Novel ion channels in neurogenic pain

It was hypothesized that modulation of expression of sensory ion channels and receptors by disease or trauma results in spontaneous or ectopic discharges, mediated mainly via sodium channels, and hypersensitivity of nerve terminals, mainly via receptors of the TRP family and the purinoceptor P2X7. Sensory neurons and characterised tissues were studied, using immunocytochemistry, in common clinical chronic pain states. The key novel findings are: (1) TRPVI is the most selective pain target of the TRP family - it is abundant in pelvic afferents, and TRPV1-positive fibres are increasd in vulvodynia; TRPV1 blockade may be particularly effective in visceral hypersensitivity. Studies in cultured human sensory neurons demonstrate that Nerve Growth Factor and other neurotrophic factors may regulate the increased expression of TRPV1; (2) P2X₇ receptor levels were increased in painful injured human nerves. In mice with a disrupted P2X₇ gene, inflammatory and neuropathic hyperalgesia was completely absent. P2X₇ receptor appears pivotal in chronic inflammatory and neuropathic sensitization to noxious stimuli, and (3) there is an up-regulation of the β3 subunit which modulates sodium channel activation, in human peripheral nerves after injury, and thus represents a novel selective target for spontaneous pain. In conclusion, multiple molecular mechanisms are thus involved in pain states, and strategies which combine drugs aimed at these targets may be necessary for improved clinical efficacy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo