Endogenous opioid systems seem to have both neurodestructive and neuroprotective roles in CNS injury. Whereas mu and kappa 1 receptors appear to mediate neuroprotective actions, kappa 2 receptors may be involved in secondary injury responses. Among the endogenous opioids, dynorphin has marked neurotoxic effects when given intrathecally to rats; when administered in subinjury doses, dynorphin exacerbates the response to brain or spinal cord trauma. Because of the neurotoxic effects of dynorphin, one should employ this compound with great caution in human studies of addiction treatment. It has not been established which endogenous opioids might be protective. Taken together, these observations may suggest novel approaches to the treatment of CNS injury using selective mixed opioid agonist-antagonist compounds such as buprenorphine.