Peripheral nerve or spinal cord injuries can result in pain states characterized by sharp spontaneous noxious sensations (dysesthetic pain) or pronounced pain generated by low threshold mechanical stimulation (allodynia). Such pain states are frequently observed after trauma (as in the vicinity of a bullet wound or a bone fracture), intentional surgical resection (as with thoracotomies or post mastectomy) or in states of chronic compression (as with a tumor). These states are associated with clinical syndromes, such as causalgia and reflex sympathetic dystrophy. Though controversial, these syndromes frequently are comparatively less sensitive to conventional analgesic therapies, such as opiates. Pre- clinical studies have revealed comparable changes in sensitivity following peripheral nerve compression injuries and with protracted afferent input (as with the injection of formalin into the paw). Importantly, in a wide variety of studies it has been shown that these allodynic and hyperalgesic states are mediated by spinal glutamate receptors of the N-methyl-D- Aspartate (NMDA) type. Thus, even in neurogenic pain models where opiates have little effect upon the allodynia, there is a powerful suppression produced by the spinal delivery of NMDA. These observations form part of a very large convergent body of literature convincingly showing a prominent role for spinal glutamate release and a subsequent action at NMDA receptors in mediating these anomalous pain states evoked by otherwise innocuous stimuli. Given these parallels, it is appropriate to consider the role of NMDA receptor antagonist in pain states that are poorly controlled, if at all, by other therapeutic modalities. Because NMDA antagonists have unacceptable supraspinal actions (dysphoria, loss of organized thinking processes), and because the prevailing data emphasizes the role of the spinal NMDA receptor, it is necessary to consider the spinal delivery of these agents in man. No agents of this class currently exist which have been appropriately examined for safety to allow their spinal delivery in man. We have chosen to examine three agents: ketamine, dextrorphan and memantine which bind to the NMDA channel; which have been shown to have antinociceptive actions in allodynic pain models and which are available commercially as GMP preparations. Using two well defined models (rat and dog) for chronic spinal drug delivery, we will examine the spinal toxicology of these agents. Specifically, in rats, we will examine the effects of daily repeated intrathecal injections of these agents on behavior and histopathology; and determine the effects on spinal cord blood flow. In dogs, we will examine the effects of 28 days of continuous intrathecal infusion of two of the three NMDA antagonists on behavior and histopathology; and, define the kinetics of the intrathecally delivered drugs. These studies will provide the essential basis for supporting subsequent studies examining the effects of spinal NMDa antagonists in human pain states that reflect therapeutic dilemmas.
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