Sodium Channels Pain and Analgesia PDF
2.74 MB PDF
The treatment of chronic pain, for example that resulting from damage or dysfunction of the nervous system, or that associated with cancer, is at present inadequate and pain still represents a serious unmet clinical need. The costs of pain, in terms of personal anguish, finance and in national healthcare costs are enormous. Because sodium channels confer excitability on neurones in nociceptive pathways and exhibit neuronal tissue-specific and injury-regulated expression, their study has become an important branch of pain research, and they form the focus of this book. As well as reviewing why sodium channel subtypes are potentially important drug targets in the treatment of pain, this volume also brings together recent insights into the control of expression, functioning and membrane trafficking of nervous system sodium channels.
A recent previous review of sodium channel function, with particular emphasis on the ways in which aberrant sodium channel behaviour can contribute to nervous system pathophysiology, was based on a Novartis Foundation symposium held in London in 2000, chaired by Stephen Waxman. At that time it had become clear that sodium channels were a group of proteins exhibiting both molecular and functional diversity, and that neuronal hyperexcitability, contributing to such phenomena as chronic pain following nerve injury, might be explained by changes in sodium channel function. This included the selective upregulation and downregulation of expression of different sodium channel genes. The control of sodium channel gene expression in the nervous system following injury has remained very much a hot topic in the intervening years and is an important theme in this book. Evidence has also accrued on the importance of G-protein pathway control of sodium channel function, and the post-translational modification of channel function based on phosphorylation is also discussed in this volume.
The ability to discriminate pharmacologically between sodium channel subtypes, which show substantial sequence homology, is another important theme and one where key developments are expected. The technologies used for screening compounds on sodium channel function are reviewed in this book. Sodium channel subtypes appear to be distributed to specific regions of the axon, and may therefore make highly individual contributions to normal acute noxious sensation. These must include tetrodotoxin-resistant channels, known to be functional in at least some of the smallest peripheral endings. Furthermore, sodium channels are chaperoned to the neuronal membrane and are tethered there by a complex of proteins, contacting both the extracellular matrix and the intracellular cytoskeleton. Many protein–protein interactions must ensure correct channel function and turnover. These interactions can be sodium channel sub-type specific, for example that between p11 and Nav1.8. Thus, certain channel associated molecules might provide additional drug targets in the treatment of pain.
Our understanding of pain transmission and transduction in mammals has been greatly facilitated by the development of sodium channel gene knockout mice. This has allowed us to assign roles to certain sodium channel subtypes that could not be selectively targeted by pharmacological methods, and the endeavour has allowed sodium channel subtypes to be validated as potential future drug targets. The further sophistication of gene knockout technology, developed at least in part to overcome lethality, has been the use of tissue-specific nulls where the activation of a tissue- specific gene promoter can be used to express the bacteriophage cre-recombinase. Finally, the use of tissue-specific inducible nulls is expected to contribute to the future study of sodium channel function. This technology holds out the promise of gene deletion without developmental compensation resulting in a diluted phenotype, and thus may provide the clearest insight possible into the function of genes in subsets of neurones.
This book aims to summarise the current understanding of voltage-gated sodium channels, their association with pain and their potential as targets for the development of novel analgesics. Individual chapters address the potential therapeutic role of voltage-gated sodium channels and their respective roles in neuropathy and nerve injury, brain disorders, visceral pain and dental pain. Further chapters address the role of these molecules in nociceptive endings, the regulation and modulation of sodium channels, channel gating and drug blockade. A specific chapter is devoted to the Nav1.8 channel, viewed by many as an important therapeutic target, and the final chapter discusses current opinion and future direction in sodium channel research.
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