret 激酶抑制剂 AST487 可逆转机械性痛觉过敏，在未接受治疗的小鼠中可诱导热痛觉过敏。XIB4035 激活 Ret 信号诱导 RTX 神经病小鼠的机械性痛觉过敏和热痛觉减退，在 4MC 之前，这些神经病变行为已被正常化。在 RTX 诱导的小纤维神经病中，不同的神经营养因子受体 TrkA 和 Ret 分别负责阴性和阳性神经病变行为：TrkA 负责热痛觉减退，Ret 负责机械性痛觉过敏和热痛觉减退。
