Pilot: Novel Therapeutic Treatment of Neuropathic Pain after Spinal Cord Injury
Principle Investigator: Olivera Nesic, PhD
Neuropathic pain sets in after an injury has healed, in contrast to acute pain, which happens before healing has occurred. Many different kinds of chronic pain are associated with spinal cord injury (SCI): burning, prickling pain; pain on touch; or pain caused by stimuli that normally do not produce pain (allodynia).The majority of people with SCI report chronic, unpleasant sensations or pain. About a third of SCI patients describe their chronic pain as severe and debilitating.
Chronic pain after SCI is a devastating condition primarily because there is no cure, or even adequate treatment. Pharmaceutical interventions are only partially and transiently effective; at best they reduce chronic pain by 20-30%. Unfortunately, even the results of clinical trials with new drugs for treating pain after SCI have been negative. Furthermore, there is a significant reinforcement of chronic pain with stress, depression, anxiety and posttraumatic stress disorder.
As a result, untreated SCI pain becomes worse with time, so effective treatment of SCI pain is greatly needed. We are proposing a new mechanism for the development of chronic pain after SCI. Exaggerated, pathological signaling in pain-processing pathways in almost all neuropathic pain conditions, including SCI pain, involves amplified glutamatergic signaling. However, inhibitors of glutamate (Glu) signaling, although effectively reducing neuropathic pain in animal models, are toxic in humans because they also block Glu transmission which is necessary for normal functioning of the brain and spinal cord.
Therefore, we propose to target glutamate release pathway that is activated only after SCI, and thus can be safely inhibited. We hypothesize that SCI-induced swelling of astrocytes in chronically injured spinal cords produces excessive release of Glu via volume-regulated anion channels (VRAC), overactivation of Glu receptors in nociceptive pathways and chronic pain. We also hypothesize that inhibition of VRACs with FDA approved drug tamoxifen will reduce chronic pain in a rat model of contusion SCI.