The Oral Neuroscience arm of the Integrated Bioscience research group covers three main areas: Mechanisms of inflammatory pain, Mechanisms of neuropathic pain and Managing trigeminal nerve injuries and enhancing peripheral nerve repair.
Research Group Leader: Professor FM Boissonade
Summary and Principal Aims
The overall aim of our research is to improve the treatment of patients with pain and sensory disturbances arising as a consequence of nerve injury or disease.
Our group includes basic scientists and clinicians, thus we are able to pursue a wide range of activities, from investigations undertaken within the field of basic bioscience through to clinical investigations on our patients. We also run clinical services for the treatment of patients with facial pain and with nerve injuries.
Much of our work is at the academic–industrial interface, funded by both industry and Research Councils UK. Collaborations with GlaxoSmithKline, Pfizer and Eli Lilly include a wide range of translational studies, using pre-clinical models and human tissues to identify and validate a range of regulators of neuronal excitability as potential targets for novel analgesics. Other projects, with Renovo plc, are directed towards improvement of nerve regeneration.
Our Research is divided into three main areas:
Mechanisms of inflammatory pain
Mechanisms of neuropathic pain
Managing trigeminal nerve injuries and enhancing peripheral nerve repair
Trigeminal nerve injuries are common and can be extremely distressing for the patient. The inferior alveolar and lingual nerves are most frequently damaged during lower third molar removal, but may also suffer injury during surgery for facial deformity or as a result of facial fractures. Although the majority of patients regain normal sensation within a few weeks or months, a proportion are left with abnormal sensation or pain, which can cause difficulty with speech and mastication, and is a frequent cause of litigation against the surgeon.
In the past, little was offered to these patients, either in terms of a clear prognosis or possible surgical intervention to improve the level of recovery. Now, as a result of our work, there is a scientific basis for the management of this problem. Our studies have answered a number of fundamental questions in the following areas:
Intervention is required in some circumstances, as nerve repair can improve recovery. We have shown that repair of a cut lingual nerve using epineurial sutures is more effective than entubulation and, if a damaged nerve segment has to be excised, repair by stretching the ends under slight tension is better than grafting. If a graft is essential, a frozen skeletal muscle autograft is as good as a sural nerve graft and avoids donor site morbidity.
Clinically, delay prior to lingual nerve repair is essential as, in the early stages after injury, it is not possible to distinguish between anaesthesia resulting from a crush injury (which will not require intervention) and that resulting from a section injury (which requires repair). This distinction can normally be made at approximately three months post-injury and, fortunately, our studies have shown that this delay has little effect on the outcome.
Our prospective, quantitative assessment of the outcome of lingual nerve repair has revealed that, although the outcome is variable, there is a highly significant improvement in the majority, and patients consider the surgery worthwhile.
We have shown that incorporation of growth factors at a site of nerve repair can preferentially enhance the regeneration of specific groups of nerve fibres. This suggests that future therapeutic enhancement of regeneration after peripheral nerve injury may require a combination of different growth factors, appropriate to the damaged nerve.
Scarring at a site of nerve repair is thought to impede the regeneration of damaged nerve fibres. Our recent studies have shown that anti-scarring agents (such as antibodies to TGFβ1 and 2) can be used to reduce this problem, and hopefully will result in enhanced regeneration.
Prevention of injury
The most important approach to nerve injuries is prevention. The incidence of lingual nerve injuries during third molar surgery in the UK is significantly higher than in other parts of Europe and in the USA. We have shown that this difference results from the UK method of elevation of a lingual flap and insertion of a Howarth´s periosteal elevator.
We undertook the first randomised controlled trial into the effect of this surgical technique, and found that avoidance of lingual flap retraction resulted in a significant reduction in lingual nerve injury. We concluded that, for the majority of cases, lingual retraction should be avoided. This has led to an evidence-based change in the recommended surgical technique taught in the UK, and has had a substantial impact on clinical practice.
Reducing injury-induced pain
At present, little can be offered to patients who develop the persistent painful condition of dysaesthesia after nerve injury, and understanding the aetiology of this disorder remains one of our key objectives.
We have undertaken a series of investigations on specimens of human lingual nerve tissue (obtained at the time of nerve repair) in an attempt to identify characteristics that are unique to those patients who have developed pain. This has shown that neuropeptides accumulate at the injury site and we think that this may be associated with the development of spontaneous activity and mechanical sensitivity in some damaged axons. Modifying the action of these neuropeptides could provide a pharmacological approach to treatment.
Ultrastructural studies on this human tissue have shown that both myelinated and unmyelinated fibres are smaller than normal and there is a significantly higher incidence of both axonal exposure and axonal apposition. These ultrastructural changes may account for some of the altered behaviour of the damaged nerve fibres, possibly leading to the development of pain.
In other studies we have found changes in other regulators of neuronal excitability, such as nitric oxide and specific sodium channel subtypes. These changes may also contribute to the development of abnormal activity from the damaged nerve fibres.
In pharmacological studies we have found that the application of corticosteroids to an injury site could decrease the pain evoked by mechanical stimulation of the damaged nerve fibres, and carbamazepine could reduce the spontaneous pain. We are undertaking clinical trials on the use of potential agents for the treatment of dysaesthesia.
This area of research has been funded by grants from:
- Wellcome Trust
- Action Medical Research
- Sir Jules Thorne Charitable Trust
Key recent publications
- Current management of damage to the inferior alveolar and lingual nerves as a result of removal of third molars. P P Robinson, A R Loescher, J M Yates and K G Smith. British Journal of Oral & Maxillofacial Surgery, 42; 285-292, 2004.
- Peripheral mechanisms for the initiation of pain following trigeminal nerve injuries. P P Robinson, F M Boissonade, A R Loescher, K G Smith, J M Yates, et al J Orofacial Pain, 18; 287-292, 2004.
- Close apposition and exposure of non-myelinated axons in traumatic neuromas of the human lingual nerve. A R Vora, A R Loescher, F M Boissonade & P P Robinson. J Peripheral Nervous System, 9; 200-208, 2004.
- Ultrastructural characteristics of axons in traumatic neuromas of the human lingual nerve A R Vora, A R Loescher, F M Boissonade & P P Robinson. J Orofacial Pain, 19; 22-33, 2005.
- Nav1.7 sodium channel expression in human lingual nerve neuromas. E V Bird, F M Boissonade, P P Robinson. Archives of Oral Biology, 2007.
- Inflammatory cell accumulation in traumatic neuromas of the human lingual nerve. A R Vora, S Bodell, K G Smith, A R Loescher, P P Robinson & F M Boissonade. Archives of Oral Biology, 52; 74-82, 2007.
- Vanilloid receptor 1 (TRPV1) expression in human lingual nerve neuromas from patients with or without symptoms of burning pain. J E Biggs, J M Yates, A R Loescher, N M Clayton, F M Boissonade, P P Robinson. Brain Research, 1127; 59-65, 2007.
Toothache is one of the most common and unpleasant pain sensations experienced by man. Unfortunately, it is also fairly resistant to normal analgesics, and affected individuals can suffer severe symptoms and disturbed sleep. Tooth decay (caries) is the main cause of pulpal inflammation, which, in turn, may cause dental sensitivity or spontaneous pain. On occasions, the management of advanced tooth decay and pulp inflammation regrettably necessitates root canal therapy (removal of the dental pulp) or an extraction.
Our research group has a particular interest in pain mechanisms, and the tooth pulp provides us with an extremely valuable and interesting experimental model of inflammatory pain.
Essentially, we use pulp tissue obtained from patients requiring tooth extraction (with their informed consent) to try to correlate reported pain symptoms with histological findings. We use immunocytochemical techniques to specifically label a variety of structures including nerves, blood vessels and immune cells.
In addition, we have been studying a range of neuropeptides, neurotransmitters, and ion channels to gain a greater insight into the more subtle neural changes underlying pain and neurogenic inflammation. Our analysis of immunolabelling is both qualitative and quantitative and relies principally on the use of sophisticated image analysis software.
To date, our investigation of the tooth pulp, both in health and disease, have revealed some notable findings. Some of these are summarised below:
- With caries progression there is a significant increase in the overall density of pulpal nerves, although this increased innervation does not appear to be associated with reported pain symptoms. It is likely, however, that this neural proliferation has importance in inflammation and healing.
- There is a marked increase in the neural expression of substance P, (a neuropeptide with nociceptive function) in teeth from patients with toothache, when compared to teeth with a similar degree of caries, but no symptoms. This suggests that substance P plays a key role in painful pulpitis.
- The vanilloid receptor, TRPV1, also shows a significant increased in expression in painful pulp tissue, and may also have an important role in dental pain.
- There are differences between the innervation, immune cell accumulation and vascularity in human primary and permanent teeth, and this may have biological and clinical importance.
We are keen to further our knowledge and understanding of the basic neural mechanisms associated with dental pain and inflammation. We hope that a greater appreciation of these cellular events will ultimately lead to improved clinical management of dental pain for our patients, young and old.
This area of research has been funded by grants from:
- Royal College of Surgeons
- Shirley Glasstone Hughes Memorial Prize Fund
- Proctor & Gamble
- Professor Fiona Boissonade
- Professor Helen Rodd
Key recent publications
- Comparative immunohistochemical analysis of the peptidergic innervation of human primary and permanent tooth pulp. H D Rodd and F M Boissonade. Arch Oral Biol. 47; 375-85, 2002.
- Immunocytochemical investigation of neurovascular relationships in human tooth pulp. H D Rodd and F M Boissonade. J Anat. 202;195-203, 2003.
- Vascular status in human primary and permanent teeth in health and disease. H D Rodd and F M Boissonade. Eur J Oral Sci. 113; 128-34, 2005.
- Vanilloid receptor 1 expression in human tooth pulp in relation to caries and pain. C R Morgan, H D Rodd, N Clayton, J B Davis and F M Boissonade. J Orofac Pain. 19; 248-60, 2005.
- Immunocytochemical investigation of immune cells within human primary and permanent tooth pulp. H D Rodd and F M Boissonade. Int J Paediatr Dent. 16; 2-9, 2006.
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