Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury
Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury
复制标题
DOI：
10.1523/jneurosci.0300-04.2004
复制
发表时间：
2004-05-19
影响因子：
5.3
通讯作者：
Waxman, SG
中科院分区：
文献类型：
--
作者：
Hains, BC;Saab, CY;Waxman, SG
已知外周神经损伤可上调一级脊髓感觉神经元内快速激活的Na(V)1.3钠通道。在这项研究中，我们假设(1)周围神经损伤后，二级背角神经元异常表达Na(V)1.3，这(2)参与了这些背角神经元的反应性和疼痛相关行为。为了验证这些假说，成年大鼠进行了坐骨神经慢性压迫损伤(CCI)。CCI后10d，出现明显的痛觉超敏和痛觉过敏。原位杂交、定量逆转录-聚合酶链式反应和免疫细胞化学分析表明，Na(V)1.3在背角伤害性神经元中表达上调，但在星形胶质细胞和小胶质细胞中不表达，单位记录显示背角感觉神经元具有高反应性。鞘内针对Na(V)1.3的反义寡核苷酸可降低Na(V)1.3基因和蛋白的表达，降低背角神经元的高反应性，减轻CCI后的疼痛相关行为，这些作用在反义注射停止后恢复。这些结果首次证明了周围神经损伤后高阶脊髓感觉神经元中钠通道的表达发生了变化，并提示Na(V)1.3钠通道的错误表达与导致周围神经损伤后神经病理性疼痛的中枢机制之间存在联系。
Peripheral nerve injury is known to upregulate the rapidly repriming Na(v)1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that ( 1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na(v)1.3, which ( 2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na(v)1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na(v)1.3 decreased the expression of Na(v)1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na(v)1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.