Diminished synaptic inhibition in the superficial spinal dorsal horn contributes to exaggerated pain responses that accompany peripheral inflammation and neuropathy. α2GABAA receptors (α2GABAAR) constitute the most abundant GABAAR subtype at this site and are the targets of recently identified antihyperalgesic compounds. Surprisingly, hoxb8-α2-/- mice that lack α2GABAAR from the spinal cord and peripheral sensory neurons exhibit unaltered sensitivity to acute painful stimuli and develop normal inflammatory and neuropathic hyperalgesia. Here, we provide a comprehensive analysis of GABAergic neurotransmission, of behavioral phenotypes and of possible compensatory mechanisms in hoxb8-α2-/- mice. Our results confirm that hoxb8-α2-/- mice show significantly diminished GABAergic inhibitory postsynaptic currents (IPSCs) in the superficial dorsal horn but no hyperalgesic phenotype. We also confirm that the potentiation of dorsal horn GABAergic IPSCs by the α2-preferring GABAAR modulator HZ-166 is reduced in hoxb8-α2-/- mice and that hoxb8-α2-/- mice are resistant to the analgesic effects of HZ-166. Tonic GABAergic currents, glycinergic IPSCs, and sensory afferent-evoked EPSCs did show significant changes in hoxb8-α2-/- mice rendering a compensatory up-regulation of other GABAAR subtypes or of glycine receptors unlikely. Although expression of serotonin and of the serotonin producing enzyme tryptophan hydroxylase (TPH2) was significantly increased in the dorsal horn of hoxb8-α2-/- mice, ablation of serotonergic terminals from the lumbar spinal cord failed to unmask a nociceptive phenotype. Our results are consistent with an important contribution of α2GABAAR to spinal nociceptive control but their ablation early in development appears to activate yet-to-be identified compensatory mechanisms that protect hoxb8-α2-/- mice from hyperalgesia.

中文翻译：

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缺乏脊髓 α2GABAA 受体的小鼠：改变 GABA 能神经传递，减少 GABA 能抗痛觉过敏，以及防止痛觉过敏表型的潜在代偿机制。

浅表脊髓背角的突触抑制减弱导致伴随外周炎症和神经病变的过度疼痛反应。α2GABAA 受体 (α2GABAAR) 构成了该位点最丰富的 GABAAR 亚型，并且是最近发现的抗痛觉过敏化合物的靶标。令人惊讶的是，缺乏来自脊髓和外周感觉神经元的 α2GABAAR 的 hoxb8-α2-/- 小鼠对急性疼痛刺激表现出未改变的敏感性，并产生正常的炎症和神经性痛觉过敏。在这里，我们对 hoxb8-α2-/- 小鼠的 GABA 能神经传递、行为表型和可能的补偿机制进行了全面分析。我们的结果证实，hoxb8-α2-/- 小鼠的浅背角中 GABA 能抑制突触后电流 (IPSC) 显着减少，但没有痛觉过敏表型。我们还证实，在 hoxb8-α2-/- 小鼠中，α2 偏好的 GABAAR 调节剂 HZ-166 对背角 GABA 能 IPSC 的增强作用降低，并且 hoxb8-α2-/- 小鼠对 HZ-166 的镇痛作用具有抗性. 强直 GABA 能电流、甘氨酸能 IPSC 和感觉传入诱发的 EPSC 确实在 hoxb8-α2-/- 小鼠中显示出显着变化，使得其他 GABAAR 亚型或甘氨酸受体的补偿性上调不太可能。尽管在 hoxb8-α2-/- 小鼠的背角中血清素和血清素产生酶色氨酸羟化酶 (TPH2) 的表达显着增加，腰椎脊髓血清素能末梢的消融未能揭示伤害性表型。我们的结果与 α2GABAAR 对脊髓伤害性控制的重要贡献一致，但它们在发育早期的消融似乎激活了尚未确定的补偿机制，可保护 hoxb8-α2-/- 小鼠免受痛觉过敏。