Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo.
Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo.
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DOI：
10.1186/1744-8069-5-68
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发表时间：
2009-11-19
期刊：
影响因子：
3.3
通讯作者：
Kurejova M
中科院分区：
文献类型：
--
作者：
Gangadharan V;Agarwal N;Brugger S;Tegeder I;Bettler B;Kuner R;Kurejova M
γ-氨基丁酸（γ-aminobutyric acid，GABA）是一种重要的抑制性神经递质，主要通过亲离子型（GABAA）和亲代谢型（GABAB）受体介导其对神经元的作用。GABAB受体在中枢和外周神经系统中广泛表达。虽然有证据表明GABAB受体在疼痛调节中具有关键功能，但外周表达的GABAB受体与中枢表达的GABAB受体的相对作用尚不清楚。为了阐明外周伤害感受神经元中表达的GABAB受体在疼痛调制中的功能相关性，我们产生并分析了在伤害感受器中特异性缺乏功能性GABAB（1）亚基的条件小鼠突变体，保留了在脊髓和脑中的表达（SNS-GABAB（1）-/-小鼠）。GABAB（1）亚基的缺乏阻碍了功能性GABAB受体的组装。我们分析了SNS-GABAB（1）-/-小鼠和它们的对照同窝仔在几个模型的急性和神经性疼痛。外周传入神经的电生理研究显示，SNS-GABAB（1）-/-小鼠的放电频率高于相应的对照组同窝小鼠。然而，这些组之间的基础伤害敏感性没有差异。神经性疼痛和慢性炎性疼痛的发展在两种基因型之间是相似的。与同窝对照组相比，在SNS-GABAB（1）-/-组动物中足底注射福尔马林引起的疼痛反应持续时间延长。药理学实验表明，全身性的细菌对福尔马林诱导的伤害性行为的抑制并不依赖于伤害感受器中GABAB（1）的表达。本研究探讨初级传入伤害性纤维上表达的GABAB受体对疼痛调制的贡献。我们观察到，无论是急性和慢性疼痛的发展，也不是镇痛作用的全身交付GABAB激动剂显着改变后，从外周伤害性神经元在体内的GABAB受体的特定删除。这让我们得出结论，外周神经系统中的GABAB受体在疼痛调节中发挥的作用不如中枢神经系统中的作用重要。
γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)-/- mice). Lack of the GABAB(1) subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1) expression in nociceptors. This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly changed upon a specific deletion of GABAB receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABAB receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
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