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Converging Pathways of Pain Research at NIDCR

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Table of Contents

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Pain - Beginnings of Pain Research at NIDCR - This page
- and the Dentist
- Pain Ron Dubner and the "Lone Rangers"
Pain - A New Multi-Disciplinary Unit
Pain - Behavioral & Neural Responses to Pain
- The Monkey's Informed Choices
- Findings from the Behaving Monkey Studies
Pain - Testing Old and New Drugs for Pain
- Differential Measurement of Pain Perception
- Testing Old and New Drugs for Pain
Pain - A Laboratory Model For Clinical Pain
Pain - The Biochemistry & Genetics of Pain
- Mapping the Spinal Cord
- The Dynorphin Connection
- Future Directions
Pain - Epilogue
Pain - Exhibit Index

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Table of Contents

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Introduction

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Pain is a universally known and feared human condition, yet surely it is one of the least understood. Within this century it has been a philosophic problem, an enigma of neurophysiology, a psychological puzzle, a challenge to anesthesiologists, oncologists, nurses, clinicians of all kinds; and much of what we now think we know about pain still seems contradictory and paradoxical.

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Painting Image Modified
Here is another puzzle: how did the most versatile and productive pain research unit at NIH establish itself in the National Institute of Dental Research?

Pain and the Dentist

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The story begins in the late 1950s in the dentist's office. The mass screenings of the World Wars had revealed the failure of many Americans to seek regular dental care and the disastrous consequences that followed. The American Dental Association, the National Institute of Dental Research (NIDR; renamed the National Institute of Dental and Craniofacial Research (NIDCR) in 1999), and other authorities actively promoted regular dental visits, especially for children. But increased numbers of visits only pointed to the underlying problem: many Americans associated dentistry with pain and faced each appointment with dread.

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Photograph of Edward Driscoll Edward Driscoll

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Seeking to alleviate patient fears, dentists offered general anesthesia for many routine procedures.

It is estimated," NIDR researcher Edward Driscoll wrote in 1960, "that in many parts of the country...there are nearly as many general anesthetics administered in dental offices as there are in the local hospitals."
–NIDR Annual Report, 1960

But this well-meant practice drew fire from anesthesiologists and health authorities, on several grounds. Dentists, even oral surgeons, rarely had formal training in anesthesiology or experience with many of the new agents introduced in the 1950s and 1960s. Even if they had, it was often impossible for one person both to perform the operative procedure and to monitor the patient's physiological status. The difficulty of monitoring was further complicated by the lack of information about the side effects of such new agents as sodium pentothal and sodium methohexital -- a particularly dangerous ignorance in light of the fact that patients generally left the dentist's office within an hour after the procedure. For all these reasons, dental anesthesia was condemned as unsafe, although there were few documented cases of patient injury.

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A graph illustrating a cycle of fear and pain. Clinical pain leads to a painfuldental therapy, followed by postoperative pain and apprehension to avoidance of dental care, which leads to dental pathology and clinical pain
Cycle of Fear and Pain. From Raymond A. Dionne, Pain Control in Dentistry: The Basis for Rational Therapy. Compendium of Continuing Education in Dentistry v. 6 (1985): 16.

Problems with general anesthesia in dentistry, 1960
Lack of training and experience
Lack of staff
Lack of data about agents used

Edward Driscoll of NIDR's¹ Oral Medicine and Surgery Section began conducting studies of dental anesthesia in 1957. His aims were: to establish the necessary baseline physiological data; to evaluate the effects of stress on the dental patient; and to find the best methods of alleviation. With his associates, he performed full mouth extractions on more than 1200 patients, and collected readings for pulse, blood pressure, respiration, arterial oxygen levels, EEG, and EKG. Edward Driscoll. Photograph courtesy of NIDCR Public Information Office.

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Ron Dubner and the "Lone Rangers"

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In 1964, Ronald Dubner returned to NIH from the University of Michigan. Dubner had worked in the Clinical Center from 1958 to 1961 as a young Dental Officer in the Commissioned Corps; there he had discovered his interest and talent for research, and successfully applied for NIH support for his Michigan doctoral studies in neurophysiology. Seymour Kreshover , Scientific Director of the Institute, was a major supporter of the young researcher and his plans to establish a basic neuroscience laboratory at NIDR.

Dubner set up his lab in the basement of Building 30 and hired Fred Brown, a young electrical engineer, to put together the physiological recording apparatus he needed. He began recording from nerve cells in the brain and the trigeminal nucleus that are excited by visual and auditory stimuli.

How did he relate these studies to the mission of the Dental Institute? Through the problem of dental pain. Dubner argued that an understanding of the mechanisms of pain, and the development of methods for its management and control, had to be based on a thorough knowledge of how sensory information was processed. His early work showed that the first central relay nucleus in the trigeminal system was the site of significant modifications of sensory information; and that the association cortex in the brain was possibly the site where multiple sensory inputs converged.

The trigeminal system is the medullary section of the spinal dorsal horn which processes sensory information from the face and cranium.
Dubner's was among the very first research projects to accept the challenge laid down by Melzack and Wall's gate control model (1965) to describe the complex sensory, cognitive, and affective components of clinical pain as physically embodied in an interactive nervous system.

There were several other basic scientists working in Building 30 at the time: Bruce Dow and Barry Sessle in Dubner's lab; Steve Gobel a neuroanatomist who was interested in electron microscopy studies of the trigeminal system; and a group of microbiologists. When Kreshover became Director of NIDR in 1966, Richard Gruelich , the new Scientific Director, decided to build a basic science unit around these "lone rangers", which was named the Physiology Section. The following year, Gobel, Dubner, and his team were separated from the microbiologists and designated the Neural Mechanisms Section.

Dubner and his collaborators had demonstrated by 1969 that both ascending nerve fibers from the skin and descending fibers from the brain were synaptically connected to the dorsal horn of the spinal cord (the nucleus caudalis, or the "nerve center" of the trigeminal system). This connection suggested the presence of "a rapidly conducting feedback loop", which could act to enhance or alleviate information about sensory stimuli.

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A graph showing the gate control model of pain
The Gate Control Model - Reprinted by permission - Ronald Melzack and Patrick Wall, Pain mechanisms: a new theory. Science v. 150 (1965): 975. Copyright AAAS , http://www.sciencemag.org

Photograph of Seymour Kreshover

Seymour Kreshover

Photograph of Patrick Wall and Ronald Melzack
Patrick Wall [l] and Ronald Melzack [r]

Photograph of Ron Dubner, Barry Sessle, and Eigld Moller
Ron Dubner [l] and Barry Sessle [r] with colleague Eigild Moller at International Association for Dental Research, mid

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A New Multi-Disciplinary Unit

At this point, Dubner decided that he needed to "pick the brain" of a leader in the field and arranged a year's sabbatical at University College London with Patrick Wall (1970-71). He returned from London to an expanded and growing Section. Rhyuji Sumino had arrived from Japan to begin several years of collaborative work; he would soon be joined by Donald Price and Jimmy Hu . NIDR was reorganizing both its intramural and its extramural programs; as part of this initiative, Ed Driscoll played a key role on the Institute's Ad Hoc Advisory Committee on Pain Control (1971-72).

The first major result of the Committee's recommendations was the creation in 1973 of a new extramural program for Pain Control and Behavioral Studies, under the leadership of Aaron Ganz . NIDR's extramural support provided crucial support for the International Symposium on Pain held in Issaquah, Washington, in May 1973, which led to the formation of the International Association for the Study of Pain and the founding of its journal, Pain.

John Bonica, organizer of the Issaquah meeting and the "godfather" of the multidisciplinary pain field, used NIDR grants to support his broad-based pain research program at the University of Washington. In a letter to Aaron Ganz in 1979, he noted that: "NIDR has the best record of supporting pain research [of all the Institutes]."3

The other major outcome of the NIDR reorganization was the formation of the Neurobiology and Anesthesiology Branch (NAB) in 1974, a new unit incorporating Ron Dubner's basic science work with a reactivated program to improve dental anesthesia and analgesia. John Bonica wrote in 1980 that the NAB had proven to be "one of the most productive groups of pain researchers in the world." 4

The remarkable productivity stems from the conjunction of these two events: the formation of a new pain research unit around the core group established by Dubner and the consensus reached at Issaquah that the study of pain required a multidisciplinary approach.

Most previous physiological research had treated pain as a problem in sensory perception, based on specific "hard-wired" nerve structures and mechanisms which could be isolated in the laboratory. The more complex model of Bonica, Wall, and Melzack described pain as a dynamic phenomenon of an organism reacting to the environment, or, as Bonica had written in 1953, "the compound result of physiopsychological processes whose complexity is almost beyond comprehension."5

Influenced by these three pioneers, Dubner visualized a program which would integrate electrophysiological and neurocytological studies of the trigeminal neural system with behavioral experiments in animals, and with clinical and psychophysical assessments of pain in human subjects.

Photograph of the Neurobiology and Anesthesiology Branch, 1979

The Neurobiology and Anesthesiology Branch, 1979
The Neurobiology and Anesthesiology Branch
A Multidisciplinary Research Program:
electrophysiology
neuroanatomy
neurochemistry
animal behavior
clinical pharmacology
psychophysics
For more information on the history of the pain field, see: "The Relief of Pain and Suffering" (an online exhibit).

For more information on the American Pain Society: www.ampainsoc.org

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John Bonica at the podium.

The Monkey's Informed Choices

The awake behaving monkey experiments were among the most important undertaken by the Neurobiology and Anesthesiology Branch at NIDR in the 1970s and 1980s. These were real time observations of the ways in which an animal processed, reacted to, and acted on complex environmental information, including a noxious stimulus (a contact thermode placed near the lip), while microelectrode recordings were taken of the neuronal activity in the trigeminal brainstem. Originally designed by Ron Dubner and Ralph Beitel, the behavioral studies continued through several generations of postdocs and lab workers, including Catherine Bushnell, Gary Duncan, Ron Hayes, Donna Hoffman, Daniel Kenshalo, William Maixner, and Jean-Marie Oliveras .

Essential to the project were Fred Brown's skills and almost tactile sense of electronics, which enabled him to design and build the specifically configured equipment the researchers used to make very fine and precise real-time adjustments in stimulus intensity, timing, and duration.

Ron Dubner described the monkey experiments: "You asked your questions through [the behavior]. Once you did that, and once you successfully recorded from neurons while the animal was performing the behavior, the data just fell out...The nervous system was telling you what it was doing."6

Monkeys were trained in several complex tasks. In an initial task, the monkeys responded to a perceived shift in temperature, by pressing a panel to receive "a liquid reward" (water or juice). A second model allowed the monkey to make "informed choices" and forced him to discriminate between behaviorally-relevant and non-relevant stimuli.

A schematic ofthree tasks in the awake behaving monkey experiments. The three tasks are:an innocuous thermal task; a noxious thermal task; and a visual task. And an illustration of a monkey performing tasks. The drawing identifies the thermode, the readylight & button, and the visual cue.

From Task-related responses of monkey medullary dorsal horn neurons
The monkey could choose to initiate a trial at any time by pressing a panel and could terminate any painful stimulus by releasing the panel. When he activated the stimulus, the thermode presented sequences of low and high-temperature heat pulses in a "quasi-random" sequence. If the monkey released the panel within two seconds after he detected a temperature shift downward, he received his reward. Noxious stimuli (45 oC or higher) were presented for only a few seconds and could be immediately terminated by the monkey. He would receive no reward, however, unless he waited for the downward shift. A third type of task required the monkey to earn his reward by responding to a visual cue (light), while ignoring the temperature shifts of the thermode pulse (although again, noxious stimuli could be terminated immediately.)

Once a monkey had learned the tasks, the researchers began recording trigeminal neuron activity, using a microelectrode method developed by Ed Evarts at the National Institute of Mental Health (NIMH) . The key data recorded were the time delay before the nerve responded to a stimulus and the frequency with which the nerve "fired". These were analyzed in conjunction with electrophysiological recordings from the same neurons in anesthetized animals and with anatomical and cytological observations under electron microscopy.

Back To Top | Photography Credits

References

6 Interview with Ron Dubner, 1999

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A schematic of three tasks in the awake behaving monkey experiments. The three tasks are: an innocuous thermal task; a noxious thermal task; and a visual task.
A schematic of three tasks in the awake behaving monkey experiments. The three tasks are: an innocuous thermal task; a noxious thermal task; and a visual task

An illustrationof a monkey performing tasks. The drawing identifies the thermode, the readylight; button, and the visual cue.
An illustration of a monkey performing tasks. The drawing identifies the thermode, the ready light & button, and the visual cue

The Monkey's Informed Choices

The awake behaving monkey experiments were among the most important undertaken by the Neurobiology and Anesthesiology Branch at NIDR in the 1970s and 1980s. These were real time observations of the ways in which an animal processed, reacted to, and acted on complex environmental information, including a noxious stimulus (a contact thermode placed near the lip), while microelectrode recordings were taken of the neuronal activity in the trigeminal brainstem. Originally designed by Ron Dubner and Ralph Beitel, the behavioral studies continued through several generations of postdocs and lab workers, including Catherine Bushnell, Gary Duncan, Ron Hayes, Donna Hoffman, Daniel Kenshalo, William Maixner, and Jean-Marie Oliveras .

Essential to the project were Fred Brown's skills and almost tactile sense of electronics, which enabled him to design and build the specifically configured equipment the researchers used to make very fine and precise real-time adjustments in stimulus intensity, timing, and duration.

Ron Dubner described the monkey experiments: "You asked your questions through [the behavior]. Once you did that, and once you successfully recorded from neurons while the animal was performing the behavior, the data just fell out...The nervous system was telling you what it was doing."6

Monkeys were trained in several complex tasks. In an initial task, the monkeys responded to a perceived shift in temperature, by pressing a panel to receive "a liquid reward" (water or juice). A second model allowed the monkey to make "informed choices" and forced him to discriminate between behaviorally-relevant and non-relevant stimuli.

A schematic of three tasks in the awake behaving monkey experiments. The three tasks are:an innocuous thermal task; a noxious thermal task; and a visual task. And an illustration of a monkey performing tasks. The drawing identifies the thermode, the readylight & button, and the visual cue.

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Once a monkey had learned the tasks, the researchers began recording trigeminal neuron activity, using a microelectrode method developed by Ed Evarts at the National Institute of Mental Health (NIMH) . The key data recorded were the time delay before the nerve responded to a stimulus and the frequency with which the nerve "fired". These were analyzed in conjunction with electrophysiological recordings from the same neurons in anesthetized animals and with anatomical and cytological observations under electron microscopy.

Nociceptive-Specific neurons and Wide-Dynamic-Range neurons

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References

6 Interview with Ron Dubner, 1999

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1970s

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References

1 The National Institute of Dental Research (NIDR) was renamed the National Institute of Dental and Craniofacial Research (NIDCR) on October 21, 1998.

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Versions Compared

Old Version 7

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Key

Converging Pathways of Pain Research at NIDCR

Introduction

Pain and the Dentist

Ron Dubner and the "Lone Rangers"

A New Multi-Disciplinary Unit

The Monkey's Informed Choices

The Monkey's Informed Choices

References

Office of NIH History and Stetten Museum