(385) Targeting KCNQ channels to prevent spinal cord injury-induced chronic pain

Abstract

Chronic pain is one of the most debilitating problems caused by traumatic injury to the spinal cord (SCI). The molecular mechanisms underlying SCI-induced pain remain uncertain, severely hindering the development of effective therapies. Most research has focused on CNS mechanisms, assuming that central alterations exclusively drive chronic neuropathic pain after SCI. However, we found that contusive SCI results in a chronic increase in spontaneous activity (SA) in primary sensory neurons, and this SA is associated with hypersensitivity of withdrawal reflexes to mechanical and heat test stimuli, and with an operant measure of ongoing pain. We hypothesized that reducing sensory neuron hyperexcitability during the acute phase of SCI would impair the development of chronic SCI pain. KCNQ/Kv7 channels are abundant in primary sensory neurons, potently controlling their excitability. A specific opener of KCNQ channels, retigabine, was used to test if early activation of KCNQ channels would minimize chronic SCI-induced pain. Previously we found that retigabine strongly suppresses SCI-induced SA in DRG neurons in vivo and in vitro. We produced contusive SCI at T10 in adult, male rats, which then received 10 consecutive days’ treatment with retigabine or vehicle. The early retigabine treatment significantly attenuated development of both heat and mechanical hyperreflexia tested 4-6 weeks after injury, and development of mechanical hypersensitivity of the torso below and at the injury level. Early repeated application of retigabine also prevented the development of spontaneous pain behavior after SCI. These data suggest that early treatment with retigabine may have clinical promise for impeding the development of chronic pain after SCI. Chronic pain is one of the most debilitating problems caused by traumatic injury to the spinal cord (SCI). The molecular mechanisms underlying SCI-induced pain remain uncertain, severely hindering the development of effective therapies. Most research has focused on CNS mechanisms, assuming that central alterations exclusively drive chronic neuropathic pain after SCI. However, we found that contusive SCI results in a chronic increase in spontaneous activity (SA) in primary sensory neurons, and this SA is associated with hypersensitivity of withdrawal reflexes to mechanical and heat test stimuli, and with an operant measure of ongoing pain. We hypothesized that reducing sensory neuron hyperexcitability during the acute phase of SCI would impair the development of chronic SCI pain. KCNQ/Kv7 channels are abundant in primary sensory neurons, potently controlling their excitability. A specific opener of KCNQ channels, retigabine, was used to test if early activation of KCNQ channels would minimize chronic SCI-induced pain. Previously we found that retigabine strongly suppresses SCI-induced SA in DRG neurons in vivo and in vitro. We produced contusive SCI at T10 in adult, male rats, which then received 10 consecutive days’ treatment with retigabine or vehicle. The early retigabine treatment significantly attenuated development of both heat and mechanical hyperreflexia tested 4-6 weeks after injury, and development of mechanical hypersensitivity of the torso below and at the injury level. Early repeated application of retigabine also prevented the development of spontaneous pain behavior after SCI. These data suggest that early treatment with retigabine may have clinical promise for impeding the development of chronic pain after SCI.