Gene expression mapping in neuropathic pain : molecular plasticity in nociceptors and superficial dorsal horn

RESUME : La douleur neuropathique est le résultat d'une lésion ou d'un dysfonctionnement du système nerveux. Les symptômes qui suivent la douleur neuropathique sont sévères et leur traitement inefficace. Une meilleure approche thérapeutique peut être proposée en se basant sur les mécanismes pathologiques de la douleur neuropathique. Lors d'une lésion périphérique une douleur neuropathique peut se développer et affecter le territoire des nerfs lésés mais aussi les territoires adjacents des nerfs non-lésés. Une hyperexcitabilité des neurones apparaît au niveau des ganglions spinaux (DRG) et de la corne dorsale (DH) de la moelle épinière. Le but de ce travail consiste à mettre en évidence les modifications moléculaires associées aux nocicepteurs lésés et non-lésés au niveau des DRG et des laminae I et II de la corne dorsale, là où l'information nociceptive est intégrée. Pour étudier les changements moléculaires liés à la douleur neuropathique nous utilisons le modèle animal d'épargne du nerf sural (spared nerve injury model, SNI) une semaine après la lésion. Pour la sélection du tissu d'intérêt nous avons employé la technique de la microdissection au laser, afin de sélectionner une sous-population spécifique de cellules (notamment les nocicepteurs lésés ou non-lésés) mais également de prélever le tissu correspondant dans les laminae superficielles. Ce travail est couplé à l'analyse à large spectre du transcriptome par puce ADN (microarray). Par ailleurs, nous avons étudié les courants électriques et les propriétés biophysiques des canaux sodiques (Na,,ls) dans les neurones lésés et non-lésés des DRG. Aussi bien dans le système nerveux périphérique, entre les neurones lésés et non-lésés, qu'au niveau central avec les aires recevant les projections des nocicepteurs lésés ou non-lésés, l'analyse du transcriptome montre des différences de profil d'expression. En effet, nous avons constaté des changements transcriptionnels importants dans les nocicepteurs lésés (1561 gènes, > 1.5x et pairwise comparaison > 77%) ainsi que dans les laminae correspondantes (618 gènes), alors que ces modifications transcriptionelles sont mineures au niveau des nocicepteurs non-lésés (60 gènes), mais important dans leurs laminae de projection (459 gènes). Au niveau des nocicepteurs, en utilisant la classification par groupes fonctionnels (Gene Ontology), nous avons observé que plusieurs processus biologiques sont modifiés. Ainsi des fonctions telles que la traduction des signaux cellulaires, l'organisation du cytosquelette ainsi que les mécanismes de réponse au stress sont affectés. Par contre dans les neurones non-lésés seuls les processus biologiques liés au métabolisme et au développement sont modifiés. Au niveau de la corne dorsale de la moelle, nous avons observé des modifications importantes des processus immuno-inflammatoires dans l'aire affectée par les nerfs lésés et des changements associés à l'organisation et la transmission synaptique au niveau de l'aire des nerfs non-lésés. L'analyse approfondie des canaux sodiques a démontré plusieurs changements d'expression, principalement dans les neurones lésés. Les analyses fonctionnelles n'indiquent aucune différence entre les densités de courant tétrodotoxine-sensible (TTX-S) dans les neurones lésés et non-lésés même si les niveaux d'expression des ARNm des sous-unités TTX-S sont modifiés dans les neurones lésés. L'inactivation basale dépendante du voltage des canaux tétrodotoxine-insensible (TTX-R) est déplacée vers des potentiels positifs dans les cellules lésées et non-lésées. En revanche la vitesse de récupération des courants TTX-S et TTX-R après inactivation est accélérée dans les neurones lésés. Ces changements pourraient être à l'origine de l'altération de l'activité électrique des neurones sensoriels dans le contexte des douleurs neuropathiques. En résumé, ces résultats suggèrent l'existence de mécanismes différenciés affectant les neurones lésés et les neurones adjacents non-lésés lors de la mise en place la douleur neuropathique. De plus, les changements centraux au niveau de la moelle épinière qui surviennent après lésion sont probablement intégrés différemment selon la perception de signaux des neurones périphériques lésés ou non-lésés. En conclusion, ces modulations complexes et distinctes sont probablement des acteurs essentiels impliqués dans la genèse et la persistance des douleurs neuropathiques. ABSTRACT : Neuropathic pain (NP) results from damage or dysfunction of the peripheral or central nervous system. Symptoms associated with NP are severe and difficult to treat. Targeting NP mechanisms and their translation into symptoms may offer a better therapeutic approach.Hyperexcitability of the peripheral and central nervous system occurs in the dorsal root ganglia (DRG) and the dorsal horn (DH) of the spinal cord. We aimed to identify transcriptional variations in injured and in adjacent non-injured nociceptors as well as in corresponding laminae I and II of DH receiving their inputs.We investigated changes one week after the injury induced by the spared nerve injury model of NP. We employed the laser capture microdissection (LCM) for the procurement of specific cell-types (enrichment in nociceptors of injured/non-injured neurons) and laminae in combination with transcriptional analysis by microarray. In addition, we studied functionál properties and currents of sodium channels (Nav1s) in injured and neighboring non-injured DRG neurons.Microarray analysis at the periphery between injured and non-injured DRG neurons and centrally between the area of central projections from injured and non-injured neurons show significant and differential expression patterns. We reported changes in injured nociceptors (1561 genes, > 1.5 fold, >77% pairwise comparison) and in corresponding DH laminae (618 genes), while less modifications occurred in non-injured nociceptors (60 genes) and in corresponding DH laminae (459 genes). At the periphery, we observed by Gene Ontology the involvement of multiple biological processes in injured neurons such as signal transduction, cytoskeleton organization or stress responses. On contrast, functional overrepresentations in non-injured neurons were noted only in metabolic or developmentally related mechanisms. At the level of superficial laminae of the dorsal horn, we reported changes of immune and inflammatory processes in injured-related DH and changes associated with synaptic organization and transmission in DH corresponding to non-injured neurons. Further transcriptional analysis of Nav1s indicated several changes in injured neurons. Functional analyses of Nav1s have established no difference in tetrodotoxin-sensitive (TTX-S) current densities in both injured and non-injured neurons, despite changes in TTX-S Nav1s subunit mRNA levels. The tetrodotoxin-resistant (TTX-R) voltage dependence of steady state inactivation was shifted to more positive potentials in both injured and non-injured neurons, and the rate of recovery from inactivation of TTX-S and TTX-R currents was accelerated in injured neurons. These changes may lead to alterations in neuronal electrogenesis. Taken together, these findings suggest different mechanisms occurring in the injured neurons and the adjacent non-injured ones. Moreover, central changes after injury are probably driven in a different manner if they receive inputs from injured or non-injured neurons. Together, these distinct and complex modulations may contribute to NP.

IPH response to consultation: Introduction of 20mph speed restrictions on smaller residential streets

Conall McDevitt (SDLP MLA) launched a consultation regarding the introduction of 20mph speed restrictions in residential streets as part of his bid to introduce legislation through a Private Members Bill in the Northern Ireland Assembly.  The purpose of the Bill is to increase road safety, particularly for pedestrians and other road users, with additional health and environmental benefits. IPH submitted a response to the Private Members’ Bill regarding the introduction of 20mph speed restriction on smaller residential roads.  IPH recognises the potential public health benefits of this proposal in terms of reduced injuries and fatalities in built up areas; more opportunities for walking and cycling (helping to tackle obesity and reduce the risk of diabetes, heart disease and stroke); greater social cohesion among communities and improved mental health; and reduced emissions that contribute to climate change, air and noise pollution.

IPH response to Road Safety Authority Ireland Road Safety Strategy 2013-2020

The Road Safety Authority has responsibility for co-ordinating the development of Ireland’s Road Safety Strategy.  The Government’s road safety target of no more than 252 deaths per annum by the end of 2012 was achieved in 2009, when the number of road collision deaths in Ireland fell to 239.  The reduction in the number of fatalities was achieved through robust actions in terms of education and awareness, road engineering, and enforcement, including significant legislative milestones.  The challenge is now to ensure that the impact of these measures on collision levels is sustained and enhanced into the future through continuous education, enforcement and road engineering measures and initiatives. IPH welcomes the opportunity to respond to this consultation given the significant burden of injury, disability and mortality associated with road traffic collisions on the island of Ireland.  IPH supports the development of evidence-based strategies and actions which can maintain a transport system, in which the safety of all road users is paramount. 

IPH response to Broadcasting Authority of Ireland (BAI): General and Children's Commercial Communications Codes (June 2012)

IPH submitted their views on the Draft BAI General and Commercial Communications Code. IPH previously submitted views to the BAI in the first phase of consultation (Oct 2011). The final code will regulate the advertising of food and non-alcoholic beverages that are high in fat, salt or sugar on Irish television channels. The submission sets out approaches to appropriate scheduling and content restrictions as well as to possible exemptions.

IPH response to Your Health is Your Wealth – Health and Wellbeing Framework 2012- 2020 (Department of Health)

The remit of the Institute of Public Health in Ireland (IPH) is to promote cooperation for public health between Northern Ireland and the Republic of Ireland in the areas of research and information, capacity building and policy advice. Our approach is to support Departments of Health and their agencies in both jurisdictions, and maximise the benefits of all-island cooperation to achieve practical benefits for people in Northern Ireland and the Republic of Ireland. The Department of Health is developing a Health and Wellbeing policy to improve the health of the population and reduce health inequalities by addressing causes of preventable illnesses. The Policy Framework is at an advanced stage with a number of background analytical documents prepared and published on the Department website to allow views to be incorporated into final drafts.  IPH responded to the consultation call in 2011 and we welcome the placement of these supporting documents on the Department website with the request for additional comments.

IPH response to the DSD consultation on regulations to prohibit or restrict irresponsible promotions of alcohol in Northern Ireland

IPH responded to the Department for Social Development consultation on the banning of certain promotions that may encourage irresponsible and excessive drinking. The consultation relates to regulations Article 57A(2)(d) of the 1996 Licensing Order “involving the supply of unlimited amounts of intoxicating liquor for a fixed charge (including any charge for entry to the premises)” and Article 31A(2)(d) of the Registration of Clubs Order “restricting the price at which the holder of a licence or the licence holder’s servant or agent may sell on licensed premises a package containing two or more intoxicating liquor products”. IPH welcomes this consultation and supports the Department’s proposals to restrict promotions that involve the supply of unlimited amounts of intoxicating liquor for a fixed charge. IPH welcomes this tangible action linked to the renewed commitment to tackling alcohol-related harms on the island of Ireland set out in the Steering Group Report on a National Substance Strategy (Dept of Health, 2012) and in the New Strategic Direction on Alcohol and Drugs (DHSSPS, 2011). IPH considers that irresponsible alcohol promotions can contribute to this burden of physical and mental ill-health, accidental and non-accidental injury and other harms associated with excessive alcohol consumption in Northern Ireland. As previously stated in the IPH submissions on the introduction of powers to prohibit or restrict irresponsible alcohol promotions (Dec, 2010), IPH considers that the issues of promotion and price are inter-related. The effectiveness of the proposed restrictions could be reinforced by the expeditious introduction of minimum unit pricing of alcohol on an all-island basis.

IPH response to Seanad Consultation Committee on 'Changes in lifestyle can prevent approximately one third of cancers. How does Government and Society respond to this challenge?'

IPH responded to the Seanad Consultation Committee on the consultation topic ‘Changes in lifestyle can prevent approximately one third of cancers.  How does Government and Society respond to this challenge?’. Between 2010 and 2020 the total number of cancers in Ireland is projected to increase by 40% for women and by just over 50% for men (National Cancer Registry).  A focus is needed on developing social, economical and built environments that support healthy choices. IPH presented recommendations based on the international evidence-base as well as national cancer data and research.

IPH response to Building an Active Travel Future for Northern Ireland

IPH responded to the Department for Regional Development consultation Building an Active Travel Future for Northern Ireland, March 2012 The draft Active Travel strategy seeks to set out how to increase active travel by demonstrating that walking and cycling are safe, healthy, flexible, inexpensive and social means of travel and by setting out ways in which opportunities for active travel can be significantly improved.IPH welcomes the new Active Travel Strategy and highlights the need for a truly integrated approach to the strategy which has the potential to positively influence health in areas such as obesity, mental health and cardiovascular health.  IPH suggest a health impact assessment is undertaken on each of the Active Travel Demonstration projects to fully maximise the potential health outcomes of developing the required infrastructure for active travel.

IPH response to the Joint Committee on Health and Children and members of the Northern Ireland Assembly on “Cross-border cooperation on healthcare”

The Institute of Public Health in Ireland were asked to submit a paper on 'Cross-border cooperation on healthcare' for a joint meeting between the Oireachtas Joint Committee on Health and Children and the Northern Ireland Assembly Health Committee which took place in Leinster House on 1 March 2012. Key points from the submission included: o    The Institute of Public Health in Ireland (IPH) is an all-island organisation which promotes cooperation between the Republic of Ireland and Northern Ireland with the aim of improving population health on the island and tackling health inequalities. IPH work is focused on addressing the causes of ill health rather than the design and delivery of treatment services. o    North/South cooperation on health was mandated under the Belfast Agreement in 1998 in five domains, including health promotion. IPH has supported the North South Ministerial Council (NSMC) in respect of the health promotion strand since inception. o    The Department of Health and Department of Health, Social Services and Public Safety North-South Feasibility Study (December 2011) states that mutual benefits are most evident from cooperation in the areas of (i) anticipating trends and illnesses in a collective manner (ii) public health issues (iii) specialised services where the population or activity required to sustain the service cannot be met by either jurisdiction alone and (iv) in relation to those areas adjacent to the border. o    The European Directive on Cross-Border Healthcare will be implemented in the next few years which will have implications in relation to patients travelling for healthcare across the Republic of Ireland/Northern Ireland border. o    IPH is supporting the development of new public health strategies in the Republic of Ireland and Northern Ireland which are both due for publication this year. o    There are tangible benefits from cross-border cooperation in the health sector, both in public health and in health service planning and delivery and there are many examples of successful initiatives. However, developments are not occurring in the context of an agreed plan or overall strategic context and tend to be project-based and concentrated in border counties. o    Successful cross-border cooperation requires high level support and integration into departmental policy cycles. The provision of data on an all-island basis supports cross-border cooperation as does the operation of sustainable all-island organisations which can support research, evaluations and programmes. o    In the future, cross-border cooperation in health will be more effective if developed with a strategic planning process intrinsically linked to Departmental priorities. o    North-South cooperation in the areas of alcohol, obesity, tobacco health surveys and rare diseases will be particularly beneficial.

IPH Response to draft Framework for Sustainable Development for Ireland

The Minister for the Environment, Community and Local Government, Mr Phil Hogan has launched a draft Framework for Sustainable Development for Ireland for public consultation. The objectives of the draft Framework are to identify and prioritise policy areas and mechanisms where a sustainable development approach will add value and enable continuous improvement of quality of life for current and future generations and set out clear measures, responsibilities and timelines in an implementation plan.

IPH Response to draft Northern Ireland Programme for Government 2011-15

On 17 November 2011, the First Minister and deputy First Minister published the draft Programme for Government 2011-2015 for consultation. IPH recognise that health is influenced by a wide range of social determinants, including economic, biological, environmental and cultural factors such as housing, the environment, income, employment and access to education and health services . Improvements to health can be achieved through a well-designed PfG which addresses the economy, creates safer communities and delivers efficient public services.  IPH welcome this opportunity to submit our views to the Northern Ireland Executive on the Draft Programme for Government 2011-15. Key points from the IPH response include: • Northern Ireland has a poor population health status in key areas when compared to other regions in the United Kingdom and in the Republic of Ireland. IPH support and particularly welcome allocation of an increased proportion of the Northern Ireland budget to public health. • IPH endorses the perspective in the PfG that good population health makes a central contribution to economic and social development.   However we would welcome greater acknowledgement of the links between social deprivation and health outcomes.  • IPH welcomes the adoption of a social determinants of health approach to improving population health and tackling health inequalities which is in line with current health policy and recent policy developments across the United Kingdom and internationally (See report of the Commission on the Social Determinants of Health (CSDH))

IPH response to NICE consultation on new indicators for Quality and Outcomes Framework (QOF)

IPH responded to the consultation on potential new indicators for the 2013/14 Quality and Outcomes Framework (QOF) in the UK. The 20 potential new indicators relate to chronic obstructive pulmonary disease (COPD), heart failure, coronary heart disease, diabetes, depression, hypertension, rheumatoid arthritis, asthma and cancer. The consultation asked people to consider whether there were any barriers to the implementation of the care described by any of the indicators; whether there were potential unintended consequences to the implementation of any of the indicators; whether there was potential for differential impact (in respect of age, disability, gender reassignment, pregnancy and maternity, race, religion or belief, sex and sexual orientation); and whether the indicators may have an adverse impact in different groups in the community.”

IPH response to RICHE questionnaire on child health research in Europe

Request to participate in an expert group review of child health research gaps and priorities in Ireland and Northern Ireland IPH responded to a questionnaire from the FP7 funded project - RICHE ( www.childhealthresearch.eu). The project goal is to produce an inventory of child health research in Europe, identify gaps in existing and on-going research, and devise a series of roadmaps for the future of child health research. This is co-ordinated by Anthony Staines from DCU, and Michael Rigby, from the Nordic School. This specific phase of the project is being co-ordinated by Matilde Leonardi and Giorgio Tamburlini in Italy.

IPH response to Social Investment Fund Consultation

The Social Investment Fund aims to reduce poverty, unemployment and physical deterioration in areas through area based interventions of significant scale which will be delivered in partnership with communities. The fund will encourage communities, statutory agencies, businesses and departments to work together in a coordinated way, reducing duplication, sharing best practice and enhancing provision for the benefits of those communities most in need. IPH calls for a consideration of health to be included in the Social Investment Fund.  Each of the four objectives of the programme will have the potential to positively impact on health by increasing education attainment and skill levels, tackling deprivation, increasing community support and enhancing the physical regeneration of communities.  IPH also call for greater clarification on the links with other area based partnerships.

IPH Response to Dept of Justice and Equality Review of the Code of Practice on the Sale and Display of Alcohol in Mixed Trading Premises

IPH responded to the Department of Justice, Equality and Defence review of the voluntary Code of Practice for the display and sale of alcohol in supermarkets, convenience stores and similar mixed trading outlets. The voluntary Code was introduced in 2008 as an alternative to the statutory rules for structural separation of alcohol products in mixed trading outlets which are set out in section 9 of the Intoxicating Liquor Act 2008. Interested bodies and individuals were invited to submit comments on the Compliance Report for 2011 and on the effectiveness of the voluntary approach to structural separation by 20th December 2011. The Minister said he intended to also seek the views of the Minister for Health and the Joint Oireachtas Committee on Justice, Defence and Equality before reaching any decision on whether to bring the statutory rules in the 2008 Act into operation.