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Title: Investigations into the descending control of primary and secondary inflammatory hyperalgesia : a pronociceptive role for prostaglandin signalling in the periaqueductal grey
Author: Drake, Robert Andrew Rodger
ISNI:       0000 0004 5923 8320
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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The periaqueductal grey (PAG) together with downstream nuclei in the rostral ventral medulla (RVM) and adrenergic nuclei in the pons (e.g. Locus coeruleus) form the archetypal descending control network that is able to bi -directionally regulate the ascending flow of nociceptive information and so the level of perceived pain. Tissue damage leads to nociceptor sensitisation and an increase in sensitivity to noxious stimuli (hyperalgesia), which can develop within the site of tissue damage (primary hyperalgesia) as well as outside it (secondary hyperalgesia). Previous work from our laboratory demonstrates that COX activity and prostaglandin signalling within the ventrolateral PAG (vIPAG) facilitates spinal nociceptive processing in the normal animal. Work herein utilises a complete Freund's adjuvant (CFA) model of primary (s.c. paw) and secondary (La. knee joint) hyperalgesia to explore the hypothesis that this prostanergic descending facilitation (PDF) enhances spinal nociceptive processing and contributes to both primary and secondary hyperalgesia. Additionally, any differential control of A- and C-nociceptor inputs by the PAG was determined by using a ramping thermal stimulus protocol that preferentially activates A- or C-nociceptor inputs. Acute inflammation of the dorsal hind-paw (hairy skin) produced a primary mechanical, but not thermal hyperalgesia, and only a transient (-1h) sensitisation of reflex withdrawal evoked by A- and C-heat nociceptor activation. An equivalent inflammation in glabrous skin produced a persistent hyperalgesia (thermal/mechanical) and reflex sensitisation. The transience of reflex sensitisation in acute inflammation (<4h) was attributed to a rapidly acting descending noradrenergic inhibition, which could be blocked by the alpha-2-adrenoceptor antagonist yohimbine, affecting nociceptor inputs arriving from inflamed hairy, but not from glabrous, skin. There was no evidence for a contribution of PDF from the PAG to acute primary hyperalgesia in hairy skin. Prolonged (7 days) inflammation of the knee joint led to a secondary mechanical and thermal hyperalgesia of the hind-paw that was associated with a sensitisation of spinal processing of A-nociceptor inputs from the secondary site. Delivery of the non-selective COX inhibitor, ketoprofen, or a prostaglandin EP1 or EP3 receptor antagonist into the vIPAG, but not dIPAG, increased withdrawal thresholds to both A- and C-nociceptor activation in an area of secondary hyperalgesia. Moreover, antagonism of vIPAG EP3 receptors increased the firing threshold and reduced the stimulus encoding capacity of spinal dorsal horn wide dynamic range neurones to C-, but not A-, nociceptor activation in an area of secondary hyperalgesia. It was concluded that during prolonged inflammation, prostaglandin signalling in the vIPAG enhances spinal nociceptive processing of inputs arriving from the secondary hyperalgesic site and so contributes to secondary hyperalgesia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available