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Pain in the Trigeminal System: from Orofacial Nociception to Neural Network ModelingUniversité d’Auvergne Clermont 1, INSERM E 0216, U.F.R. d’Odontologie, Faculté de Chirurgie Dentaire, 11, bd Charles-de-Gaulle, 63000 Clermont-Ferrand, France; alain.woda{at}u-clermont1.fr
Key Words: trigeminal nucleus • nociception • oralis subnucleus • orofacial pain
At the time of my entry into dental research, I read a paper describing the properties of periodontal receptors (Jerge, 1963). As a junior in research and teaching, I discovered with this article that dental research in my field could be published in a leading journal of neurophysiology. The emotion that I felt following this simple event indicates the weakness of dental research in neurosciences at the end of the 1960s. Today, dentists have taken prominent positions in the scientific orchestra in neurobiology. They have mixed with others, many laboratories in dental faculties have been recognized at the top level among labs from other disciplines, and many dentists hold leading positions in sciences and education world-wide. This evolution took more than thirty years. It was based on many scientific adventures. This article tells one of them in which knowledge was transmitted from a science to a dental faculty through a human chain.
All French dental faculties are 35 years old, since they joined the University in 1968. As a young staff member of the newly founded dental faculty of the University René Descartes in Paris, I was encouraged by Professor Marcel Gaspard to register in the faculty of sciences. Pr Gaspard was a comparative anatomist who had been recruited in this dental school to help develop research in basic sciences. Two years later, in 1973, and still backed by Professor Gaspard, I applied to join Professor Denise Albe-Fessard, whose group was a world leader in nociception studies. Boundaries between disciplines existed, and French dentistry was still looked on with surprise and curiosity by scientists, but Prof. Albe-Fessard was open-minded, and she agreed to accept a dentist as a student in her laboratory. Two years later, she offered to explore together the trigeminal sensory complex. At that time, the brain stem nuclear complex was the center of an unexplained paradox. The trigeminal sensory complex is made of two nuclei: the main nucleus, responsible for messages resulting in tactile sensations, and the spinal nucleus, divided into three subnuclei (from rostral to caudal)—oralis, interpolaris, and caudalis (Fig. 1  ).
Sjöqvist (1938) had reported that tractotomy, which interrupts the inputs to the spinal nucleus by severing the descending root at the upper level of the caudalis, was an efficient treatment for idiopathic trigeminal neuralgia. The effect of caudalis deafferentation by "tractotomy" had been repeatedly confirmed by neurosurgeons and animal researchers, and the caudalis was therefore considered as the crucial brain stem center for oro-facial nociception processing. Paradoxically, the single extracellular recordings from the caudalis performed through the 1960s failed to detect neurones activated by nociceptive stimulations (Darian-Smith, 1966). This formed a paradox with the already-recognized role of the caudalis (Wall and Taub, 1962) and was in contrast to the well-described nociceptive neurones found in the lumbar spinal dorsal horn (Wall, 1973). Denise Albe-Fessard and I were joined by another young dentist, Jean Azerad. Dr. Albe-Fessard was at the top of her career, while J. Azerad and I were at the very beginning, but for the two years we spent recording neurones from the full rostrocaudal extent of the trigeminal sensory complex, she was fully involved in the experiments, even when they ended late at night. Also, her curiosity about a problem that seemed marginal to nociception studies was not faked. This impressed me for life. We made two important findings (Woda et al., 1977; Azerad et al., 1982). First, it appeared that the isolated nociceptive neurones that had been described in the caudal parts of the complex (Gordon et al., 1961; Kruger and Michel, 1962) were part of a larger group. This indicated that nociception in the caudalis was organized on the same model as in the dorsal horn of the spinal cord, with a group of nociceptive neurones sending their axons to the nociceptive ascending pathways (Wall, 1973; Mosso and Kruger, 1972; Yokota, 1975; Price et al., 1976; Besson and Chaouch, 1987). The similarity with the spinal dorsal horn was confirmed by others (Sessle, 1987), and the caudalis was alternatively called the medullary dorsal horn (Gobel et al., 1981). Subsequently, the caudalis was extensively used for the study of general problems relevant to nociception (Dubner and Bennett, 1983; Villanueva and Le Bars, 1985; Oliveras et al., 1986; Bouhassira et al., 1987; Chen and Huang, 1992). The second finding was totally unexpected and directed our interest to the trigeminal sensory complex itself. A second group of nociceptive neurones activated from the orofacial area was observed rostrally in the oralis. This discovery confirmed some of the glimpses that had already been obtained in previous work (Wall and Taub, 1962; Eisenman et al., 1963), but it also shed light on the unexplained results that we had previously obtained with Jean Azerad when we worked under the direction of Jean-Marie Besson and Gisèle Guilbaud. We had just finished an experiment on the jaw-opening nociceptive reflex in the cat in which tractotomy was intended to remove the afferent messages from the caudalis (Azerad and Woda, 1976). The expected result, the abolition of the nociceptive tooth-pulp-induced jaw-opening reflex, was never observed. The results of micro-electrode recordings clarified the persistence of the nociceptive reflex after tractotomy, since it suggested that oralis nociceptive neurones were also involved in oro-facial nociception. This important insight had been made possible thanks to a group of famous researchers—one scientist, D. Albe-Fessard, one pharmacologist, JM. Besson, and one physician, G. Guilbaud—who were generous enough to spend considerable time and energy to investigate a new topic proposed by two dental students. These seminal years gave us the bases of neurophysiological techniques that became essential for the future development of this research in the environment of a dental faculty.
The above results were obtained in the simple context of doctoral studies. Things were going to be quite different in the following years, after I accepted the task of founding a research group in Clermont-Ferrand, a medium-sized city in the center of France, far from my parent laboratory. Financial support, laboratory space, equipment, and collaborators did not exist and had to be found in a university used to regarding the dental faculty as being devoid of research. Changing the way the non-dental academics looked at us took time, but I was rapidly surprised to discover several students ready to explore a career totally new in the context of their immediate surroundings. Subsequently, some of these individuals, such as Martine Hennequin and Dominique Roux, were regarded as the founders of hospital dentistry. Others, such as Patrick Raboisson and Radhouane Dallel, performed parallel work in basic research. A laboratory was progressively built. The results of the experiments done in Paris were extended. Nociceptive oralis neurones were the medium for the transmission of scientific methodology to a dental lab. Simultaneously, it became obvious that the oralis convergent neurones shared all the properties of other neurones of the deep spinal dorsal horn or of deep layers of the caudalis (Dallel et al., 1990, 1996; Hu et al., 1992; Raboisson et al., 1995). Another crucial advance was obtained through co-operation with Barry Sessle’s group in Toronto. Several bilateral summer visits to Clermont-Ferrand and Toronto over many years helped describe trigeminal cell responses among which was plasticity, a property expressed by both caudalis and oralis convergent neurones (Hu et al., 1986, 1992, 1999; Parada et al., 1997; Dallel et al., 1999; Woda et al., 2001). This property, by which nociceptive messages coming from the periphery are modified in a lasting way, is one of the basic features of chronic pain (Woda and Pionchon, 2001).
The initial reaction of the scientific community was to accept a role in motor adjustment to pain for the oralis but to reject the idea of a sensory role. Indications that oral and peri-oral pain sensation depends on the oralis came from the exclusion of the caudalis by tractotomy performed in man (Young, 1982), the cat (Vyklicky et al., 1977), and the rat (Dallel et al., 1989). It showed that the presence of the oralis alone is sufficient for pain sensation or nociceptive behaviors to occur after stimulation of a buccal site. A further step had to be brought about by demonstration of the existence of contested ascending projections from the oralis to the upper levels of the brain, e.g., the thalamus and cortical cortex. This implicated the need for immunocytochemical studies that were not controlled by the group. In an interesting repetition of circumstances, Patrick Raboisson and Radhouane Dallel went back to my former laboratory, headed at that time by J.M. Besson, in Paris. They studied for two years under Luis Villanueva, a full-time reseacher and one of the French leaders of pain studies, who had been trained in Chile as a dentist. Under his guidance, they learned an anterograde tracing technique which confirmed the presence of anatomical projections from the oralis to higher level of the brain (Dallel et al., 1997). This had been previously suggested by anatomy with only retrograde tracings (Mantle-St. John and Tracey, 1987; Luo and Dessem, 1995) and by micro-electrode recording of nociceptive thalamic neurones after stimulation of oral and peri-oral fields (Dallel et al., 1988; Raboisson et al., 1989). Later, retrograde labeling after injection in the thalamus showed that the densities of projecting cells were similar in the oralis and caudalis, conferring on these two divisions equally important roles in trigeminal nociception (Voisin et al., 2001).
At that point, it had become clear that the oralis was involved in pain sensation from the oral cavity. At that time, the laboratory was functional, and the original topic that had arisen from a laboratory in the science faculty in Paris was completed in the dental faculty in Clermont-Ferrand. This was concomitant with a change in the status of my more prominent pupils. The time had come for them to be leaders. For familial reasons, Patrick Raboisson left for a management position with a pharmacological society in Sweden. Radhouane Dallel was the next link in the transmission chain. He belonged to a new generation, one that felt at home in the university, which certainly helped him to benefit fully from his hard work and finally to express a new and important concept that turned out to be decisive for the future of the group.
The nature of the differences between he oralis and the spinal or caudalis dorsal horn was not well-understood. Some differences were well-known, such as the lack of substantia gelatinosa in the oralis, although it exists in the caudalis. Substantia gelatinosa is composed of a group of small interneurones located in the superficial part of the dorsal horn and has long been known to be implicated in nociception by controlling message transmission through the dorsal horn. Substantia gelatinosa receives terminals of the small unmyelinated afferent C-fibers that play a major role in nociception. Interestingly, the C-fiber primary afferent endings are scarce in the oralis, and almost all of them are found in the superficial layers of the caudalis. This had long been known (Windle, 1927) but had been forgotten. Radhouane Dallel pointed out that the C-fiber activities recorded via the oralis had to relay via another structure that appeared to be the substantia gelatinosa of the caudalis. This was illustrated when the C-fiber activity recorded from oralis nociceptive neurones was interrupted by morphine micro-injected into the caudalis substantia gelatinosa (Dallel et al., 1998) (Fig. 2
This organization of trigeminal nociception, with the oralis "commanded" by the caudalis substantia gelatinosa, constitutes a remarkable experimental model (Fig. 2  ) and offers a unique possibility of recording from deep-layer nociceptive neurones (i.e., in the oralis) while injecting neurochemicals into the modulating structure (i.e., in the caudalis substantia gelatinosa). This is possible in the trigeminal sensory complex because of a 3- to 4-mm gap separating the oralis from the caudalis. Recording from the spinal cord or from the caudalis with injection into the substantia gelatinosa would not be possible because the injected and recorded sites are almost adjacent and the injected drugs would spread over the recording site.
This model helped the laboratory pass another landmark. At the beginning of 2003, the laboratory, now headed by Radhouane Dallel, was officially recognized by the "Institut National de la Santé et de la Recherche Médicale", the French equivalent of the US NIH. Attracted by this model, two French senior researchers, D. Voisin and L. Villanueva, decided to join the group in Clermont-Ferrand. The trigeminal model is now used to answer general questions related to nociception. More precisely, it can tell how nociceptive neurones of the deep dorsal horn are modulated by the substantia gelatinosa. It was first applied to study the role of N-methyl-D-aspartate (NMDA) receptors in the amplification of the nociceptive messages when they arrive in the dorsal horn. A combination of intrathecal, systemic, and micro-injections in the oralis or caudalis, with recordings from these same two subnuclei, indicated that an increase is due to activation of NMDA receptors located in the deep layers of the dorsal horn, while a decrease results from activation of NMDA receptors located in the substantia gelatinosa (Parada et al., 1997; Luccarini et al., 2001; Woda et al., 2001). Similar approaches are now in progress with other mediator-receptor systems of the spinal-trigeminal dorsal horn. The challenge of continuing to "diffuse" science is undoubtedly a key task of the present laboratory veterans: to maintain the transmission of knowledge both inside and outside the dental environment.
The evolution of this research, focused on the organization of a single subnucleus of the trigeminal sensory complex, is one of the many examples of how dentistry had to deepen its specificity to ultimately widen its field. There is no "dental" research. Scientific disciplines are overlapping from the point of view of ideas, techniques, and researchers. It is possible that a landmark of maturity for a growing group can be found when it becomes impossible to distinguish any professional features in its activity. In our case, this was achieved by the transmission of knowledge through many different persons, coming from different disciplines but all interested in a wide diffusion of science. Finally, the feeling of not being a full member of the academic community was a unilateral perception; it was not shared by the scientists I had the opportunity to meet. The transmission of science and knowledge knows no boundaries.
We are indebted to P.J. Riordan for language correction and to A.M. Gaydier for her excellent secretarial services. This work was supported by a grant from European Community BIO 4.98.0076 and Direction Générale des Armées (Contract 0134.012.00470.75.10). Received for publication January 23, 2003. Accepted for publication June 13, 2003.
Journal of Dental Research, Vol. 82, No. 10,
764-768 (2003) This article has been cited by other articles:
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