New insights into pain mechanisms

To feel pain is a good thing because it persuades you to protect yourself from danger and it helps you to heal after hurting a part of your body. But, sometimes, pain is not useful and it can torment you long after an old injury has healed. To add to the misery, pain treatments are often only partially effective with side effects being common. My work aims to help us to better understand and treat pain. Everyone is born with a ‘library‘ of ‘instruction books‘ called genes, which describe how to carry out jobs such as building a heart. Unfortunately, a book can sometimes contain an error called a mutation; and if the book describes a very important job, then this can result in a disease. I work with patients who either can‘t feel pain or who have episodes of excruciating pain and I try to find mutations by using amazing sequencing technology, which can rapidly read all ~23000 human genes. Once a mutation has been found I can learn how the error causes disease, e.g. pain insensitivity, by looking at how the comparable gene works in mice. This can, ultimately, lead to the development of better pain-killing drugs.

At any one time 6% of the population is in severe pain. Despite this huge clinical burden, our understanding of the cellular mechanisms involved in pain processing is limited and the treatments available are often only partially effective. I study rare families in which pain insensitivity or paroxysmal pain are caused by a mutation in a single gene in order to gain powerful insights into pain mechanisms and to give a route to new therapies. This is exemplified by my previous work showing that Channelopathy-associated Insensitivity to Pain (CIP) is caused by loss of function of Nav1.7, a nociceptor-expressed voltage-gated sodium channel; and by Familial Episodic Pain Syndrome which was shown to be caused by an activating mutation in TRPA1, the chemosensitive transient receptor potential channel. This proposal aims to further characterize the function of Nav1.7 through the analysis of two C-terminal CIP mutations and find other crucial genes involved in human pain sensing which I will then extensively study by generating and analysing mouse mutants. Through collaborations with European-based pain clinicians I have access to a rich cohort of patients with Mendelian pain disorders in which known disease genes have been excluded. This cohort includes (1) a three generation family with 6 affected individuals with pain insensitivity that segregates autosomal dominantly; (2) three consanguineous families with pain insensitivity due to congenital or progressive neuropathies; (3) four singletons with complete absence of pain sensation but with peripheral nerves intact; (4) a collection of patients with paroxysmal pain disorders (including paroxysmal pain and congenital erythermalgia); (5) a mother and daughter with extreme cold allodynia; and (6) three individuals who cannot sense cold pain. The strategy which will be adopted to find each disease gene will involve the use of whole exome sequencing, which is already being performed in a collaborating laboratory for a subset of this cohort. Once the disease genes are proven I will prioritise two of the most interesting for transgenic mouse creation and characterize the pain phenotype using appropriate behavioural, anatomical and electrophysiological assays. The mouse mutant analysis will capitalize on expertise in the Wood lab who routinely use the Cre-Lox P approach to conditionally knock out genes. By identifying and functionally characterizing novel pain genes this proposal has the real potential to lead to a better understanding of pain production and could lead to the development of better analgesics which will benefit us all.