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dc.contributor.authorDowd, Eilísen
dc.date.accessioned2018-01-31T11:42:50Z
dc.date.available2018-01-31T11:42:50Z
dc.date.issued1999en
dc.identifier.urihttp://hdl.handle.net/1842/27936
dc.description.abstracten
dc.description.abstractThe development of novel analgesics would be facilitated if the mechanisms underlying nociception and inflammatory pain were fully understood. Adenosine 5'triphosphate (ATP) and adenosine can cause pain in humans when applied to a blister base, but the algogenic mechanism of action is still unclear. Cells contain millimolar concentrations of ATP, which is released into the extracellular space when the cells are damaged, and is subsequently metabolised to adenosine. Consequently, levels of the purines are increased in damaged, inflamed or ischemic tissues and this makes them ideal candidates to signal the presence of tissue injury. It is thought that ATP and adenosine might be involved in the initiation of pain by directly or indirectly activating distinct subtypes of P2 or P 1 receptors respectively. 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.en
dc.description.abstractATP 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 neurones in the trigeminal and dorsal root iii ganglia respectively, these cells were retrogradely labelled using fluorogold and subsequently examined for co- localisation of fluorogold 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.en
dc.description.abstractImmunoreactivity 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 neurones in the dorsal root ganglia. ATP, the stable P2X1 and P2X3 selective agonist, aß- methylene ATP and the P2 agonists, ATPyS 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 ATPyS also caused a delayed- onset, long- lasting increase in firing which was probably mediated by adenosine Al receptors since adenosine, and the Al selective agonists GR79236 and CPA evoked a similar response. These slow -onset responses were antagonised by the Al selective antagonist DPCPX. Paradoxically, systemic injections of DPCPX were not analgesic in behavioural studies, while the adenosine uptake inhibitor, dipyridamole, which increases the extracellular levels of endogenous adenosine, was. GR79236 had no effect on the pain of arthritis but did possess anti -inflammatory properties. The ability of ATP to indirectly activate rat knee joint nociceptors via P2X7 receptors expressed on inflammatory cells was assessed by injecting high concentrations of BzATP, ATPyS and ATP intraiv articularly to the knee joint and monitoring their effects on spontaneous and bradykinin- evoked neural discharge. BzATP did not cause any increase the basal action potential discharge rate nor did it sensitise the nociceptors to bradykinin. The data from the other agonists was complicated by their metabolism to adenosine but, like BzATP, no evidence was found for a sensitising effect.en
dc.description.abstractThis data supports the hypothesis that ATP and its metabolite, adenosine can directly excite nociceptors innervating the rat knee joint via P2X and Al receptor subtype(s), respectively. However, it does not support a role for P2X mediated initiation of pain from the cat or rat cornea nor does it indicate that ATP could cause pain via an indirect action on inflammatory cells. These findings have implications for the development of novel therapies for the treatment of pain.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2017 Block 16en
dc.relation.isreferencedbyAlready catalogueden
dc.titleThe role of ATP and adenosine in nociception and inflammatory painen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelen
dc.type.qualificationnamePhD Doctor of Philosophyen


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