Friend, Lauren; (2018) Exploring dopamine function in the rat ventral tegmental area: the influence of persistent pain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes an investigation into the pharmacological and neurobiological nature of one of the key neural populations in the interactions between pain- and reward-related information - the dopaminergic (DA) neurones of the ventral tegmental area (VTA). The aim of these experiments collectively was to increase understanding of the functioning of the VTA neurones in various pain-related contexts, in the hope that this information will act as a foundation upon which further developments in knowledge occur. Ultimately, it is hoped that such advances in understanding could lead to the development of effective therapeutics down the line. Through a series of five projects employing intra-VTA in vivo electrophysiology in the anaesthetised rat in combination with a variety of pharmacological and nociceptive manipulations, the work described in this thesis explored the activity of spontaneously firing VTA neurones. Initial experiments attempted to both electrophysiologically and pharmacologically identify the DA neurones amongst interspersed non-DA populations in vivo. From a series of results, it was concluded that there was likely significant heterogeneity amongst VTA DA and non-DA groups, resulting in a confusing picture of cell identity. Through adopting the pharmacological measure of response to systemic L-DOPA injection, recorded neurone populations were reliably split into two sub-populations with a size, response direction and dose dependency in line with DA and GABAergic identities, respectively. However, neurochemical identity was not confirmed, and the possibility of alternatives was considered throughout the thesis. Subsequent investigations moved on to test how the induction of persistent pain altered the activity of VTA neurones: first in a carrageenan-induced tonic inflammatory pain model, and secondly, in a spinal nerve ligationinduced chronic neuropathic pain model. Concurrently, the role of endogenous µ-opioid receptor (MOR) agonists in regulation of VTA neurone activity was unmasked though administration of the MOR antagonist, naloxone. It was found that the induction of a tonic inflammatory pain state caused changes in the firing rate and pattern of VTA neurones subpopulations. An effect of naloxone on neuronal firing rate was no longer apparent in the tonic inflammatory pain state, suggesting a down-regulation of tonic µ-opioid control. Unexpectedly, neurones recorded in naïve and neuropathic pain states showed very similar characteristics. It was suggested that this result may be underlined by longer-term reactions to the sustained increased nociceptive input. Several possible explanations for the above results are discussed, along with the functional implications in terms of a wider role for VTA dopamine neurones in the pain-processing system. Finally, it was noted that the current methodology possessed a few inherent limitations when it comes to translating these findings to an awake, freely moving state, and that that future efforts should attempt to address these.

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