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Proposed NIH Blueprint for Neuroscience Research Initiative (2011)

NIH Blueprint for Neuroscience Research: Collaborative Approaches to Study the Mechanisms Underlying the Transition from Acute to Chronic Neuropathic Pain (R01)
The overall goal of this FOA is to harness what has been learned about neural plasticity in other, related scientific disciplines and apply it to current pain research endeavors. An expansion of the pool of investigators is necessary to bring additional expertise in neural plasticity and cutting edge technologies into the pain field.

The objectives of this Initiative are to: 1) facilitate the partnering of non-pain neuroscientists with pain scientists - the study of neurobehavioral transitions in addiction, depression, cognitive decline, and tinnitus may share common features with maladaptive transitions in pain and knowledge garnered from these studies can contribute to our understanding of altered neural signaling in chronic pain; and 2) develop a detailed molecular, cellular, and systems level understanding of the neurobiological basis of the transition from acute to chronic pain. In this regard it is critical to understand the mechanisms underlying the neuroplasticity mediating the increased sensitivity to noxious and innocuous stimuli and the amplification of pain signaling in chronic pain patients.

The NIH Blueprint for Neuroscience Research
This is an initiative of the NIH Blueprint for Neuroscience Research. The Neuroscience Blueprint is a collaborative framework through which 16 NIH Institutes, Centers and Offices jointly support neuroscience-related research, with the aim of accelerating discoveries and reducing the burden of nervous system disorders. Each Blueprint Institute contributes a percentage of its neuroscience-related budget to a common pool of funds in order to support multi-year Initiatives. The NIDCR is the lead Institute for development and implementation of this Initiative.

Scope/Magnitude of the Problem
Pain conditions are a major health problem in the US and their economic burden approaches $100 billion per year in lost productivity and medical expenses. These conditions lead to medical morbidity and a reduced quality of life for millions of Americans. Several chronic painful disorders are of major interest to the NIH Neuroscience Blueprint Institutes and encompass a set of disorders affecting everyone from pediatric to geriatric populations. Chronic neuropathic pain conditions are especially difficult to treat. Current therapies for these conditions may lead to drug dependence and tolerance, and some also have abuse potential. For many patients, available therapies are minimally effective, if at all.

We currently have a relatively incomplete understanding of the etiology and pathology of chronic neuropathic pain conditions. NIH supported research is addressing the mechanisms of acute nociceptive responses after nervous system damage. A largely unaddressed challenge is our lack of knowledge in determining who will transition to a chronic pain state and how to treat patients to prevent this transition. There is a need to understand, mechanistically, how pain changes from an acute, high threshold, protective response to a chronic, low threshold, and spontaneous dysfunctional behavior. While most researchers believe that the transition from acute to chronic neuropathic pain is the result of maladaptive plasticity in the nervous system, we do not fully understand how acute pain progresses to chronic pain at any level, from the molecular to systems.

The study of neuroplasticity in other neuroscience disciplines has advanced rapidly. Our understanding of the molecular and cellular mechanisms surrounding normal adaptive responses and maladaptive changes in cognition, neurodevelopment, and the stress response has increased. Neuroscientists have a detailed knowledge of synaptic plasticity changes in the hippocampus that lead to long-term memory formation. The mechanisms underlying the induction and maintenance of long term potentiation and long term depression have been extensively studied, not only in the hippocampus, but in other brain regions including the cerebellum, striatum, and amygdala. The close linkage between the neuroplastic changes that are induced by chronic stress and the reversal of these changes by antidepressant drug therapy has been extensively studied by neuroscientists studying mood disorders. These discoveries have been aided by the application of novel molecular, electrophysiological, imaging, and genetic technologies. There is an opportunity for neuroscientists in these related fields to apply their expertise, techniques, and extensive knowledge of neuroplasticity to pain research. Our understanding of the neuroplastic changes that occur in the dorsal horn of the spinal cord and in the brain when patients transition to a chronic pain state will be enhanced by the participation of these researchers in chronic pain studies.

Gaps in Our Knowledge
The overriding concern is that current research is not focused on understanding how chronic pain emerges from an acute painful event or a pain-free state. Most basic research has focused on mechanisms, molecules, and circuitry involved in acute pain or after chronic pain has been established. While results from studies of acute pain may be suggestive of events leading to chronicity, they only give an initial snapshot without providing the trajectory of subsequent events. Results from studies of chronic pain describe the end result and not the pathway to reach chronicity. Likewise, clinical research is performed in acute pain conditions, in models where ongoing pain is measured, or where evoked responses to noxious stimuli are used as measures of pain. Other clinical trials are performed on patients with previously established chronic pain and focus on symptom reduction. Thus, the current basic and clinical research focus is on studies before and after neuropathic injury has developed into a chronic pain condition but has not been centered on how this transition occurs. In many respects the maladaptive changes in the nervous system established at the transition leading to persistent pain represent a disease state of the nervous system and provide our best opportunities to prevent the induction of chronic pain.

Effective treatment of chronic neuropathic pain is a major unmet need. In addition, there are no means to identify which patients will transition from acute to chronic pain and conversely which ones are protected from developing chronic pain. Although temporal changes are being explored, their implications for the transition to chronic pain are not a research priority. Several therapies that are currently used or in development for neuropathic pain target very different aspects of pain pathways including ion channel blockade, neurotransmitter reuptake inhibition, neuroimmune modulation, monoamine regulation, enhancers of neuronal inhibition, and kinase/phosphatase regulation. While these therapies reduce symptoms, they are not targeted at preventing the transition to chronic pain. The unmet need that must be addressed is the effective diagnosis, prevention, and treatment of chronic pain. In order to begin to meet this need an emphasis on research at the transition from acute to chronic pain is critical to understand how nervous system changes during this period of time lead to chronic pain. By changing the research focus, we will be able to support research to predict who is at risk of developing chronic pain conditions and to develop novel therapies to prevent the transition to chronicity. It is time to redirect the current focus of basic, translational, and clinical research from mechanisms of acute pain to the maladaptive neural plasticity changes that occur in the transition to a chronic pain state.

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This page last updated: February 26, 2014