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This paper is the introduction to the following papers, which were presented at the National Academy of Sciences colloquium “The Neurobiology of Pain,” held December 11–13, 1998, at the Arnold and Mabel Beckman Center in Irvine, CA.

The neurobiology of pain

R ONALD D UBNER * AND M ICHAEL G OLD

Department of Oral and Craniofacial Biological Sciences, University of Maryland, School of Dentistry, Baltimore, MD 21201

This is a very exciting time in the field of pain research. Major advances are occurring at every level of analysis, from development to neural plasticity in the adult and from the transduction of a noxious stimulus in a primary afferent neuron to the impact of this stimulus on cortical circuitry. The molecular identity of nociceptors, their stimulus transduction processes, and the ion channels involved in the generation, modulation, and propagation of action potentials along the axons in which these nociceptors are present are being vigorously pursued. Similarly, tremendous progress has occurred in the identification of the receptors, transmitters, second messenger systems, transcription factors, and signaling molecules underlying the neural plasticity observed in the spinal cord and brain stem after tissue or nerve injury. With recent insight into the pharmacology of different neural circuits, the importance of descending modulatory systems in the response of the nervous system to persistent pain after injury is being reevaluated. Finally, imaging studies have revealed that information about tissue damage is distributed at multiple forebrain sites involved in attentional, motivational, and cognitive aspects of the pain experience.

These major advances in pain research were the subject of a National Academy of Sciences colloquium entitled “The Neurobiology of Pain,” held at the Beckman Center of the Academy in Irvine, California on December 11–13, 1998. The meeting was organized by John Liebeskind (deceased), Ronald Dubner, and Michael Gold. Its purpose was to bring together pain research scientists and those in related fields who have made recent major advances in the development, cellular, and molecular biology and integrative neurosciences related to the neurobiology of pain. The colloquium was organized into six sessions, each with a separate theme: channels, receptors, imaging and systems neuroscience, growth factors and cytokines, development and plasticity, and molecular genetics. There was ample opportunity for the discussion of the most fruitful and exciting lines of research and the identification of important future directions. One hundred and sixty scientists attended the colloquium. We are indebted to Glaxo Wellcome, Inc. for its generous support that helped defray the expenses of graduate students and the social events, as well as to Fran Addison for her invaluable assistance in the organization of the colloquium.

This colloquium was held because of John Liebeskind’s commitment to the study of pain. Elected to the Academy after more than 20 years of pioneering research in the field, John always maintained that a critical component to progress in this or any field was a forum in which leaders in the field could assemble to discuss recent advances and future directions. Given the tremendous advances that have occurred in the field of pain research over the last decade, John felt that a colloquium held under the auspices of the Academy would be both timely and appropriate. Over two years ago, he approached us and asked that we help him organize this colloquium. Soon after the program was approved and the date was set, John learned that he had terminal cancer, and he died in September, 1997. He would have been very pleased by the depth and breadth of research covered as well as the lively interactions of all the participants. While John was remembered by many of the speakers, Greg Terman, one of his former students, delivered a moving and informative tribute ( 1 ).

The colloquium got underway with a spirited discussion of the role of ion channels in peripheral nerve, particularly their expression in nociceptors. Researchers have long since appreciated that, in the presence of injury, nociceptors may become hyperexcitable. A change in the expression of ion channels is one mechanism that may contribute to this hyperexcitability. Steve Waxman ( 2 ) summarized data from an elegant series of experiments indicating that sodium channel expression in dorsal root ganglion neurons is dynamic, changing markedly after tissue or nerve injury. Importantly, different forms of injury induce different changes in the expression of sodium channels. For example, nerve injury in the form of axotomy results in a decrease in the expression of tetrodotoxin (TTX)-resistant currents and an increase in a rapidly repriming TTX-sensitive sodium current. In contrast, inflammation results in an increase in the expression of TTX-resistant sodium currents and a decrease in the expression of a TTX-sensitive current. Utilizing a different nerve injury model than that employed by Waxman and colleagues, in combination with antisense oligodeoxynucleotides, Frank Porreca ( 3 ) presented evidence indicating that a TTX-resistant sodium channel called SNS/PN3 is critical for the initiation and maintenance of nerve injury-induced hyperalgesia and allodynia. In contrast, NaN, another TTX-resistant sodium channel recently identified by Waxman and colleagues ( 4 ), does not appear to contribute to the maintenance of nerve injury-induced changes in nociceptive thresholds. Michael Gold ( 5 ) reported on the role of the TTX-resistant sodium currents in inflammation and showed that the current is modulated by inflammatory mediators such as prostaglandin E2, 5-HT, and adenosine, consistent with its role in peripheral sensitization. Gold provided additional data indicating that TTX-resistant channels are not only present and functional in the peripheral terminals of nociceptors, but that modulation of these channels contributes to prostaglandin-induced mechanical hyperalgesia. Daniel Weinreich ( 6 ) switched the focus of the discussion to other channels by addressing the role of a calcium-dependent potassium current in controlling the excitability of vagal afferents. Through a beautiful series of experiments, Weinreich was able to assess the relative contribution of various sources of calcium responsible for the gating of the potassium currents.

   

PNAS is available online at www.pnas.org .

   

Abbreviations: TTX, tetrodotoxin; NGF, nerve growth factor.

*  

To whom reprint requests should be addressed at: Department of Oral and Craniofacial Biological Sciences, University of Maryland, School of Dentistry, 666 West Baltimore Street, Room 5E-08, Baltimore, MD 21201.



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