Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Faculté des Sciences de la Vie, Université de Strasbourg, Strasbourg, France Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA.
Pain. 2011 Sep;152(9):2131-2137. doi: 10.1016/j.pain.2011.05.022. Epub 2011 Jul 26.
Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic transmission through spinal β(2)-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in β(2)(∗)-knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that β(2)(∗)-nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic β(2)(∗)-nAChR control of mechanical nociceptive thresholds might implicate GABAergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the GABA(A) receptor antagonist bicuculline decreased the mechanical threshold in wild-type but not β(2)(∗)-KO mice, and the agonist muscimol restored basal mechanical threshold in β(2)(∗)-KO mice. Thus, β(2)(∗)-nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, β(2)(∗)-KO mice were also hyperresponsive to capsaicin-induced C-fiber stimulation. Our results indicate that β(2)(∗)-nAChRs are implicated in the recruitment of inhibitory control of nociception, as shown by delayed recovery from capsaicin-induced allodynia, potentiated nociceptive response to inflammation and neuropathy, and by the loss of high-frequency transcutaneous electrical nerve stimulation (TENS)-induced analgesia in β(2)(∗)-KO mice. As high-frequency TENS induces analgesia through Aβ-fiber recruitment, these data suggest that β(2)(∗)-nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling through β(2)(∗)-nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord.
虽然胆碱能药物被认为可以调节伤害感受，但内源性乙酰胆碱在伤害感受处理中的作用仍不清楚。在本研究中，我们评估了通过脊髓β(2)-亚单位包含的烟碱型乙酰胆碱受体进行的胆碱能传递在控制伤害感受阈值中的作用。我们发现机械和热伤害感受阈值在β(2)(∗)-敲除(KO)小鼠中显著降低。在这些小鼠中使用烟碱型拮抗剂，我们证明β(2)(∗)-nAChRs 负责在脊髓水平对机械阈值进行紧张性抑制控制。我们进一步假设，紧张性β(2)(∗)-nAChR 对机械伤害感受阈值的控制可能涉及 GABA 能传递，因为脊髓 nAChR 刺激可以增强抑制性传递。事实上，GABA(A)受体拮抗剂荷包牡丹碱降低了野生型但不是β(2)(∗)-KO 小鼠的机械阈值，激动剂 muscimol 恢复了β(2)(∗)-KO 小鼠的基础机械阈值。因此，β(2)(∗)-nAChRs 似乎是 GABA 能控制伤害感受信息所必需的。由于这种抑制控制的缺陷，β(2)(∗)-KO 小鼠对辣椒素诱导的 C 纤维刺激也表现出超敏反应。我们的结果表明，β(2)(∗)-nAChRs 参与了伤害感受抑制控制的招募，如辣椒素诱导的痛觉过敏恢复延迟、炎症和神经病变时伤害感受反应增强以及β(2)(∗)-KO 小鼠高频经皮电神经刺激(TENS)诱导的镇痛丧失所示。由于高频 TENS 通过 Aβ 纤维募集诱导镇痛，这些数据表明β(2)(∗)-nAChRs 对于通过非伤害感受性感觉输入对伤害感受信息进行门控控制可能是至关重要的。总之，通过β(2)(∗)-nAChRs 的乙酰胆碱信号似乎对于通过控制脊髓中的 GABA 能抑制来设定伤害感受阈值是必不可少的。
