Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization.
Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization.
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DOI：
10.1152/jn.00339.2004
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发表时间：
2004-11
影响因子：
2.5
通讯作者：
R. Sun;Y. Tu;N. Lawand;Jing-Yin Yan;Q. Lin;W. Willis
中科院分区：
文献类型：
--
作者：
R. Sun;Y. Tu;N. Lawand;Jing-Yin Yan;Q. Lin;W. Willis
降钙素基因相关肽 (CGRP) 通过 CGRP 受体发挥作用，在大鼠中产生机械痛觉过敏的行为症状，并使脊髓背角的宽动态范围 (WDR) 神经元敏化。尽管CGRP受体参与中枢敏化已被证实，但CGRP受体刺激激活的第二信使系统并参与疼痛传递尚不清楚。本研究测试了 CGRP 受体激活对 WDR 神经元的痛觉过敏和敏化作用是否由蛋白激酶 A 或 C（PKA 或 PKC）信号介导。缩爪阈值测试显示，大鼠鞘内注射 CGRP 会产生机械性痛觉过敏。 CGRP1 受体拮抗剂 CGRP8-37 显着减弱 CGRP 诱导的痛觉过敏。 PKA 抑制剂 (H89) 或 PKC 抑制剂（氯化白屈菜红碱）也会显着减弱该作用。电生理学实验表明，脊髓灌注 CGRP 诱导脊髓背角神经元敏化。 CGRP 效应可被 CGRP8-37 阻断。 PKA 或 PKC 抑制剂（H89 或白屈菜红碱）也减弱了 CGRP 的这种作用。这些结果与 CGRP 通过直接作用于脊髓背角 CGRP1 受体而产生痛觉过敏的假设一致，并表明 CGRP 的作用是由 PKA 和 PKC 第二信使途径介导的。
Calcitonin gene-related peptide (CGRP), acting through CGRP receptors, produces behavioral signs of mechanical hyperalgesia in rats and sensitization of wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Although involvement of CGRP receptors in central sensitization has been confirmed, the second-messenger systems activated by CGRP receptor stimulation and involved in pain transmission are not clear. This study tested whether the hyperalgesia and sensitizing effects of CGRP receptor activation on WDR neurons are mediated by protein kinase A or C (PKA or PKC) signaling. Intrathecal injection of CGRP in rats produced mechanical hyperalgesia, as shown by paw withdrawal threshold tests. CGRP-induced hyperalgesia was attenuated significantly by the CGRP1 receptor antagonist, CGRP8-37. The effect was also attenuated significantly by a PKA inhibitor (H89) or a PKC inhibitor (chelerythrine chloride). Electrophysiological experiments demonstrated that superfusion of the spinal cord with CGRP-induced sensitization of spinal dorsal horn neurons. The CGRP effect could be blocked by CGRP8-37. Either a PKA or PKC inhibitor (H89 or chelerythrine) also attenuated this effect of CGRP. These results are consistent with the hypothesis that CGRP produces hyperalgesia by a direct action on CGRP1 receptors in the spinal cord dorsal horn and suggest that the effects of CGRP are mediated by both PKA and PKC second-messenger pathways.