MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA Department of Physiology, Southern Medical University, Guangzhou 510515, China.
Pain. 2011 Jun;152(6):1263-1271. doi: 10.1016/j.pain.2011.01.054. Epub 2011 Mar 4.
Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole-cell patch-clamp recording from rat's spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced N-methyl-d-aspartate (NMDA) receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor-deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching, and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the noncompetitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat's spinal cord dorsal horn, and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin's spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain. A functional link is demonstrated between leptin, an adipocytokine, and the cellular mechanisms of neuropathic pain via enhancement of function and expression of spinal N-methyl-d-aspartate receptors.
最近的研究表明，瘦素（一种脂肪细胞因子）在神经损伤引起的伤害性行为中发挥着重要作用，但这种作用的细胞机制尚不清楚。使用大鼠脊髓切片的全细胞膜片钳记录，我们发现瘦素在脊髓切片上的超射剂量依赖性地增强了脊髓层 II 神经元中 N-甲基-D-天冬氨酸（NMDA）受体介导的电流。在细胞水平上，瘦素对脊髓 NMDA 诱导电流的作用是通过瘦素受体和 JAK2/STAT3（而不是 PI3K 或 MAPK）途径介导的，因为瘦素受体缺失（db/db）小鼠中的瘦素作用被消除，并且被 JAK/STAT 抑制剂抑制。此外，我们在未处理的大鼠中证明，单次鞘内给予瘦素增强了鞘内 NMDA 诱导的自发咬、抓和舔行为，并且重复鞘内给予瘦素引起热痛觉过敏和机械性痛觉过敏，这可被非竞争性 NMDA 受体拮抗剂 MK-801 减弱。鞘内瘦素还上调了大鼠脊髓背角中 NMDA 受体和 pSTAT3 的表达，并且鞘内 MK-801 也减弱了这种瘦素作用。我们的数据表明，瘦素与 NMDA 受体介导的脊髓神经元兴奋之间存在关系，并且在伤害性行为中具有功能作用。由于瘦素有助于神经损伤引起的伤害性行为，因此目前的研究结果表明，瘦素的脊髓作用与 NMDA 受体介导的神经性疼痛的细胞机制之间存在重要的细胞联系。通过增强脊髓 N-甲基-D-天冬氨酸受体的功能和表达，证明了脂肪细胞因子瘦素与神经性疼痛的细胞机制之间存在功能联系。
