Wang Z, Gardell L R, Ossipov M H, Vanderah T W, Brennan M B, Hochgeschwender U, Hruby V J, Malan T P, Lai J, Porreca F
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA.
J Neurosci. 2001 Mar 1;21(5):1779-86. doi: 10.1523/JNEUROSCI.21-05-01779.2001.
Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.
虽然组织损伤会增加脊髓强啡肽的表达，但这种上调与持续性疼痛的功能相关性尚不清楚。在此，研究了缺乏前强啡肽基因的小鼠在实验性神经性疼痛诱导前后对非伤害性和伤害性刺激的敏感性。前强啡肽基因敲除（KO）小鼠对急性非伤害性刺激有正常反应，对一些伤害性刺激的敏感性略有增加。在脊髓神经结扎（SNL）后，野生型（WT）和KO小鼠对无害机械刺激和伤害性热刺激的阈值均降低，表明强啡肽不是神经性疼痛起始所必需的。然而，WT小鼠的神经性疼痛持续存在，而KO小鼠在SNL后第10天恢复到基线水平。在WT小鼠中，SNL在损伤后第10天而非第2天上调腰段强啡肽含量。鞘内注射强啡肽抗血清在SNL后第10天（强啡肽上调时）可逆转WT小鼠的神经性疼痛，但在SNL后第2天则不能；鞘内注射MK-801在两个时间点均可逆转SNL疼痛。WT和KO小鼠之间的阿片类（μ、δ和κ）受体密度和G蛋白激活没有差异，且不受SNL损伤影响。这些观察结果表明：（1）神经性疼痛有一个早期的、不依赖强啡肽的阶段和一个后期依赖强啡肽的阶段；（2）脊髓强啡肽上调具有促痛作用，是维持持续性神经性疼痛所必需的；（3）神经性疼痛状态起始和维持所需的过程是不同的。确定维持神经性疼痛的机制对于治疗神经性疼痛的策略似乎很重要。
