La Hausse De Lalouviere, LPA; (2013) The processing of inflammatory joint pain in the developing spinal cord. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Approximately 10 in 100,000 children develop inflammatory arthritis every year and a large proportion of those are diagnosed as having Juvenile Idiopathic Arthritis (JIA). A major cause of suffering in the disease is pain, and indeed it contributes significantly to the morbidity of this condition when assessed by various disability scores. Pain from affected joints causes sleep disturbance, limits normal activities, disrupts school attendance and results in considerable psychosocial stress. Very little is understood about arthritic pain processing in the immature nervous system. Both clinical and neurobiological studies in animal models show that CNS nociceptive connections differ in juveniles and adults and that the normal maturation of these connections depends upon early life stress and pain experience. The immaturity of synaptic connections and integrated circuits means that children’s pain experience is different from that of adults and may impact upon pain in later life. It was our aim to develop and characterise a rodent model of joint inflammation to better understand the neurobiological basis of joint pain in early life and to establish whether joint inflammation in childhood influences joint pain sensitivity as an adult. In the first results chapter (Chapter 2), the normal development of joint evoked and cutaneous reflexes were mapped out over the postnatal period. In the second Results chapter (Chapter 3), monoarthritis of the ankle was induced in Sprague-Dawley rats of different postnatal ages using complete Freund’s adjuvant (CFA) and the effect of this inflammation upon spinal circuits was studied using behavioural and electrophysiological measures. Electromyographic (EMG) recordings show that inflammation leads to widespread reflex hypersensitivity to mechanical stimuli in young animals that differs significantly from the effects of adult joint inflammation. In adults, a significant attenuation of reflexes, or ‘protective inhibition’ phase was observed at 24 hours and 4 days post-inflammation, followed by a ‘hypersensitivity phase’ at 10 days when reflexes to pinch were dramatically enhanced. These effects were not detected with simple behavioural observation. In the third results chapter (Chapter 4), the long-term effects of joint inflammation (6 weeks) were investigated and shown to be highly dependent upon the age at which the inflammation occurred. Baseline nociceptive reflexes were enhanced in animals that had experienced joint inflammation when young (postnatal day (P) 8) but slightly reduced if the inflammation had occurred at the same time interval, but in adult life. The effects of a second injury in adulthood also depended on the past history of the animal. Animals first inflamed in early life, displayed a significantly greater ‘protective inhibition’ than adult inflamed controls, while animals first inflamed in adult life displayed enhanced hypersensitivity to joint inflammation. The results here describe previously unknown characteristics and mechanisms of joint pain in early life which will contribute to a better understanding and treatment of pain in JIA.

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