The effect of motor-targeted epidural spinal stimulation on neuropathic pain and dorsal horn circuitry

The National Institute of Neurological Disorders and Stroke, part of the Department of Health and Human Services National Institutes of Health, awarded $150,342 to the University of Washington on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds investigation of how long-term, closed-loop, epidural spinal cord stimulation affects neuropathic pain symptoms in rats with cervical spinal cord injury. The research examines whether motor-targeted electrical spinal cord stimulation that was previously observed to depress nociceptive transmission in acute settings maintains that effect over extended therapy timelines necessary for motor function recovery. The recipient will quantify sensory dimensions of neuropathic pain across three modalities before and after stimulation therapy, and will conduct gain and loss of function manipulations to determine the role of neuropeptide Y positive inhibitory interneurons in the dorsal horn in both spinal cord injury-associated neuropathic pain and in stimulation therapy success. The work includes viral vector delivery to express diphtheria toxin receptors in target interneuron populations and subsequent ablation to assess functional impact.

The University of Washington Office of Sponsored Programs administers the award as the prime recipient. Performance occurs in Seattle, Washington, with an ultimate completion date of August 15, 2029.

Abstract

Around 18,000 people in the united states receive a new spinal cord injury (SCI) each year. This injury results in a wide range of symptoms due to the disruption of all modalities of neural control - motor, sensory, and autonomic. Around 50% of people with SCI develop neuropathic pain (SCI-NP) where pain is felt in response to non-noxious or otherwise mild stimuli due to damage to central pain processing circuits. The pain felt in response to these stimuli is often severe and intractable to analgesic medications like opioids, and new therapeutic methods are greatly needed to improve the quality of life of people with SCI-NP. A recent study by bandres ET AL, suggested that acute electrical spinal cord stimulation (SCS) that is targeted towards motor function recovery might also be depressing nociceptive transmission in the spinal cord of rats with SCI-NP, but IT is unclear whether this depression is maintained over longer therapy timelines, which are necessary for motor function recovery. Here, we will investigate how long-term, closed-loop, epidural SCS affects SCI-NP symptoms in rats with cervical SCI. Moreover, we will investigate the role of inhibitory interneurons on both SCI-NP and in SCS therapy by manipulating neuropeptide y positive interneurons (NPY+ INS) in the dorsal horn, a populous inhibitory interneuron population that's loss has been implicated as a cause of neuropathic pain. We will assay three different sensory modalities to quantify the sensory dimensions of neuropathic pain before and after SCS therapy. Then, we will perform gain and loss of function manipulations to determine the role of dorsal horn NPY+ INS in SCI-NP and SCS therapy success. First, we will use an adeno-associated virus to express diphtheria toxin receptors in NPY+ INS. Then we will use diphtheria toxin to ablate them and quantify how their loss impacts SCI-NP. In separate animals, we will use optogenetics to stimulate NPY+ INS after SCI to measure whether their activation reduces SCI-NP. We hypothesize that neuropathic pain will be reduced in females but increased in males over the course of SCS therapy and that NPY+ in activation will be critical to avoid neuropathic pain after cervical SCI. Accomplishing these aims will provide US with both translational and basic science data. Confirming whether motor-targeted, chronic, SCS improves neuropathic pain in addition to motor recovery would be an important discovery for the translation of this therapy into human health care. For basic science, this proposal will start to untangle the complicated spinal interneuron pathways that are involved in the breakdown of pain gating after SCI. Moreover, as the effects of SCS are poorly understood, data on the importance of dorsal horn interneurons on its effectiveness would help define its mechanisms of action.