Rohde D S, McKay W R, Abbadie C, Basbaum A I
Program in Biomedical Sciences, University of California San Francisco 94143-0452, USA.
Brain Res. 1997 Jan 16;745(1-2):83-95. doi: 10.1016/s0006-8993(96)01132-8.
In this study, we monitored Fos-like immunoreactivity in the sacral spinal cord to identify neurons that are likely to contribute to the autonomic manifestations of opioid antagonist-precipitated withdrawal in morphine-tolerant rats. Injection of systemic antagonist increased the Fos-like immunoreactivity throughout the first sacral segment, particularly in laminae I/II, X, and in the sacral parasympathetic nucleus (SPN). Selective peripheral withdrawal, with a hydrophilic antagonist that does not cross the blood-brain barrier (BBB), induced diarrhea, but no other withdrawal signs were evident. Compared to rats that withdrew systemically, peripherally withdrawal evoked significantly less Fos-like immunoreactivity in laminae V/VI, X and the SPN. By contrast, selective spinal withdrawal, by intrathecal injection of an opioid antagonist that does not cross the BBB, provoked hyperactivity of the hindlimbs and tail, but no diarrhea. These animals demonstrated significantly increased Fos-like immunoreactivity in laminae I/II, V/VI, the SPN, and the ventral horn compared to rats that withdrew systemically. Animals treated neonatally with capsaicin, to eliminate C-fiber input, demonstrated withdrawal behavior similar to intact withdrawing rats, except that the capsaicin-pretreated rats had significantly greater weight loss. However, this group had less Fos-like immunoreactivity in laminae V/VI, X and SPN compared to the intact withdrawing rats. These data suggest that withdrawal from morphine evokes hyperactivity of sacral neurons, particularly those involved in regions that process nociceptive and autonomic information. Peripheral withdrawal is sufficient to induce diarrhea, but it does not fully explain the associated weight loss. Unmyelinated primary afferents may contribute a tonic peripheral inhibition of circuits that regulate gut motility and intestinal fluid transport. Taken together, these data suggest that chronic exposure to opioids induces a latent sensitization in sacral cord neurons that can be manifested as neuronal hyperactivity during withdrawal; this mechanism may underlie withdrawal-induced hyperalgesia and gut hypermotility.
在本研究中，我们监测了骶脊髓中Fos样免疫反应性，以确定可能导致吗啡耐受大鼠中阿片类拮抗剂诱发戒断的自主神经表现的神经元。全身注射拮抗剂增加了整个第一骶节段的Fos样免疫反应性，特别是在I/II层、X层和骶副交感核（SPN）中。用一种不穿过血脑屏障（BBB）的亲水性拮抗剂进行选择性外周戒断，会诱发腹泻，但没有其他明显的戒断迹象。与全身戒断的大鼠相比，外周戒断在V/VI层、X层和SPN中诱发的Fos样免疫反应性明显较少。相比之下，通过鞘内注射一种不穿过血脑屏障的阿片类拮抗剂进行选择性脊髓戒断，会引发后肢和尾巴的多动，但不会引起腹泻。与全身戒断的大鼠相比，这些动物在I/II层、V/VI层、SPN和腹角中表现出明显增加的Fos样免疫反应性。新生期用辣椒素处理以消除C纤维输入的动物，表现出与完整戒断大鼠相似的戒断行为，只是辣椒素预处理的大鼠体重减轻明显更多。然而，与完整戒断的大鼠相比，该组在V/VI层、X层和SPN中的Fos样免疫反应性较低。这些数据表明，吗啡戒断会诱发骶神经元的多动，特别是那些参与处理伤害性和自主神经信息区域的神经元。外周戒断足以诱发腹泻，但不能完全解释相关的体重减轻。无髓初级传入神经可能对调节肠道运动和肠液运输的回路产生紧张性外周抑制。综上所述，这些数据表明，长期接触阿片类药物会在骶脊髓神经元中诱导潜在的敏化，在戒断期间可表现为神经元多动；这种机制可能是戒断诱导的痛觉过敏和肠道运动亢进的基础。
