Dysregulation of Vesicular Glutamate Transporter VGluT2 via BDNF/TrkB Pathway Contributes to Morphine Tolerance in Mice.
Dysregulation of Vesicular Glutamate Transporter VGluT2 via BDNF/TrkB Pathway Contributes to Morphine Tolerance in Mice.
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通过 BDNF/TrkB 途径的囊泡谷氨酸转运蛋白 VGluT2 失调导致小鼠吗啡耐受
DOI：
10.3389/fphar.2022.861786
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发表时间：
2022
影响因子：
5.6
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
He, Liqiong;Xu, Wei;Zhang, Chengliang;Ding, Zhuofeng;Guo, Qulian;Zou, Wangyuan;Wang, Jian
吗啡被广泛用于治疗中度至重度疼痛。长期使用吗啡可引起耐受和痛觉过敏等不良反应。囊泡谷氨酸转运体2（VGluT 2）将谷氨酸积累到突触囊泡中，并在中枢神经系统中发挥多种作用。然而，VGluT 2在吗啡耐受中的具体作用尚未完全阐明。在此，我们研究了VGluT 2在吗啡耐受中的调节作用，并评估了脑源性神经营养因子（BDNF）/酪氨酸激酶B（Trk B）通路在VGluT 2介导的小鼠吗啡抗伤害耐受中的潜在作用。在本研究中，我们发现，VGluT 2上调后，在脊髓吗啡耐受的发展。此外，用其拮抗剂（芝加哥天蓝6 B，CSB 6 B）抑制VGluT 2或通过慢病毒敲低VGluT 2恢复吗啡的镇痛作用，抑制星形胶质细胞和小胶质细胞的活化，并减少胶质细胞衍生的促炎细胞因子。VGluT 2过表达的慢病毒促进吗啡耐受和机械性痛觉过敏。此外，我们发现慢性吗啡给药后脊髓中BDNF的表达与VGluT 2的表达相关。鞘内注射BDNF/TrkB通路阻断剂K252 a可减轻吗啡耐受的形成，并降低脊髓VGluT 2的表达，提示BDNF/TrkB通路参与了VGluT 2在吗啡耐受中的调节。这项研究阐明了VGluT 2在调节吗啡耐受中的功能能力，并确定了一种新的机制和有前途的治疗靶点。
Morphine is widely used in the treatment of moderate to severe pain. Long-term use of morphine leads to various adverse effects, such as tolerance and hyperalgesia. Vesicular glutamate transporter 2 (VGluT2) accumulates glutamate into synaptic vesicles and plays multiple roles in the central nervous system. However, the specific role of VGluT2 in morphine tolerance has not been fully elucidated. Here, we investigated the regulatory role of VGluT2 in morphine tolerance and assessed the potential role of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) pathway in VGluT2 mediated morphine antinociceptive tolerance in mice. In the present study, we found that VGluT2 is upregulated in the spinal cord after the development of morphine tolerance. Furthermore, inhibition of VGluT2 with its antagonist (Chicago sky blue 6 B, CSB6B) or knockdown of VGluT2 by lentivirus restored the analgesic effect of morphine, suppressed the activation of astrocytes and microglia, and decreased glial-derived pro-inflammatory cytokines. Overexpression of VGluT2 by lentivirus facilitated morphine tolerance and mechanical hyperalgesia. In addition, we found the expression of BDNF is correlated with VGluT2 expression in the spinal cord after chronic morphine administration. Intrathecal injection of the BDNF/TrkB pathway antagonist K252a attenuated the development of morphine tolerance and decreased the expression of VGluT2 in the spinal cord, which suggested the BDNF/TrkB pathway participates in the regulation of VGluT2 in morphine tolerance. This study elucidates the functional capability of VGluT2 in modulating morphine tolerance and identifies a novel mechanism and promising therapeutic target for morphine tolerance.
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影响因子：
8.8
作者：
Hayhurst, Christina J.;Durieux, Marcel E.
通讯作者：
Durieux, Marcel E.
影响因子：
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作者：
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Plamondon, Helene
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Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
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De Koninck Y
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16.2
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通讯作者：
DiAntonio, A
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64.8
作者：
Bohn, LM;Gainetdinov, RR;Caron, MG
通讯作者：
Caron, MG