Xing Guo-Gang, Liu Feng-Yu, Qu Xiao-Xiu, Han Ji-Sheng, Wan You
Department of Neurobiology, Key Laboratory for Neuroscience of the Ministry of Education and Public Health, Peking University, 38 Xue-Yuan Road, Beijing 100083, People's Republic of China.
Exp Neurol. 2007 Dec;208(2):323-32. doi: 10.1016/j.expneurol.2007.09.004. Epub 2007 Sep 12.
Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.
我们之前的研究报道，在患有神经性疼痛的大鼠中，2 Hz低频电针（EA）对机械性异常性疼痛和热痛觉过敏的镇痛作用比100 Hz高频EA更强且更持久。然而，不同频率的EA如何对神经性疼痛产生不同的镇痛作用尚不清楚。脊髓中的神经元可塑性变化可能有助于神经性疼痛的发生和维持。在本研究中，我们调查了神经性疼痛大鼠在神经性疼痛发生过程中脊髓突触可塑性的变化及其受EA的调节情况。在假手术大鼠和脊髓神经结扎（SNL）大鼠中，细胞外记录脊髓背角神经元的场电位。我们首次发现，SNL大鼠背角中诱导C纤维诱发电位长时程增强（LTP）的阈值显著低于假手术大鼠。与对照大鼠相比，SNL大鼠诱发C纤维诱发电场电位的阈值也显著降低，且场电位的幅度更高。在有效治疗神经性疼痛的穴位足三里（ST 36）和三阴交（SP 6）施加2 Hz低频EA，可诱导SNL大鼠C纤维诱发电位的长时程抑制（LTD）。这种效应可被N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801和阿片受体拮抗剂纳洛酮阻断。相反，对治疗神经性疼痛无效的100 Hz高频EA在SNL大鼠中诱导LTP，但在假手术大鼠中诱导LTD。与2 Hz EA在SNL大鼠中诱导的LTD不同，100 Hz EA在假手术大鼠中诱导的LTD依赖于内源性γ-氨基丁酸能（GABAergic）和5-羟色胺能（serotonergic）抑制系统。我们目前的研究结果表明：（1）神经损伤后脊髓伤害性突触传递可能会出现兴奋性过高，这可能有助于神经性疼痛的发生；（2）低频或高频EA对神经性疼痛大鼠脊髓突触可塑性的调节作用不同。低频或高频EA对脊髓LTD或LTP的不同调节可能是EA对神经性疼痛产生不同镇痛作用的潜在机制。SNL大鼠脊髓背角突触强度的LTD可能有助于2 Hz EA的持久镇痛作用。
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