TRANSLATIONAL MODEL FOR NOVEL THERAPEUTICS IN SPINAL CORD INJURY PAIN

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DESCRIPTION (provided by applicant): Chronic pain is a frequently debilitating and poorly understood consequence of spinal cord injury (SCI). In addition to reduced quality of life, the presence of untreated pain can interfere with the ability to fully participate in rehabilitative strategies, thus reducing potential long-term gains in functional recovery. SCI pain is notoriously difficult to treat, and the complexities of available animal models impede the rapid identification and screening of promising pharmacotherapies and novel interventive strategies. The goal of this exploratory/developmental R21 proposal in response to PA-06-542 (Mechanisms, models, measurement, & management in pain research) is to develop a strong predictive model to streamline this process and facilitate translation of promising therapies more rapidly to the clinic. Our laboratory is exploring a spinal compression injury model which can overcome the complications of other SCI pain models, particularly for below-injury neuropathic pain. Preliminary findings demonstrate robust and persistent reproducible SCI pain symptoms. Thus, the spinal compression model offers an opportunity to generate a rapid screening formula for evaluating the effects of clinically relevant analgesic drugs and novel therapeutics. The primary objectives will be: 1) To characterize the compression injury model for use in rapid screening for SCI pain, using a battery of evoked and spontaneous outcome measures; 2) To develop a model incorporating these behavioral outcomes using agents that are already approved and readily available for clinical use; 3) To utilize this rapid screening model for evaluation of potentially synergistic combination strategies and serve as guidance for achieving substantial improvement in the management of chronic SCI pain. Initially, clinically approved pharmacologic agents will be evaluated, as they are likely to have untapped potential efficacy in reducing SCI pain, particularly when administered in selected and synergistic combinations and, since they face fewer regulatory hurdles, can be more rapidly brought to patients. Since patients experience a constellation of symptoms, evaluation will include tests for mechanical allodynia, heat hyperalgesia, cold hypersensitivity, and ongoing spontaneous pain (Aim 1). A model will be developed for selection of promising agents, based initially on efficacy in reducing these various neuropathic pain symptoms, and incrementally adjusted as data is collected (Aim 2). Potential novel synergistic combinations will be done using isobolographic analysis (Aim 3). The co-administration of agents with distinct mechanisms should allow them to be given in substantially lower doses with reduced untoward side effects, and can result in potent analgesia with subeffective or marginally effective doses of individual agents. If successful, the development of this approach should rapidly accelerate the process of bringing effective analgesic therapies, including novel interventive strategies, to SCI patients with chronic pain. Project Narrative: Following spinal cord injury, many patients suffer from long-lasting pain, which can be severe and debilitating, and limit participation in rehabilitation programs, resulting in poorer prognosis and reduced functional recovery. Pharmacological options for patients with SCI pain are limited and marginally effective in current practice, and thus SCI pain is notoriously difficult to treat. The goal of the proposed studies is to develop and implement a predictive and efficient model for rapidly screening and translating promising analgesic therapies to markedly improve the treatment of clinical spinal cord injury pain.