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Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010.

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Translational Pain Research: From Mouse to Man.

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Preface

The progress and remarkable expansion of pain research in the past decade prompted Taylor & Francis executive Barbara Norwitz to inquire about a new edition of their now decade-old Methods in Pain Research. The query was serendipitously timed to coincide with a highly successful session at the 2007 Spring Brain Conference in Sedona, Arizona, at which Jeff Kennedy had organized a session presenting the progress and ideas driving a burgeoning expansion of research programs in the pharmaceutical industry, focusing on translational aspects of pain research. Despite the general dominance of scientific meetings by researchers in academia, the impact of Big Pharma revealed a trend presaging a new era in which the practical consequences of basic research at the level of molecular biology was becoming relevant to clinical aspects of pain therapy and control. The industry refers to such studies as preclinical. While methodology continues to advance, and some spectacular new twists have emerged in the past decade, the gradual shift to “translation” of basic science knowledge to its applications relevant to the human condition appears to have become an important trend in pain research.

Translation in modern biomedical parlance seems approximately equivalent to applied—and not necessarily from animals to humans, because the reverse can occur. The earliest attempts at uncovering cerebral localization by producing focal cerebral lesions in dogs were published by the French military surgeon Francois Pourfour du Petit in 1710, based on post-mortem observations of head wounds and related neurological deficits in soldiers—something akin to a “retrograde translation.” Surprisingly, the earliest prominent example of translation that we have uncovered does not employ the word but expresses the concept—the discovery by Edward Jenner that cowpox could provide a vaccine to protect humans from the serious rampant scourge of smallpox in the late 18th century.

A congratulatory letter to Jenner from Thomas Jefferson (from the University of Virginia Archive) reveals the following unexpected judgment:

A TRIBUTE OF GRATITUDE

To Dr. Edward Jenner from Thomas Jefferson,

Monticello, May 14, 1806

SIR, I have received a copy of the evidence at large respecting the discovery of the vaccine inoculation which you have been pleased to send me, and for which I return you my thanks. Having been among the early converts, in this part of the globe, to its efficiency, I took an early part in recommending it to my countrymen. I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility. Harvey’s discovery of the circulation of the blood was a beautiful addition to our knowledge of the animal economy, but on a review of the practice of medicine before and since that epoch, I do not see any great amelioration that has been derived from that discovery. You have erased from the calendar of human afflictions one of its greatest. Yours is the comfortable reflection that mankind can never forget that you have lived. Future nations will know by history only that the loathsome small-pox has existed and by you has been extirpated.

Accept my fervent wishes for your health and happiness and assurances of the greatest respect and consideration.

The devastating demise of a huge proportion of the Native American population, totally lacking in immunity to smallpox, as well as the protection of many of the English settlers, enabled Jefferson to easily recognize the profound importance of “translating” observations from cows to human welfare. But contrasting that with the seemingly less important understanding of the circulation of blood derived from William Harvey’s observations might surprise modern scientists who recognize the profound importance of the inductive empiricism embodied in the scientific method developed by Harvey—the foundation of modern medicine. Two centuries later the long-term value of basic science is evident in its enormous governmental financial support. The practical payoff of translation is a relatively recent phenomenon, turning threat to promise.

The study of pain is of enormous human importance for the obvious reason that in the course of a lifetime, few individuals manage to evade disruption of their lives by consequential pain experiences. Pain is the most common clinical complaint for which people seek medical care. While it can be described as a sensation, it is sensu stricto, a response to a variety of stimuli, including some that are ordinarily innocuous and often unrelated to any detectable stimulus or visible sign of an inflammatory process. Pain behaviors are widely known in such diverse inflammatory diseases as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and liver disease, but they are also in central nervous system (CNS) diseases such as multiple sclerosis. This book begins with a valuable and original systems approach to the organization of a “systems” approach and then moves on to the details of new information on nociceptor sensitization from the Koerber lab, visceral afferents in disease (Davis lab), and the innovation of a rodent model of bone cancer pain from the Mantyh laboratory providing an explicit pain model, easily equated with similar disease associated with considerable human suffering and leading to remarkable recent progress in treatment of cancer pain derived from animal experimentation.

We have only recently begun to identify insight into the signaling cytokines and the involvement of CNS microglia and their role in recruitment of monocytes in pain syndromes, and we are fortunate in presenting contributions from the laboratories of De Leo and of Shubayev, sources from which key knowledge has been derived by employing animal models. Similarly, the elusive, devastating fibromyalgia syndromes studied in the Light laboratories reveal the validity of exploiting animal models for translation to pain responsible for high-incidence human suffering, and a review by McCord and Kaufman provides original insights and practice in this field.

Several chapters in this book address new technical advances in areas that were dormant or nonexistent in the previous Methods in Pain Research volume in this series. These are largely based upon advances in molecular biology found in most of the contributions, but also include exceedingly important advances in tract tracing from the Basbaum lab, new detailed descriptions of visceral pain innervation (Davis lab), an account from the Spigelman lab of the significance of endocannabinoids, as well as cannabis as a therapeutic agent, the current state of advances in gene therapy for pain and the promise of siRNA gene knockdown (Nishimura lab), and some unexpected very recent discoveries about the role of P2X receptors and ATP from Khakh and his colleagues that presage important strides in human therapy. With the discovery of the capsaicin receptor and a specific ion channel related to cardiac pain, it has been anticipated that the tools of molecular biology will lead to broadly available new therapeutics and better understanding of relevant genetic implications, but this has not yet been fully realized despite realistic high hopes.

We are now at a crossroad, with methodologies derived from animal experiments that can impinge upon and perhaps profoundly alter human suffering. Somewhat surprisingly, we have also reached an intersection where methods of studying pain in humans are providing guidance for study of experimental animals where such reciprocity can generate unexpected new insights, such as a new understanding of the “thalamic pain” derived from recent brain-imaging studies from the Llinas laboratory. Critical commentaries from the Apkarian and Greenspan laboratories as well as others active in brain imaging should provide valuable guidance in how to interpret what the imaging methods can and cannot tell us about the localization of brain mechanisms underlying pain.

It should be noted that the emphasis of this volume is directed toward what we consider the noble enterprise of addressing the relief of human suffering in a field of scientific endeavor that must be carefully and sensibly scrutinized to avoid cruelty and needless suffering in experimental subjects. We here must reiterate the admonition introducing the prior Methods volume—"it is … the responsibility of pain researchers to define their aims and to weigh carefully the ethical, legal, and political consequences of pain research with an enthusiasm that matches their desire to understand and control pain for its obvious human benefit.” Myriad experiments of enormous importance in gaining insight into molecular mechanisms relevant to pain are based on mouse models that do not exist in nature but are manufactured (i.e., literally man-made) by laboratory scientists for the sole explicit purpose of understanding the biological mechanisms essential to our existence. It should be noted that pain research is regulated by federal and state statutes, as well as by serious, dedicated local committees at each research institution. Experimental protocols are designed to narrowly restrict the duration and magnitude of noxious stimuli or to avoid conditions of ascertainable misery. It is the special responsibility of pain researchers to reach out to critics of their endeavors, especially the anti-vivisectionists and animal rights advocates, to persuade them to comprehend that analyzing pain and its deleterious consequences in all animals, but especially the increasingly populous human species, is an enterprise worthy of their support and tolerant understanding.

There are other societal issues of perhaps greater concern because historically the suffering of pain has been largely controlled by opiates; potent drugs that are addictive, controlled illegal substances that constitute the lifeblood of a criminal underworld, the magnitude of which exceeds that of most large industries, and whose impact undermines national interests globally. The economic consequences of unregulated trade in illicit drugs heavily impacts attempts to reorganize the fiscal structure and availability of health care in almost every country. Public policy worldwide concerning pain therapy sometimes succumbs to assertion substituting for reasoned ideas. This year, a leader in clinical testing of pain medications admitted to being variously motivated to certify experimental medications and admitted to numerous publications based on faked data requiring withdrawal from anesthesiology and pain journals while some of these substances remain on the market. We are particularly pleased to present several thoughtful articles from Big Pharma in this volume. The pharmaceutical industry has proven remarkably sensitive to the difficulty and high cost of bringing new medications to the licensing stage in a world that is struggling with the concept of controlled substances, including several crucial for pain control. Despite the exigencies of mergers and acquisitions and the seemingly erratic rules imposed by controlling federal and state agencies, leadership in setting standards for thoughtful, caring use of large animals in pain research and most importantly, clinical human trials of medications derived from animal experimentation, have proceeded with sensitive restraint and concern for human welfare. We are particularly indebted to Jeff Kennedy for leadership in organizing the three insightful papers in this volume outlining the key role of pharmaceutical companies in rendering this subject truly susceptible to translation. We have omitted the various surgical and nerve block procedures in common use today, as well as nontraditional therapies, for practical reasons but also because these modalities have proven less amenable to the translational theme.

Other modalities of pain control are also subject to regulation and perhaps social structure changes susceptible to policy modification; for example, the role of cannabinoids or exotic employment of hypnotic states. Although this volume does not pretend to properly address such issues of social policy in medicinal treatment, it attempts to recognize and promulgate the importance of the legitimate, worldwide pharmaceutical industry. Unfortunately, pain is one end of a hedonic spectrum whose opposite end is exquisite pleasure—and often susceptible to crippling addiction. Thus, it is the aim of translational pain research to alleviate human suffering from pain without substituting the dangerous, deleterious consequences of drug addiction. This volume attempts to bring attention to the present status of recent strides in bringing laboratory science (much of it at the molecular level) to our understanding of pain phenomena in humans, with the ultimate goal of reducing the suffering that often accompanies pain and its indirect consequences.

Copyright © 2010 by Taylor and Francis Group, LLC.
Bookshelf ID: NBK57256

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