We have suggested that endogenous opioids and opiate receptors play a role in the pathophysiology of secondary spinal cord injury that follows trauma, based on the therapeutic effects of opiate antagonists in certain models of spinal cord injury. Increasing circumstantial evidence from our laboratory over the past two years has implicated the dynorphin opioid system and the Kappa opiate receptor in the injury process: the goals of the studies are to more specifically address these questions. A series of parallel, multidisciplinary studies in the rat are planned. These includes: (a) measurement of changes in endogenous opioid immunoreactivity in spinal cord after trauma; (2) determining whether dynorphin tolerance reduces the pathophysiological consequences of spinal cord trauma, including changes in somatosensory-evoked responses, blood pressure, spinal cord blood flow, histopathology and neurological function; (3) evaluating whether acute dynorphin infusions, below those necessary to produce paralysis, exacerbate the consequences of traumatic spinal injury; (4) examinaing whether intrathecal infusions of antibody to dynorphin A-(1-17) reduce the severity of spinal injury produced by trauma; (5) investigating the effects of upregulation of opiate receptors (through use of chronic administration of opiate antagonists) on the response to injury; and (6) comparing the effects of a recently developed opiate antagonist (with increased activity at Kappa sites), its dextrostereoisomer and naloxone on outcome after traumatic spinal injury; and determining whether beneficial effects of opiate antagonists are mediated by stemic actions or through local effects in the spinal cord. Taken together, the proposed studies address the hypothesis that a specific endogenous opioid (dynorphin), acting through a specific opiate receptor (Kappa-receptor), mediates certain pathophysiological consequences of spinal cord trauma. Such findings, if demonstrated, would serve to enhance understanding of the mechanism of secondary spinal cord injury and suggest more effective forms of pharmacological therapy.
