| Summary: | <p>Pain is a fascinatingly malleable sensory percept, evoking a unique experience for each individual. Most people who have experienced pain have an inherent understanding of its unpleasantness, and under most conditions this negative affect drives short- and long-term behavioural changes, which serve to protect organisms from potential further harm relating to the offending stimulus. Most commonly, pain is short-lasting, associated with observable physical damage to the body, and reversible. Chronic pain is long-lasting, persisting even after recovery of tissue damage, which can instil societal stigma towards sufferers. ‘Neuropathic’ pain, associated with prior lesion of the nervous system, is typified by spontaneous pain sensation and pain evoked by non-noxious stimuli – a debilitating symptomatic experience and major global health burden.</p>
<p>Presently, we lack satisfactory treatments for neuropathic pain due to insufficient understanding of maladaptive structural and pathophysiological changes occurring in the nervous system. Neuronal hyperexcitability is a key feature of neuropathic pain. Potassium channels have long been known as regulators of neuronal activity – they are instrumental in ensuring appropriate generation and propagation of action potentials and regulate neural communication by influencing presynaptic neurotransmitter release. There is now a large body of evidence that K+ channel dysfunction is mechanistically involved in the initiation and maintenance of neuropathic pain, offering novel therapeutic targets.</p>
<p>Ostensibly, the relative ease of genetic manipulation in mice enables us to study individual genes in isolation and assess their functions in health or disease. This thesis comprises an in-depth genetic, anatomical, physiological, and behavioural investigation of two different Kv1.6 knock-out mice. The results of the present study simultaneously reveal an unconventional role for this potassium channel in thermal nociception and a major flaw in the design of certain transgenic animals – namely, that overexpression of exogenous LacZ gene products is not necessarily benign but may induce unsolicited and confounding neurotoxic effects.</p>
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