Porreca F, Tang Q B, Bian D, Riedl M, Elde R, Lai J
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Brain Res. 1998 Jun 8;795(1-2):197-203. doi: 10.1016/s0006-8993(98)00292-3.
Previous studies in rats have shown that spinal morphine loses potency and efficacy to suppress an acute nociceptive stimulus applied to the tail or the paw following injury to peripheral nerves by tight ligation of the L5/L6 spinal nerves. Additionally, intrathecal (i.th.) morphine is ineffective in suppressing tactile allodynia at fully antinociceptive doses in these animals. The molecular basis for this loss of morphine potency and efficacy in nerve injury states is not known. One possible explanation for this phenomenon is a generalized, multi-segmental loss of opioid mu (mu) receptors in the dorsal horn of the spinal cord after nerve injury. This hypothesis was tested here by determining whether nerve injury produces (a) a decrease in mu receptors in the lumbar spinal cord; (b) a decrease in the affinity of ligand-receptor interaction, (c) a decrease in the fraction of high-affinity state of the mu receptors and (d) a reduced ability of morphine to activate G-proteins via mu receptors. Lumbar spinal cord tissues were examined 7 days after the nerve injury, a time when stable allodynia was observed. At this point, no differences were observed in the receptor density or affinity of [3H]DAMGO (mu selective agonist) or [3H]CTAP (mu selective antagonist) in the dorsal quadrant of lumbar spinal cord ipsilateral to nerve injury. Additionally, no change in morphine's potency and efficacy in activating G-proteins was observed. In contrast, staining for mu opioid receptors using mu-selective antibodies revealed a discrete loss of mu opioid receptors localized ipsilateral to the nerve injury and specific for sections taken at the L6 level. At these spinal segments, mu opioid receptors were decreased in laminae I and II. The data indicate that the loss of mu opioid receptors are highly localized and may contribute to the loss of morphine activity involving input at these spinal segments (e.g., foot-flick response). On the other hand, the lack of a generalized loss of opioid mu receptors across spinal segments makes it unlikely that this is the primary cause for the loss of potency and efficacy of mu opioids to suppress multi-segmental reflexes, such as the tail-flick response.
先前在大鼠身上进行的研究表明，通过紧密结扎L5/L6脊神经损伤外周神经后，脊髓吗啡抑制施加于尾部或爪子的急性伤害性刺激的效力和效果会降低。此外，鞘内注射吗啡在这些动物中以完全抗伤害感受剂量抑制触觉异常性疼痛时无效。在神经损伤状态下吗啡效力和效果丧失的分子基础尚不清楚。对于这种现象的一种可能解释是神经损伤后脊髓背角中阿片μ（μ）受体普遍的多节段性丧失。本研究通过确定神经损伤是否会导致（a）腰段脊髓中μ受体减少；（b）配体 - 受体相互作用亲和力降低；（c）μ受体高亲和力状态比例降低；以及（d）吗啡通过μ受体激活G蛋白的能力降低来验证这一假设。在神经损伤7天后检查腰段脊髓组织，此时观察到稳定的异常性疼痛。此时，在神经损伤同侧腰段脊髓背侧象限中，[3H]DAMGO（μ选择性激动剂）或[3H]CTAP（μ选择性拮抗剂）的受体密度或亲和力未观察到差异。此外，未观察到吗啡激活G蛋白的效力和效果有变化。相反，使用μ选择性抗体对μ阿片受体进行染色显示，在神经损伤同侧且特定于L6水平切片处，μ阿片受体出现离散性丧失。在这些脊髓节段，I层和II层中的μ阿片受体减少。数据表明，μ阿片受体的丧失高度局限，可能导致涉及这些脊髓节段输入（如甩尾反应）的吗啡活性丧失。另一方面，脊髓节段间缺乏阿片μ受体的普遍丧失，这使得其不太可能是μ阿片类药物抑制多节段反射（如甩尾反应）的效力和效果丧失的主要原因。
