Publications
APS Bulletin • Volume 14, Number 6, 2004
History of Pain
Marcia Meldrum, PhD, Department Editor
Dental Chickens and Puzzled Monkeys: The Story of Pain Research at NIDCR, Part 1
Marcia Meldrum, PhD
Editor’s Note:
This is the first in a two-part series of articles about the beginnings of the Neurobiology and Anesthesiology Branch (NAB) and the work of Edward Driscoll, Ronald Dubner, and some of their early colleagues.
The researchers of the NAB made many important contributions to psychophysics, clinical analgesic trials, neuroanatomy, pain and development, and the biochemistry and genetics of neuropeptides active in pain transmission and modulation. These will be discussed in Part 2, "The Story of Pain Research at NIDCR", which will appear in the next issue of the APS Bulletin. NIDR was renamed NIDCR in 1998. Throughout the period discussed in this article, it was NIDR.
Between the 1960s and 1990s, a small research group in the National Institute of Dental Research (NIDR), now the National Institute of Dental and Craniofacial Research (NIDCR), evolved into one of the most productive programs in the pain field. How did this happen?
Beginnings: The Problem of Dental Anesthesia
In the late 1950s, the American Dental Association and NIDR actively promoted regular dental visits, especially for children. Even though Americans visited the dentist more often, many of them associated their visits with pain and anxiety. Dentists tried to alleviate patients’ fears by offering general anesthesia for many routine procedures. “It is estimated,” NIDR researcher Edward Driscoll wrote in 1960, “that in many parts of the countrythere are nearly as many general anesthetics administered in dental offices as there are in the local hospitals” (Driscoll, 1960). This well-meant practice drew fire from anesthesiologists and health authorities, however. Dentists rarely had formal training experience with many of the new anesthetic agents. Even if they had the training, it was impossible for one person to both perform the operative procedure and monitor the patient’s physiological status. And there was little information about the side effects of new agents, such as sodium pentothal and sodium methohexital. This was a risky practice, because 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.
In 1957 Driscoll, of NIDR’s Oral Medicine and Surgery Section, began conducting systematic studies of dental anesthesia. His aims were to establish the necessary baseline physiological data, evaluate the effects of stress on the dental patient, and find the best methods of analgesia. With his associates, he performed full-mouth extractions on more than 1,200 patients and collected readings of pulse, blood pressure, arterial oxygen level, and other indicators. His studies provided the first data on the efficacy and risks of dental anesthesia, but unfortunately, most of this information was never published.
Ronald Dubner and the “Lone Rangers”
Meanwhile, Seymour Kreshover, NIDR scientific director in the 1960s, was determined to establish a basic neuroscience research laboratory at the Institute. Kreshover provided support to Ronald Dubner, a young public health service officer, to get his PhD in neurophysiology at the University of Michigan. When Dubner returned to the National Institute of Health in 1965, he was given lab space in the basement of Building 30. He hired Fred Brown, a young electrical engineer, to build the physiological recording apparatus needed to begin recording from nerve cells in the brain and the trigeminal nucleus that are excited by visual and auditory stimuli.
Dubner and Kreshover used the problem of dental pain as a rationale to link this basic research to the mission of the Dental Institute. They argued that an understanding of the mechanisms of pain and the development of better methods for its management had to be based on a thorough knowledge of how sensory information was processed. Dubner’s early work showed that the first central relay nucleus in the trigeminal system was the site of significant modifications of sensory information. His was one of the first research projects that rose to the challenge laid down by the gate-control model (Melzack & Wall, 1965) to describe the complex sensory, cognitive, and affective components of clinical pain as physically embodied in an interactive nervous system.
There were several basic scientists working in Building 30 at the time, including Bruce Dow and Barry Sessle, fellows in Dubner’s lab; Steve Gobel, a neuroanatomist interested in electron microscopy studies of the trigeminal system; and a group of microbiologists. When Kreshover became Institute director in 1966, the new scientific director, Richard Gruelich, created a basic science unit, named the Physiology Section, around these “lone rangers.” The following year, Gobel and the Dubner group were separated from the microbiologists and designated as the Neural Mechanisms Section.
By 1969 Dubner and his collaborators had demonstrated that both ascending nerve fibers from the skin and descending fibers from the brain were connected synaptically to the dorsal horn of the spinal cord. Evidence of this connection suggested the presence of a rapidly conducting feedback loop, which could act to enhance or alleviate information about sensory stimuli.
A New Multidisciplinary Unit
At this point, Dubner decided that he needed to “pick the brain” of a leader in the field, so he arranged in 1970 for a year’s sabbatical at University College London with Patrick Wall. When he returned to NIDR from London, a new group of colleagues joined him. Rhyuji Sumino had arrived from Japan to begin several years of collaborative work in the section. Donald Price and Jimmy Hu would soon join him.
The Institute was in the process of reorganizing its intramural and its extramural programs. Driscoll played a key role in this process, serving on the ad hoc Advisory Committee on Pain Control (1971–72). A major result of his 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. This new program provided crucial support for the International Symposium on Pain, held at Issaquah, WA, in May 1973. This in turn led to the formation of the International Association for the Study of Pain and the founding of the journal, Pain. John Bonica also used NIDR grants to support his broad-based pain research program at the University of Washington and acknowledged to Ganz that “NIDR has the best record of supporting pain research of all the institutes” (Bonica, 1979).
The formation of the Neurobiology and Anesthesiology Branch (NAB) in 1974, a new unit incorporating Dubner’s basic science work with a reactivated program to improve dental anesthesia and analgesia, was another important outcome of the NIDR reorganization. In the next 10 years, NAB became “one of the most productive groups of pain researchers in the world” (Bonica, 1980). The remarkable productivity of the unit resulted from the historical conjunction of the following two events: (1) the formation of a dedicated pain research unit around the core group established by Dubner and (2) the consensus reached at Issaquah that the study of pain requires 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 that could be isolated in the laboratory. The more complex model of Bonica, Wall, and Ronald Melzack described pain as a dynamic phenomenon of an organism reacting to the environment and “the compound result of physiopsychological processes whose complexity is almost beyond comprehension” (Bonica, 1953). Influenced by these three pioneers, Dubner visualized a multifaceted program. NAB integrated 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.
The Monkeys’ Informed Choices
The awake-behaving monkey experiments were among the most important experiments undertaken by NAB at NIDR in the 1970s and 1980s. These were real-time observations of the ways in which animals processed, reacted to, and acted on complex environmental information. For example, one observation involved a noxious stimulus (e.g., a contact thermode placed near the lip), while microelectrode recordings were taken of the neuronal activity in the trigeminal brain stem. Originally designed by Dubner and Ralph Beitel, the behavioral studies continued through several generations of postdocs and several lab workers, including Catherine Bushnell, Gary Duncan, Ron Hayes, Donna Hoffman, Daniel Kenshalo, William Maixner, and Jean-Marie Oliveras. Essential to the project were 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 precise real-time adjustments in stimulus intensity, timing, and duration.
Dubner described the monkey experiments like this: “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” (Dubner, 1999).
The monkeys were trained in several complex tasks. In an initial task, the monkeys responded to a perceived temperature shift by pressing a panel to receive a liquid reward (e.g., water or juice). A second model allowed the monkeys to make informed choices and forced them to discriminate between behaviorally relevant and nonrelevant stimuli. The monkeys could choose to initiate a trial at any time by pressing a panel and could terminate any painful stimulus by releasing the panel. When they activated the stimulus, the thermode presented sequences of low- and high-temperature heat pulses in a quasi-random sequence. If the monkeys released the panel within two seconds after they detected a temperature shift downward, they received a reward. Noxious stimuli (i.e., 45°C or higher) were presented for only a few seconds and could be immediately terminated by the monkeys. They would not receive a reward, however, unless they waited for the downward shift. A third type of task required the monkeys to earn their reward by responding to a visual cue (i.e., light) while ignoring the temperature shifts of the thermode pulse—although again, noxious stimuli could be terminated immediately.
After the monkeys had learned the tasks, the researchers began recording their trigeminal neuron activity using a microelectrode method developed by Ed Evarts at the National Institute of Mental Health. 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.
Dubner and his colleagues identified two types of nociceptive neurons in the trigeminal system and the spinal cord. Nociceptive-specific neurons responded with high levels of activity, but wide-dynamic-range (WDR) neurons responded with graded sensitivities, depending on the intensity of the stimulus. Even light touch applied to the center of the WDR neuron’s receptive field would trigger a response, but at the perimeter of the field, only a painful stimulus, such as a pinch, would cause the neurons to fire. Behavioral recordings from these different neurons during the awake-behaving monkey studies indicated that the WDR neurons, which were active at both innocuous and noxious stimulus levels, appeared to be the most involved in the monkeys’ perception of temperature shifts (Dubner, Price, Deitel, & Hu, 1977).
As the researchers offered well-trained monkeys more choices and decisions to make, they established that nonbehaviorally significant stimuli (e.g., any change in temperature that was irrelevant to the monkeys’ reward-seeking actions) led to only low levels of response from the WDR neurons. But light or heat stimuli important to the monkeys’ choices and behavior triggered very high, rapid levels of firing. These variations in nerve response were independent of the actual level of stimulus intensity; thus, the nerve activity was the product of both sensory input and behavioral state. These observations supported the concepts that pain is a dynamic phenomenon and that the nervous system is highly plastic and adaptive as an organism learns from and behaves within its outside environment.
References
Bonica, J.J. (1953). The management of pain. Philadelphia: Lea & Febiger.
Bonica, J.J. (1979). Letter to Aaron Ganz. In J. J. Bonica Papers, MS Coll. 118, John C. Liebeskind History of Pain Collection. University of California, Los Angeles.
Bonica, J.J. (1980). Pain research and therapy: Past and current status and future needs. In J. J. Bonica & L. Ng, Pain, discomfort, and humanitarian care (pp. 1–48). Amsterdam and New York: Elsevier.
Driscoll, E. (1960). Studies of dental anesthesia. Bethesda, MD: NIDR Annual Report.
Dubner, R. (1999). Oral history interview. MS Coll. 112, John C. Liebeskind History of Pain Collection. University of California, Los Angeles.
Dubner, R., Price, D.D., Beitel, R.E., & Hu, J.W. (1977). Peripheral neural correlates of behavior in monkeys and humans related to sensory-discriminative aspects of pain. In D.J. Anderson & B. Matthews (Eds.), Pain in the trigeminal region (pp. 57–66). Amsterdam and New York: Elsevier.
Melzack, R., & Wall, P.D. (1965). Pain mechanisms: A new theory. Science, 150, 971–979.
Please direct your comments or suggestions about this article or department to Marcia Meldrum, PhD, Department Editor, at mlynnmel@earthlink.net.