Modulation of the sensitivity of nociceptive neurones by cannabinoids and SNSR

Change log
Honan, Stuart Andrew 

The sensation of pain is evoked when the body experiences noxious stimuli, and such stimuli are detected by specialised primary sensory neurones called nociceptors. Modulation of the sensitivity of these nociceptors occurs physiologically when they are exposed to inflammatory exudates. A fuller understanding of the means by which these neurones are modulated will provide relevant information for the rational development of analgesics. The receptors for cannabinoids, the active ingredients of cannabis, have been found in some primary sensory neurones. Given the known ability of these receptors to inhibit adenylate cyclase, the activation of which leads to the sensitisation of nociceptors, calcium imaging was used to assess if the application of a synthetic cannabinoid agonist (WIN 55,212-2) would attenuate the responsiveness of nociceptors in vitro. After examining this in both a nonsensitised model and a model of sensitisation employing prostaglandin E2 (PGE2), it was evident that, in the in vitro model employed, the method of activating cannabinoid receptors did not result in any significant effect. Another family of G-protein coupled receptors found exclusively in sensory neurones (Sensory Neurone Specific Receptors or SNSRs) were then examined to see if the application of their agonist, bovine adrenal medulla peptide (BAM (8-22)), modulated the response of nociceptors in vitro. A sub-population of neurones was seen to sensitise in their response to capsaicin after exposure to BAM (8-22). A selection of kinase inhibitors was then employed to elucidate the intracellular pathway involved in this sensitisation, and protein kinase C (PKC) was found to play a significant role. The specific PKC-isoform involved, however, was not able to be elucidated using immunocytochemistry. Whole cell patch clamp studies both confirmed the findings from the calcium imaging study, and established that the transient receptor potential vanilloid receptor itself was sensitised by the application of BAM (8-22).

Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Digitisation of this thesis was sponsored by Arcadia Fund, a charitable fund of Lisbet Rausing and Peter Baldwin.