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Developmental aspects of NMDA antagonist sensitivity in rats - An electromyographic study using the withdrawal reflex

de Lima, Jonathan Carlos; (2000) Developmental aspects of NMDA antagonist sensitivity in rats - An electromyographic study using the withdrawal reflex. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

NMDA antagonists play an adjunctive role in many clinical pain management regimens including those in paediatric post-operative care. Progressive alterations in NMDA receptor structure and function during development have been well established. These changes may lead to significant changes in the antinociceptive effects of NMDA antagonists during this period. Unfortunately, pharmacodynamic studies of analgesic agents in human infants are fraught with methodological and ethical difficulties. Non-clinical means of investigating pain states and analgesic efficacy during early development are therefore particularly useful for defining appropriate paediatric dosing schedules. The research project undertaken here is aimed at establishing an animal model for quantitative assessment of analgesic drug effects relevant to acute post-operative pain states. By studying an inflammatory state in rat pups at three ages, the study attempts to define age- related changes in the antinociceptive effects of NMDA antagonists. The model is based on electromyographic recording of the hindlimb withdrawal reflex. Age related changes in the features of this reflex have been studied and described. The reflex has been used to characterise a carrageenan-induced inflammatory state at three developmental stages (Postnatal day 3, 10 and 21). The antinociceptive effects of epidurally delivered drugs on this state have then been assessed. Ketamine, aminophosphonopentanoic acid (AP5) and morphine were injected epidurally and the effects on the EMG recordings determined. Dose-response curves have been created for each agent at the three developmental stages mentioned above. Age related changes in drug sensitivity have been defined by comparing ED50 values estimated from the dose-response curves generated. At all three developmental stages tested, carrageenan inflammation significantly potentiated the withdrawal reflex. In carrageenan-inflamed pups the response was dose- dependently reduced by epidural ketamine, AP5 and morphine at doses that were ineffective if given systemically. NMDA antagonists (ketamine and AP5) did not have this effect in non-inflamed pups. The following ED50 values were estimated from dose-response curves. [diagram] This animal model has successfully provided a means of assessing antinociceptive effects of drugs active at the level of the spinal cord during early development.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Developmental aspects of NMDA antagonist sensitivity in rats - An electromyographic study using the withdrawal reflex
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Clinical pain management
URI: https://discovery.ucl.ac.uk/id/eprint/10099656
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