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Title: The role of ATP and adenosine in nociception and inflammatory pain
Author: Dowd, Eilís
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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In this thesis, behavioural, electrophysiological, and immunohistochemical techniques were used to test the hypothesis that ATP and adenosine are involved in the initiation of pain by directly and/or indirectly activating nociceptors innervating the cornea and the knee joint in vivo. ATP and ATP analogues were administered to the normal cat cornea and the normal rat knee joint under pentobarbitone anaesthesia and their effects on the discharge of nociceptors innervating these tissues were recorded. The effects of inflammation caused by photorefractive keratectomy of the cornea or Freund's adjuvant induced monoarthritis of the knee joint on the sensitivity to the purines was also determined. In behavioural studies, ATP analogues were instilled into the eyes of conscious rats and any changes in behaviour indicative of pain were assessed. To establish whether the P2X3 receptor subtype for ATP was expressed in the cell bodies of mouse corneal and rat knee joint neurons in the trigeminal and dorsal root ganglia respectively, these cells were retrogradely labelled using fluoro-gold and subsequently examined for co-localisation of fluoro-gold fluorescence with P2X3 immunoreactivity. Adenosine and adenosine analogues were also administered to the normal and arthritic rat knee joint and, in behavioural studies, the effect of adenosine agonists, adenosine antagonists and increasing the levels of endogenous adenosine on the pain and inflammation associated with experimental arthritis were determined. Immunoreactivity to P2X3 receptors was found in cell bodies of mouse corneal nociceptors, but none of the ATP analogues tested excited cat corneal nociceptors or caused pain when instilled into the eyes of conscious rats. The P2X3 subtype was also expressed in knee joint neurons in the dorsal root ganglia. ATP, the stable P2X1 and P2X3 selective agonist, αβ-methylene ATP and the P2 agonists, ATPγS and benzoylbenzoyl ATP (BzATP), caused a rapid-onset, short-lasting increase in action potential discharge from nociceptors innervating the rat knee joint. These responses were antagonised by the P2 antagonist PPADS. ATP and ATPγS also caused a delayed-onset, long-lasting increase in firing which was probably mediated by adenosine A1 receptors since adenosine, and the A1 selective agonists GR79236 and CPA evoked a similar response. These slow-onset responses were antagonised by the A1 selective antagonist DPCPX.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available