Terman G W, Eastman C L, Chavkin C
Department of Anesthesiology, and the Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, Washington 98195-6540, USA.
J Neurophysiol. 2001 Feb;85(2):485-94. doi: 10.1152/jn.2001.85.2.485.
Long-term potentiation (LTP) involves a prolonged increase in neuronal excitability following repeated afferent input. This phenomenon has been extensively studied in the hippocampus as a model of learning and memory. Similar long-term increases in neuronal responses have been reported in the dorsal horn of the spinal cord following intense primary afferent stimulation. In these studies, we utilized the spinal cord slice preparation to examine effects of the potently antinociceptive mu opioids in modulating primary afferent/dorsal horn neurotransmission as well as LTP of such transmission. Transverse slices were made from the lumbar spinal cord of 10- to 17-day-old rats, placed in a recording chamber, and perfused with artificial cerebrospinal fluid also containing bicuculline (10 microM) and strychnine (1 microM). Primary afferent activation was achieved in the spinal slice by electrical stimulation of the dorsal root (DR) or the tract of Lissauer (LT) which is known to contain a high percentage of small diameter fibers likely to transmit nociception. Consistent with this anatomy, response latencies of LT-evoked field potentials in the dorsal horn were considerably slower than the response latencies of DR-evoked potentials. Only LT-evoked field potentials were found to be reliably inhibited by the mu opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)] enkephalin-ol (DAMGO, 1 microM), although evoked potentials from both DR and LT were blocked by the AMPA/kainate glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione. Moreover repeated stimulation of LT produced LTP of LT- but not DR-evoked potentials. In contrast, repeated stimulation of DR showed no reliable LTP. LTP of LT-evoked potentials depended on N-methyl-D-aspartate (NMDA) receptor activity, in that it was attenuated by the NMDA antagonist APV. Moreover, such LTP was inhibited by DAMGO interfering with LTP induction mechanisms. Finally, in whole cell voltage-clamp studies of Lamina I neurons, DAMGO inhibited excitatory postsynaptic current (EPSC) response amplitudes from LT stimulation-evoked excitatory amino acid release but not from glutamate puffed onto the cell and increased paired-pulse facilitation of EPSCs evoked by LT stimulation. These studies suggest that mu opioids exert their inhibitory effects presynaptically, likely through the inhibition of glutamate release from primary afferent terminals, and thereby inhibit the induction of LTP in the spinal dorsal horn.
长时程增强（LTP）是指在重复传入输入后神经元兴奋性的长时间增加。这种现象在海马体中作为学习和记忆的模型已被广泛研究。在强烈的初级传入刺激后，脊髓背角也有类似的神经元反应长期增加的报道。在这些研究中，我们利用脊髓切片标本，研究强效抗伤害性μ阿片类药物在调节初级传入/背角神经传递以及这种传递的LTP方面的作用。从10至17日龄大鼠的腰段脊髓制作横向切片，置于记录室中，并用含有荷包牡丹碱（10微摩尔）和士的宁（1微摩尔）的人工脑脊液灌注。通过电刺激背根（DR）或Lissauer束（LT）在脊髓切片中实现初级传入激活，已知Lissauer束含有高比例可能传递伤害性感受的小直径纤维。与这种解剖结构一致，背角中LT诱发的场电位的反应潜伏期比DR诱发的电位的反应潜伏期慢得多。仅发现LT诱发的场电位能被μ阿片受体激动剂[D-Ala(2)，N-Me-Phe(4)，Gly(5)]脑啡肽醇（DAMGO，1微摩尔）可靠地抑制，尽管DR和LT诱发的电位都被AMPA/海人藻酸谷氨酸受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮阻断。此外，重复刺激LT可产生LT诱发电位的LTP，但DR诱发电位则无。相反，重复刺激DR未显示可靠的LTP。LT诱发电位的LTP依赖于N-甲基-D-天冬氨酸（NMDA）受体活性，因为它被NMDA拮抗剂APV减弱。此外，这种LTP被DAMGO干扰LTP诱导机制所抑制。最后，在I层神经元的全细胞电压钳研究中，DAMGO抑制了LT刺激诱发的兴奋性氨基酸释放所引起的兴奋性突触后电流（EPSC）反应幅度，但不抑制 puff 到细胞上的谷氨酸所引起的反应幅度，并增加了LT刺激诱发的EPSC的双脉冲易化。这些研究表明，μ阿片类药物可能通过抑制初级传入终末的谷氨酸释放而在突触前发挥其抑制作用，从而抑制脊髓背角LTP的诱导。
