Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that compensatory pathways limit improvement. Gene expression profiles of mice deficient in Ngr1, which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of ORL1, which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O-linked glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined Ngr1 deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and Ngr1 null mice.

脊髓损伤后的轴突生长受到内源性抑制剂的限制，内源性抑制剂的选择性阻滞促进了部分神经系统的恢复。部分修复表型表明补偿途径限制改善。缺乏Ngr1的小鼠的基因表达谱，Ngr1编码髓鞘相关的轴突再生抑制剂（如Nogo）的受体，表明创伤增加了ORL1的mRNA表达，它编码阿片相关肽Nociceptin的受体。内源性和过表达的ORL1与未成熟的NgR1蛋白共免疫沉淀，并且ORL1增强了HEK293T和Neuro2A细胞以及原代神经元中O联糖基化和NgR1的表面表达。ORL1过表达抑制皮质神经元轴突再生独立于NgR1。此外，再生被ORL1激动剂抑制，并通过ROCK依赖性机制被ORL1拮抗剂J113397增强。胸中脊髓背侧半切后用J113397处理的小鼠恢复了更大的运动功能，并表现出腰臀旁轴突发芽。结合使用Ngr1可以进一步增强这些效果删除和ORL1抑制。因此，ORL1通过增强NgR1成熟来直接和间接地限制神经修复，而ORL1拮抗剂可增强野生型和Ngr1缺失小鼠的中枢神经系统损伤后的恢复。