Advance-CTR

Advance RI-CTR New Discovery Award

"Susceptibility of spinal nociceptors to developmental injuries"

Pain is the most prevalent co-morbidity of cerebral palsy (CP): up to 86% of children with CP experience pain which decreases quality of life, and often necessitates prescription opiates. Yet the pathophysiology of pain has not been researched in the context of CP. The pervasive view is that pain is a secondary effect of physical stressors including spasticity, hip subluxation and joint contractures. Physical stressors alone do not account for the incidence of pain in CP. Pain does not correlate with gross motor function classification system (GMFCS) level in people with CP. Unfortunately, little or no consideration has been given to the possibility that direct insults to the central nervous system (CNS) are causative not only of motor dysfunction, but nociceptive dysfunction as well. 

A common thread in many developmental injuries is hypoxia-ischemia (HI). Perinatal HI can occur with maternal infection, inflammation, placental insufficiency, and a difficult birth, and causes white matter injury, cortical damage, thinning of the corticospinal tract (CST) and motor deficits. I use a rabbit model of CP caused by 40 minutes of HI at 70% gestation. Offspring born naturally after prenatal HI show many parallels to CP in humans, including white matter injury, cortical damage, thinning of the CST, and motor deficits (hyperreflexia and hypertonia), all consistent with spastic CP. In contrast, rodent models are inadequate as they do not develop prominent motor deficits even after severe brain injuries. Perhaps unsurprisingly, we have recently noticed that HI rabbits show behavioral changes that could be related to pain. Specifically, HI rabbits respond more readily to noxious mechanical and thermal stimuli (based on von Frey and Hargreaves tests, respectively) and have an expansion of peptidergic nociceptors in the spinal cord dorsal horn. This appears to be another parallel to CP in humans, which is so often accompanied by pain. 

How prenatal injuries lead to chronic pain has not been studied. This proposal will help to fill this knowledge gap and will lead to funding that will generate new translational approaches for minimizing impacts of prenatal injuries and/or developing new therapeutics to treat pain in people with CP.