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Unformatted text preview: 120 80 40 40 mV 120 80 40 40 mV 1 Na v 1.7 Na v 1.4 a b 2 1 600 ms (0.23 mV ms 1 ) % o f p e a k c u r r e n t % o f p e a k c u r r e n t Godshouts in our pain. It is his megaphone C. S. Lewis Pain can be useful when it warns us that a hot object is burning us, for instance. Yet the amelioration of pain is essential to modern medicine, permitting surgery to take place and making many illnesses more bearable. Even so, some pain doesnt respond to current treat- ments; in particular neuropathic pain, which can occur in the absence of noxious stimuli following injury to the nervous system, and some types of inflammatory pain. In this issue, Cox et al. (page 894) 1 describe a rare inher- ited mutation that renders the people carry- ing it unable to feel any pain. The mechanism behind this deficit could aid the search for novel painkillers. Where does pain come from, and how can we understand it so that we can tame it? Pain- ful stimuli are conveyed in the form of trains of electrical impulses. These impulses travel from nociceptive (pain-signalling) dorsal root ganglion (DRG) neurons originating in the bodys periphery, through ascending spinal pathways, to the brain. Ion channels in the cell membranes of these nociceptive neurons, including several different types of sodium channel, collaborate to produce such nerve impulses, although the relative roles of the different channels are not fully understood. Ten different genes encode ten versions (isoforms) of the sodium-channel protein that all share a common structure but have different constituent amino-acid sequences. One of these genes, SCN9A , encodes a sodium channel known as Na v 1.7, which is preferen- tially expressed at high levels in two types of neuron: nociceptive DRG neurons and sym- pathetic ganglion neurons, which are part of the involuntary, or autonomic, nervous sys- tem 2 . Na v 1.7 is deployed at the endings of pain- sensing nerves (the nociceptors), close to areas where the impulse is initiated 2 . Stimulation of the nociceptor nerve endings produces genera- tor potentials small changes in the voltage across the neuronal membranes. The Na v 1.7 channel amplifies these membrane depolariza- tions 3 (Fig. 1), and when the membrane poten- tial difference reaches a certain threshold, the neuron fires. Clues that Na v 1.7 is involved in pain came from the observation 4 that DRG neurons in animal models of inflammatory pain show increased expression of Na v 1.7. Also, mice genetically engineered to lack Na v 1.7 spe- cifically in their nociceptors show markedly reduced responses to inflammatory pain 5 . The painful inherited human neuropathy known as erythromelalgia, in which sufferers expe- rience a severe burning pain in response to mild warmth, is due to mutations 68 in Na v 1.7 that cause excessive channel activity 9,10 . This suggests that Na v 1.7 sets the gain on pain signalling in humans....
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This note was uploaded on 01/31/2011 for the course CBNS 120 taught by Professor Adams during the Winter '10 term at UC Riverside.
- Winter '10