Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain.
Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain.
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DOI：
10.1017/s1740925x12000026
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发表时间：
2011-05
影响因子：
--
通讯作者：
Cao L
中科院分区：
文献类型：
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作者：
Malon JT;Maddula S;Bell H;Cao L
在神经性疼痛的临床前模型中，神经肽降钙素基因相关肽（CGRP）在周围神经损伤后从初级传入神经元释放后发挥了促进伤害的作用。我们之前证明了脊髓小胶质细胞CD40在脊神经L5横断（L5Tx）诱导的机械超敏反应的发展中起关键作用。在此，我们研究了CGRP是否参与cd40介导的行为超敏反应。首先，发现L5Tx在野生型（WT）小鼠中显著诱导CGRP表达至L5Tx后14天。在l5tx后第14天，CD40敲除（KO）小鼠的CGRP表达增加减少。鞘内注射CGRP拮抗剂CGRP8-37可显著阻断l5tx诱导的机械超敏反应。在体外，CGRP诱导胶质细胞IL-6和CCL2的产生，CD40刺激增加了CGRP对新生儿胶质细胞的作用。此外，与WT小鼠相比，l5tx后21天CD40 KO小鼠的CCL2生成减少。然而，CGRP8-37对WT小鼠L5Tx后脊髓CCL2的产生没有显著影响。总之，这些数据表明，CD40在一定程度上通过两种不同的途径参与周围神经损伤后行为超敏反应的维持，即CGRP表达的增强和脊髓CCL2的产生。
The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.