Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.
Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.
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DOI：
10.3389/fendo.2022.887238
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
慢性疼痛被定义为持续六个月以上的疼痛。慢性疼痛通常伴随着焦虑障碍，这两者往往会相互加剧。这可能会使这些疾病的治疗更加困难。葡萄糖依赖性胰岛素性多肽（GIP）是肠促胰岛素激素家族的一员，在葡萄糖代谢中起重要作用。以往的研究已经证明了GIP在生理和病理过程中的多重作用。在中枢神经系统中，对GIP的研究主要集中在神经退行性疾病；因此，关于GIP在慢性疼痛和疼痛相关焦虑症中的功能知之甚少。采用后爪注射完全弗氏佐剂（CFA）建立C57BL/6小鼠慢性炎性疼痛模型。通过腹腔注射或前扣带皮质（ACC）局部显微注射给予GIPR受体（GIPR）激动剂（D-Ala2-GIP）和拮抗剂（Pro3-GIP）。采用Von Frey细丝和辐射热来评估机械和热超敏反应。采用开阔场和高架迷宫试验检测焦虑样行为。通过ACC中GIPR shRNA敲低、酶联免疫吸附法、western blot分析、全细胞膜片钳记录、免疫荧光染色和实时荧光定量PCR等方法，探讨其在周围神经系统和中枢神经系统中的潜在机制。在本研究中，我们发现后爪注射CFA可诱导小鼠疼痛致敏和焦虑样行为。cfa注射小鼠ACC中GIPR的表达明显升高。腹腔或局部微量注射D-Ala2-GIP具有镇痛和抗焦虑作用；这些被ACC中的Pro3-GIP和GIPR shRNA敲低阻断。激活GIPR可抑制神经炎症和小胶质细胞的激活，逆转NMDA和AMPA受体的上调，抑制ACC模型小鼠兴奋性神经传递的增强。研究发现，激活GIPR可产生镇痛和抗焦虑作用，部分原因是神经炎症的减弱和ACC兴奋性传递的抑制。GIPR可能是治疗慢性炎症性疼痛和疼痛相关焦虑的合适靶点。
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. The chronic inflammatory pain model was established by hind paw injection with complete Freund’s adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR. In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice. GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.
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影响因子：
5.3
作者：
Kim YK;Jeon SW
通讯作者：
Jeon SW
影响因子：
3.9
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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作者：
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