Releasing the brakes on axonal regeneration
Recovery of motor function after an injury that severs spinal cord tracts is limited by multiple inhibitors of axonal regeneration, such as the myelin-associated protein Nogo. Sekine et al. identified ORL1, a receptor for the opioid peptide nociceptin, as another inhibitor of axonal regeneration. ORL1 suppressed axonal regeneration by increasing the cell surface abundance of the Nogo receptor NgR1 and through NgR1-independent mechanisms. Recovery of locomotor function and axonal regeneration were improved in mice treated with an ORL1 antagonist after spinal cord injury, and these effects were accentuated in NgR1-deficient mice. Thus, combining ORL1 and NgR1 antagonists may yield greater improvements in locomotor function after spinal cord injury than has been possible with NgR1 antagonists alone.
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.