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Past Research
Using RNA interference to study the role of potassium channels in neuropathic pain
One of the main mechanisms for the emergence of neuropathic pain is increased spontaneous activity of neuronal components in the nociceptive pathway. Ion channels are undoubtedly implicated in the determination of a neuron?s intrinsic electrical activity and therefore their ability to generate high frequencies of action potentials. Research has traditionally focused on a number of sodium channels, mainly Nav1.7, Nav1.8 and Nav1.3, as candidates responsible for the increased ectopic activity seen in chronic pain. Recent data however indicates that mice lacking these genes develop neuropathic pain normally.

Potassium channels have mainly been explored as drug targets to reverse chronic pain symptoms by reducing the excitability of the affected neurons. Although there is circumstantial evidence for a role of a number of voltage-gated potassium channels (Kv) in chronic pain, definitive evidence is lacking. Our hypothesis is that reduced expression of Kv channels can contribute to the development of neuropathic pain, by mediating increased neuronal ectopic activity.

Our potassium channel targets are derived from a microarray study that demonstrated down-regulation of voltage-gated potassium channels (Kv) in a peripheral nerve injury model. Some of the candidates encode functional channels with widespread distribution in the nervous system, while others are electrically silent but encode subunits that potentially regulate other Kv channels. Elucidation of how the interaction and relative expression levels of Kv subunits influence neuronal excitability and promote ectopic activity, could be a significant advance in our understanding of the genesis of pain.

We aim to experimentally induce a similar down-regulation by using non-integrating lentiviral vectors encoding shRNAs against these targets. These vectors are safer for clinical applications and in preliminary experiments have been shown to efficiently transfect neuronal cells in vitro and in vivo, featuring prolonged expression as well. After validating the microarray data by RT-PCR, we will use such vectors to transfect DRG neurones in culture and down-regulate the expression of the genes of interest. The hypothesis is that this will allow us to simulate components of neuropathic pain. Co-transfection experiments with vectors encoding shRNAs against different Kv subunits will allow investigation of the synergistic effect of Kv current suppression. Cellular biology experiments will determine subunit interactions, patterns of localisation and how these are altered by the relative expression of the component subunits. Calcium imaging and patch-clamping of cultured neurons will explore how differential Kv expression influences the intrinsic neuronal excitability. Provided that the lentiviral vectors prove efficient for the knocking-down of genes in cells of interest, the experiments will be extended to the living organism. Electrophysiology and behaviour techniques will attempt to correlate electrical activity with pain phenotype.