The Translational Studies of Pain: From Spinal Neurones to Human Perception

The discovery of new treatments for chronic pain relies on the detection of pre-clinical targets and the progression to successful clinical trials. In order to improve this transition reliable translational models must be identified, based on mechanisms that underlie the symptoms of chronic pain. This thesis aimed to validate the use of 3 potential translational models: topical capsaicin, ultraviolet irradiation (UVB) and UVB rekindling. Furthermore, using a mechanism based approach to treatment, the modulation of capsaicin induced sensitisation was explored in animals and humans. In order to characterise the models in rats, in vivo electrophysiological recordings were made from single unit dorsal horn wide dynamic range neurones. Evoked responses to thermal, mechanical and electrical stimulation were quantified. To complement the animal studies, full QST profiling was undertaken on healthy human volunteers. Assessments of the pain thresholds were made, as well as numerical ratings to sub and supra threshold stimuli, in order to best compare these results with rodent data. All of the models tested evoked similar sensory changes across species, and the symptoms induced in each of the models were used to infer the peripheral and central components. Sensory changes evoked by capsaicin included mechanical hypersensitivity accompanied by a facilitation of responses in the Aδ fibre range. These are reflective of both a peripheral and central sensitisation. Furthermore, these changes were prevented by pre-treatment with the adenosine receptor 1 (A1R) agonist, CPA. UVB appeared to be a strictly peripheral model, resulting in no secondary changes or receptive field expansion. On the other hand, the UVB rekindling model showed clear signs of engaging both peripheral and central mechanisms, including thermal allodynia, secondary brush hypersensitivity and a facilitation of Aβ fibre responses. Overall, we confirmed that similar short-term sensory consequences, that may mimic certain pathophysiologies, could be engaged and quantified in rats and human volunteers in response to topical capsaicin, UVB irradiation and UVB rekindling. The UVB rekindling model induced signs of the engagement of a number of clinically relevant phenomena, such as peripheral inflammation/ sensitisation driving central modifications. As such this model will be useful in investigating mechanisms of inflammatory pain and assessing analgesic efficacy of novel medications