Molecular mechanisms of pain

• Main Author: Cregg, R.
• Published: University College London (University of London) 2012
• Subjects: 617
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625880

Recent scientific discoveries have confirmed a pivotal role for the NaV 1.7 voltage-gated sodium channel in human familial gain-of-function and loss-of-function pain syndromes. NaV 1.7 is comprised of four hexameric transmembrane domains encoded by SCN9A, a gene preferentially expressed in dorsal root and sympathetic ganglion neurons. Gain-of-function lesions in SCN9A lead to the development of primary erythromelalgia (PEM). To date, fourteen PEM mutations have been identified which all map to the first three domains of NaV 1.7. I have identified four SCN9A mutations, two of which map to the fourth domain of NaV 1.7 and have used a combination of molecular biology and electrophysiology tools to investigate the biophysical properties of the mutated channels. The results provide insights into the function of NaV 1.7 and are useful in a wider clinical context for offering a confident genetic diagnosis of pain channelopathies. Recessive loss-of-function mutations in SCN9A cause congenital insensitivity to pain in humans. It is known that global deletion of NaV 1.7 in mice is lethal whilst peripheral nociceptor-specific ablation of SCN9A (i.e. knockout in NaV 1.8-positive cells) leads to viable animals with a loss of acute and inflammatory pain but leaving neuropathic pain-sensing and noxious cold-sensing modalities intact. I investigated the effects of ablating NaV 1.7 in all sensory and sympathetic neurons by crossing the Wnt-1 Cre mouse line with the floxed SCN9A colony and performed behavioural characterization. The findings of an abolished neuropathic pain phenotype in the NaV 1.7 X Wnt-1-Cre (NaV1.7Wnt-1) knockout mice demonstrate an important role of Nav1.7 in non-nociceptive neurons which contributes to our understanding of development of pathological chronic pain conditions such as erythromelalgia. Finally, I have designed and generated a targeting construct to flox HSNII, a gene which when mutated causes the pain insensitivity disorder Human Sensory Neuropathy Type II. A mouse model generated from this construct may help to explain the function of the largely uncharacterized HSNII gene, which is critical to normal neuronal development and function.