FACIAL PAIN RESEARCH FOUNDATION 2013 RESEARCH PROGRESS
Compiled and submitted April, 2014 By Douglas K. Anderson, Ph.D. Eminent Scholar Professor and Chair Emeritus Department of Neuroscience, University of Florida College of Medicine, and Director of Research and Trustee, Facial Pain Research Foundation
Pain is the primary symptom causing individuals to consult their physicians resulting in pain-related health care costs exceeding $100 billion/year. Of these debilitating chronic pain conditions, trigeminal neuralgia (TN) is considered to be one of the most painful afflictions known to medical practice. TN is a disorder of the fifth cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric shock-like pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. It has been proposed that TN is thought to occur when the insulating myelin sheath of the trigeminal nerve is lost or damaged (demyelination) by the pulsations of an overlying blood vessel. There are other neuropathic facial pain syndromes sometimes called “Atypical Trigeminal Neuralgia” which are generally characterized by a less intense, constant, dull burning or aching pain, often with occasional electric shock-like stabs. The initial treatment for neuropathic facial pain conditions is usually with anti-convulsive and/or anti-depressant drugs. Should these medications be ineffective or produce undesirable side effects, neurosurgical procedures are available (at least for TN) to relieve pressure on the nerve or to reduce nerve sensitivity. However, in many patients (particularly those in which the pain is chronic), no current treatment is effective, either permanently or in the long term.
TN is an example of neuropathic pain which is defined as pain caused by injury to or disordered functioning of the nervous system. Despite the debilitating effects chronic pain (like that of TN) has on the activities of daily living of its victims and on the economics of health care, research funding from traditional sources (i.e., federal agencies and pharmaceutical companies) that specifically target identifying the underlying causes of neuropathic pain and developing long term treatments with minimal side effects has been and continues to be very limited. Thus, for about a decade, there has been the growing realization that if there is to be any real progress in discovering the genesis of and treatment for TN, it is going to have to be accomplished with funds raised from the private sector. To this end, The Facial Pain Research Foundation (FPRF) was created in January, 2011 to provide the critical elements that are necessary and sufficient to study these facial pain conditions. Accordingly, the sole mission of the FPRF is “…to establish a well-funded translational (i.e., fundamental discovery to clinical application) research continuum that is dedicated to identifying the mechanisms underlying neuropathic facial pain and to develop novel new therapeutic strategies that will permanently stop the pain of TN and related neuropathic pain syndromes”. Since its inception a little over three years ago, the FPRF has raised and committed approximately $650,000 to support four separate and distinct research projects. In funding these projects, the FPRF adhered to three criteria: (1) the projects were novel and unique; (2) the investigator(s) responsible for each project are among the leading researchers in their respective fields; and (3) all of the projects were not “cut from the same cloth”, i.e., there was significant diversification in the research strategies among the projects. The purpose of this review is to briefly summarize these four projects and some of the results that have been attained.
The Role of Defective Myelin in Trigeminal Neuralgia
Lucia Notterpek, Ph.D., Professor and Chair, Department of Neuroscience, University of Florida College of Medicine
The focus of Dr. Notterpek’s research is to: (a) assess the potential contribution of genetic defects in the insulating myelin sheath around nerves in generating the pain of TN; (b) identify sensitive biomarkers and behavioral (functional) tests that can accurately measure myelin damage in living animals and (c) use these criteria to develop an animal model of neuropathic pain. These are basic laboratory studies that uses animal (mice) models with defective myelin and compares them functionally, biochemically, and anatomically at different ages to mice with normal myelin. Behaviorally, Dr. Notterpek studies have shown that the sensitivity to a heat stimulus in mice with significant myelin defects is substantially more pronounced than in mice with normal myelin. Consistent with these behavioral findings, anatomical studies revealed abnormal branching of nerve terminals in the skin that these nerves grow into and biochemical assays of this tissue found significantly reduced myelin protein levels. The search for potential biomarkers in plasma has been more elusive because even in these genetically identical groups of mice, there is variability in the extent of myelin defects at given ages and in the sensory deficits displayed by individual mice. Consequently, more work is needed to identify sensitive biomarkers and behavioral assays that can accurately measure myelin damage in living animals which is prerequisite to developing a reliable animal model of neuropathic pain. These studies are currently ongoing in Dr. Notterpek’s laboratory and are supported by a grant from the National Institutes of Health (NIH) that she acquired based on the preliminary findings generated with support from the FPRF.
A Neural Signature of Trigeminal Neuralgia Pain
Andrew Ahn, M.D. Ph.D., Assistant Professor, Department of Neurology, University of Florida College of Medicine
The clinical picture of severe TN pain that is refractory to medication and which has reoccurred following surgical procedures that cause permanent loss of all sensation to the face suggests that even the early pain of TN initiates long-lasting, persistent changes within the brain that could be responsible for the long-term consequences of TN. Modern imaging techniques, such as EEG and functional MRI, have produced remarkable insights into a range of neurological conditions. These technologies could also provide better insight into the changes within the brain that are thought to take place in people with TN, and could enhance our ability to use existing therapies or prevent the long-term progression of TN. Unfortunately only a few preliminary studies have been directed at identifying the TN-induced changes in the brain and no studies have explored the possibility that the pain of TN leads to long-term alterations in the brain that perpetuate chronic TN pain.
The immediate goal of this recently initiated project is to obtain a neural signature, or “map” of brain in individuals with TN pain. If successful, these experiments should provide fundamental insights into the neurobiology of TN which would then be the foundation for identifying people at greater risk for developing intractable TN and for whom tailored therapy using new medications and/or drug-free options, such as neurostimulation and neurofeedback would provide effective and prolonged relief from TN pain. These findings could also be of relevance and future benefit to those with a range of neuropathic conditions in other body areas such as post-herpetic neuralgia, diabetic neuropathy, and neuropathy related to cancer chemotherapy.
Cell Replacement Therapy as a Treatment for Injury-Induced Neuropathic Pain
Allan Basbaum, Ph.D., FRS, Professor and Chair, Department of Anatomy, University of California San Francisco
It is well known that current treatment strategies to manage chronic pain are for the most part, unsatisfactory. However, recent studies from the laboratory of Dr. Allen Basbaum that were supported in part by the FPRF shows how cell replacement therapy might one day be used not only to quell some common types of persistent and difficult-to-treat pain, but also to cure the conditions that give rise to them.
Dr. Basbaum’s preclinical studies using mice are directed at treating neuropathic pain. As indicated earlier, neuropathic pain is purported to arise from injury to or disordered functioning of the nervous system. For example, other research has suggested that following injury, neurons in the spinal cord that normally release a pain inhibitory neurotransmitter may be lost or damaged, or neural circuitry in the CNS (central nervous system, i.e., the brain and spinal cord) may change in ways that negates signals that normally help dampen pain. This loss of mechanisms that normally reduce the transmission of pain messages to the brain can cause areas of the brain to become hyper-excitable. When the brain is in a hyper-excitable state, pain signals are enhanced and normally innocuous sensory stimuli can turn into excruciating pain.
Dr. Basbaum has taken the novel approach of transplanting immature precursor cells from the mouse brain that produce a pain inhibitory transmitter into the adult mouse spinal cord in order to raise the level of inhibitory input and block pain signals to the brain. A small fraction of the transplanted cells survived and matured into functioning neurons. The cells integrated into the nerve circuitry of the spinal cord, forming synapses and signaling pathways with neighboring neurons.As a result, pain hypersensitivity associated with nerve injury was almost completely eliminated. Dr. Basbaum is expanding his research in an attempt to discover other “…potential treatments that might eliminate the source of neuropathic pain, and that may be much more effective than drugs that aim only to treat symptomatically the pain that results from chronic, painful conditions.” These new studies are supported by a grant from the NIH that he acquired based on the preliminary findings generated with support from the FPRF.
Finding the Genes that Predispose to Trigeminal Neuralgia
Marshall Devor, Ph.D. (Project Coordinator) Professor and Chair, Department of Cell and Animal Biology, Institute of Life Sciences, Hebrew University of Jerusalem
Kim J. Burchiel, M.D. (Phenotyping and Sample Collection) Professor and Chair, Department of Neurosurgery, Oregon Health and Science University
Ze’ev Seltzer, Ph.D. (Genomics), Professor of Pain Genetics, Faculty of Dentistry; Professor of Physiology, Faculty of Medicine, University of Toronto
The remarkable progress made in genetic analysis in the past two decades of the Human Genome Project has greatly enhanced our capacity to discover genes associated with different diseases, to reveal their function, and to develop therapeutic and/or preventive approaches precisely targeted at the specific disease. This project asks the question: Are some individuals genetically predisposed to develop TN pain? This question emanates from research which shows that although 17% of mature adults have the TN lesion (usually a vascular compression of the trigeminal nerve close to where it exits the brain) only a very small minority (0.01%) of these individuals actually experience TN pain. This disconnect between lesion and pain is an important clue pointing toward a genetic predilection for TN.
This project was conceived with the assumption that the risk for getting classical TN has a genetic basis and has as its primary objective identifying genetic mutation(s) (aka, sequence variant(s) or polymorphism(s)) associated with the development of TN pain. To achieve this objective, DNA will be collected from 500 TN patients. Analysis of the whole genome will be carried out on these patients using the latest in genetic sequencing technology and compared to matched reference controls to determine if there are candidate sequence variant(s) or polymorphism(s) present in the genome of the TN patients that are not found in the controls. Such sequence variants might cause TN pain by directly affecting the function of the proteins that these genes encode, or by altering other aspects of gene expression. Either way, assuming that genetics is indeed the basis for developing TN, there is a high probability that this project will reveal the genes and ultimately the pathophysiological mechanisms that cause the lesions to be painful. With this knowledge molecular targets for treatments that will cure the pain can be identified not only of TN but perhaps also for a variety of other facial and segmental neuropathic pain conditions. To date, cheek swabs that will undergo genetic testing have been acquired from 92 professionally phenotyped TN1 patients. Phenotyping and collection of DNA samples from the first 100 TN1 patients will be done at OHSU. Preparations are underway for the sequencing these initial 100 samples with the actual sequencing scheduled to begin in 30-60 days. The remaining 400 samples will be collected from eight other sites (50 samples per site) in the USA, Canada, and England.