Infant Pain Mechanisms- short and long term effects

Lead Research Organisation: University College London
Department Name: Cell and Developmental Biology

Abstract

Many children are exposed to considerable pain as a result of disease processes, surgery or intensive care therapies but despite this, too few paediatric patients receive adequate pain relief. This problem has largely arisen because of lack of a scientific basis for clinical pain management. This proposal focuses upon developing pain pathways in the rat with the aim of providing the fundamental knowledge required to understand and prevent paediatric pain. A better understanding of the short and long term effects of infant pain will be gained by studying the underlying synaptic reorganisation and strengthening of nociceptive circuitry within the dorsal horn over the critical postnatal period and how that circuitry may be altered by excessive or inappropriate noxious inputs in early life. Specific questions addressed are A. How does the sensory dorsal horn circuitry underlying spinal pain processing become organised over the postnatal period? B. What are the mechanisms of action of key analgesics on dorsal horn pain processing in infants? C. How does alteration of sensory activity through early pain and injury influence developing sensory pathways? The study will increase our basic understanding of pain processing in young children and how it can be controlled by pain relieving drugs.

Technical Summary

Many children are exposed to considerable pain as a result of disease processes, surgery or intensive care therapies but despite this, too few paediatric patients receive adequate pain relief. This problem has largely arisen because of lack of a scientific basis for clinical pain management. This proposal focuses upon developing pain pathways in the rat with the aim of providing the fundamental knowledge required to understand and prevent paediatric pain. A better understanding of the short and long term effects of infant pain will be gained by focussing upon the underlying synaptic reorganisation and strengthening of nociceptive circuitry within the dorsal horn over the critical postnatal period and upon how that circuitry may be altered by excessive or inappropriate noxious inputs in early life. Specific questions addressed are A. How does the sensory dorsal horn circuitry underlying spinal pain processing become organised over the postnatal period? B. What are the mechanisms of action of key analgesics on dorsal horn pain processing in infants? C. How does alteration of sensory activity through early pain and injury influence developing sensory pathways? Dorsal horn cell activity will be recorded in rat pups of different postnatal ages using whole cell patch recording in spinal cord slices and extracellular recording in anaesthetised rat pups. Key projection neurons in laminae I and V will be identified by antidromic stimulation or retrograde labelling. Integrated output of dorsal horn activity will be measured using flexion reflex EMG responses. Afferent A and C fibre evoked excitatory and inhibitory synaptic activity, receptive field properties and the pattern of nociceptive and non-nociceptive activity will be investigated over the first three postnatal weeks. Identified cells filled from patch recording will be analysed morphologically and for inhibitory and excitatory receptor subunit expression. The efficacy and mechanisms of action of spinal and systemic analgesic agents in current clinical use will be tested using nociceptive EMG responses in neonatal pain models. The underlying developmental regulation of receptor expression and function will be elucidated with selective pharmacological agents and antibodies using dorsal horn cell electrophysiology and receptor expression. The role of activity on the development of dorsal horn circuits will be established using chronic peripheral and spinal administration of local anaesthetics and receptor blockers and in long term follow-up models of early infant pain. The study will provide important data on the activity dependence and long term effects of injury on pain development.

Publications

10 25 50

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Bremner LR (2008) Postnatal tuning of cutaneous inhibitory receptive fields in the rat. in The Journal of physiology

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Costigan M (2009) T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Fitzgerald M (2006) Infant pain traces. in Pain

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Hathway G (2006) A postnatal switch in GABAergic control of spinal cutaneous reflexes. in The European journal of neuroscience

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Hathway GJ (2006) Time course and dose-dependence of nerve growth factor-induced secondary hyperalgesia in the mouse. in The journal of pain : official journal of the American Pain Society

 
Description RCOG Guideline committee on fetal pain (Royal College of Obstetricians and Gynaecologists)
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact For all professionals in the field but also accessible to public, media and policy makers
URL https://www.rcog.org.uk/en/guidelines-research-services/guidelines/fetal-awareness---review-of-resea...
 
Description Science Technology Committee on Scientific Developments Relating to the Abortion Act
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact Influenced abortion law
URL https://www.rcog.org.uk/en/guidelines-research-services/guidelines/fetal-awareness---review-of-resea...
 
Description MRC DTA PhD studentship
Amount £50,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 10/2010
 
Description MRC PhD Studentship
Amount £45,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 10/2009
 
Description MRC Project Grant
Amount £815,257 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2007 
End 01/2010
 
Description MRC programme grant
Amount £1,609,398 (GBP)
Funding ID G0901269 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2009 
End 06/2015
 
Description Two Nuffield student bursaries
Amount £2,220 (GBP)
Organisation Nuffield Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2008 
End 09/2008
 
Description Wellcome PhD studentship
Amount £81,576 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 10/2009
 
Title animal models of early life pain experience 
Description Models of neonatal surgery or intensive care stress and pain 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Will be able to explore preventative approaches 
 
Description Anesthesiology, University of Cincinnati 
Organisation University of Cincinnati
Department Department of Anesthesiology
Country United States 
Sector Academic/University 
PI Contribution Expertise in developmental plasticity of pain and small animal surgery
Collaborator Contribution Training a postdoc,Dr Ingram, in whole cell patching
Impact 19675290 18400957
Start Year 2007
 
Description Anesthesiology, Wake Forest University School of Medicine, North Carolina 
Organisation Wake Forest University
Department Wake Forest School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Dr Ririe was a visiting research fellow to the lab where he learned in vivo electrophysiology and carried out this project
Collaborator Contribution Strong research and clinical links
Impact 18813050
Start Year 2008
 
Description Neuroscience, Harvard Medical School 
Organisation Boston Children's Hospital
Country United States 
Sector Hospitals 
PI Contribution Developmental approach to understanding neuroimmune interaction in the onset and maintenance of neuropathic pain
Collaborator Contribution Help with analysis of microarray results
Impact 19923276
Start Year 2007
 
Description UCL ICH paediatric pain research 
Organisation University College London
Department Developmental Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution expertise in neurobiology of pedaitric pain research, electrophysiology training
Collaborator Contribution clinical perspective
Impact Clinical/scientific meetings and discussion groups. Research projects
 
Description Government Select Committee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Evidence to the House of Commons Science and Technology Committee on Scientific Developments Relating to the Abortion Act.

This evidence was very important for the shaping UK law in this area.
Year(s) Of Engagement Activity 2007
 
Description MRC showcase meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Invited Speaker at MRC Showcase meeting of innovative science for industry, Bristol

Feedback was good
Year(s) Of Engagement Activity 2008
 
Description Royal College Committee 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Member of a Committee that wrote a report on Fetal Pain for Royal College Ostetricians and Gynaecologists

Major professional body - will influence opinion around the world
Year(s) Of Engagement Activity 2008
URL https://www.rcog.org.uk/en/guidelines-research-services/guidelines/fetal-awareness---review-of-resea...
 
Description public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact UCL Lunchtime lecture. Open to public - advertised in Time Out etc.
UCL Neuroscience Society lecture - facebook, twitter, U-tube

Good feedback
Year(s) Of Engagement Activity 2006,2013
URL http://www.youtube.com/user/uclneurosoc
 
Description schools visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Schools
Results and Impact Lab demos for 'Next Generation Science' British Council Netherlands sponsored event for students and teachers from British and Dutch schools.

Very good feedback from participants
Year(s) Of Engagement Activity 2006,2008