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dc.contributor.authorDickinson, Traceyen
dc.date.accessioned2018-05-14T10:12:23Z
dc.date.available2018-05-14T10:12:23Z
dc.date.issued1998
dc.identifier.urihttp://hdl.handle.net/1842/29729
dc.description.abstracten
dc.description.abstractChronic constriction injury (CCI) of the rat sciatic nerve, produces an animal model ofperipheral neuropathy exhibiting abnormal pain states similar to those seen in man, including behavioural signs of spontaneous pain, hyperalgesia and allodynia. Many components ofneuropathic pain are resistant to classical opioid analgesics, and anaesthetic nerve blocks or surgical sympathectomies often provide only temporary relief. Since the expression ofVasoactive Intestinal Polypeptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is markedly up-regulated in dorsal root ganglia following peripheral nerve injury, we investigated whether VIP/PACAP receptors are important regulators of the amplified sensory responses which develop following neuropathy.en
dc.description.abstractThis study addressed the role of VIP₁, VIP₂ and PACAP receptors with regard to the responses of dorsal horn neurones in normal compared to CCI animals, using novel selective agonists and antagonists. In electrophysiological experiments on anaesthetised rats, the effects of ionophoretic application of VIP₁, VIP₂ and PACAP receptor antagonists were investigated on neuronal activity induced by innocuous brushing or cold stimulation of the cutaneous receptive field, or following peripheral application of the chemical algogen mustard oil. In normal rats, VIP₁ and PACAP receptor antagonists appeared to exert a general modification of dorsal horn neurone responses, inhibiting both brush- and mustard oil-induced activity to similar extents. In contrast, a novel VIP₂ receptor antagonist selectively inhibited mustard oil-evoked activity, whilst showing negligible effects on brush-evoked activity.en
dc.description.abstractThe effects of the VIP/PACAP receptor antagonists changed markedly in CCI animals so that antagonists for all three receptor subtypes showed negligible effects on brush-induced activity of dorsal horn neurones. In contrast, VIP,/PACAP receptor antagonists significantly inhibited cold-induced activity, while a VIP₂ receptor antagonist had little effect. However, mustard oil-induced activity was significantly inhibited by all three receptor antagonists in CCI animals.en
dc.description.abstractThe activity of single, multireceptive dorsal horn neurones was markedly increased following ionophoretic administration of selective VIP₁, VIP₂ and PACAP receptor agonists both in normal and CCI rats. Following nerve injury however, two main differences were apparent, and these may reflect changes in receptor expression: the number of dorsal horn neurones activated by the VIP2 receptor agonist doubled (these neurones also showed a greater extent of cell activation than those excited in normal animals), while the percentage of neurones activated by the VIP, receptor agonist was seen to decrease. The proportion of cells activated by the PACAP receptor agonist remained unchanged.en
dc.description.abstractIn addition, in situ hybridisation histochemistry (ISHH) detection ofmRNA for the three receptor subtypes, was employed to monitor any changes in receptor expression following nerve injury. This study revealed that CCI of the rat sciatic nerve produced a significant increase in the expression of VIP₂ receptor mRNA in laminae III/IV of the spinal dorsal horn. In contrast, VIP₁ receptor mRNA was seen to markedly decrease, while the expression of mRNA for the PACAP receptor appeared to be unchanged.en
dc.description.abstractIn conclusion, these results provide evidence that VIP/PACAP receptors may be important mediators/modulators ofthe transmission of sensory information at the spinal cord level, underlining the potential for VIP/PACAP receptor antagonists as new analgesics, particularly for use in currently intractable neuropathic pain states. These data demonstrate the involvement of the VIP₂ receptor in the transmission of nociceptive (C-fibre-mediated) information, both in normal and neuropathic animals. Although VIP, and PACAP receptor antagonists are rather non-selective inhibitors of sensory inputs in normal states, they may represent useful analgesics for certain aspects of allodynia (for example cold) as well as for polymodal C-fibre responses in neuropathy.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 18en
dc.relation.isreferencedbyAlready catalogueden
dc.titleThe role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathyen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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