Durham P L, Russo A F
Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA.
J Neurosci. 1999 May 1;19(9):3423-9. doi: 10.1523/JNEUROSCI.19-09-03423.1999.
We have investigated the regulation of calcitonin gene-related peptide (CGRP) release from trigeminal neurons by the serotonergic antimigraine drug sumatriptan. Serum levels of the neuropeptide CGRP are elevated during migraine. Treatment with the drug sumatriptan returns CGRP levels to normal coincident with the alleviation of headache. However, despite this clinical efficacy, the cellular target and mechanism of sumatriptan action are not well understood beyond the pharmacology of its recognition of the 5-HT1 class of serotonin receptors. We have used cultured trigeminal neurons to demonstrate that sumatriptan can directly repress CGRP secretion from sensory neurons. The stimulated secretion in response to depolarization or inflammatory agents was inhibited, but not the basal secretion rate. Unexpectedly, sumatriptan did not lower cAMP levels, in contrast to the classical role ascribed to the 5-HT1 receptors. Instead, activation of 5-HT1 receptors caused a slow and remarkably prolonged increase in intracellular calcium. The inhibition of CGRP secretion is attenuated by the phosphatase inhibitor okadaic acid, suggesting that sumatriptan action is mediated by calcium-recruited phosphatases. These results suggest that 5-HT1 agonists may block a deleterious feedback loop in migraine at the trigeminal neurons and provide a general mechanism by which this class of drugs can attenuate stimulated neuropeptide release.
我们研究了血清素能抗偏头痛药物舒马曲坦对三叉神经节神经元降钙素基因相关肽（CGRP）释放的调节作用。偏头痛发作时，神经肽CGRP的血清水平会升高。使用舒马曲坦治疗可使CGRP水平恢复正常，同时缓解头痛。然而，尽管有这种临床疗效，但除了其对5-HT1类血清素受体识别的药理学作用外，舒马曲坦的细胞靶点和作用机制尚不清楚。我们利用培养的三叉神经节神经元证明，舒马曲坦可直接抑制感觉神经元释放CGRP。对去极化或炎症介质的刺激分泌受到抑制，但基础分泌率不受影响。出乎意料的是，与归因于5-HT1受体的经典作用相反，舒马曲坦并未降低cAMP水平。相反，5-HT1受体的激活导致细胞内钙缓慢且显著延长的增加。磷酸酶抑制剂冈田酸可减弱CGRP分泌的抑制作用，提示舒马曲坦的作用是由钙招募的磷酸酶介导的。这些结果表明，5-HT1激动剂可能在三叉神经节神经元处阻断偏头痛中的有害反馈回路，并提供了这一类药物可减弱刺激的神经肽释放的一般机制。
