What Gives Freezing Its Sting?

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Freeing knotted shoelaces with fingers that are frozen stiff is extremely difficult and can even be painful. The reason that sensitivity and dexterity are poor is that both nerves and muscles perform their tasks reluctantly when they are cold. Nevertheless ice-cold fingers ache and do so all the more in response to the lightest of knocks or squeezing.

As unpleasant as this is, it serves as protection against frost lesion. The question of how pain can still be registered despite the otherwise hampered function during cooling has recently been explained by researchers at the Institute of Physiology and Pathophysiology at the University of Erlangen-Nuremberg. Together with scientists from the Anaesthesiology Department at the same University and a group from the University College London, they have demonstrated that the endings of nerves normally involved in signaling pain are equipped with a frost tolerant igniter of nerve impulses.

In order to function properly nerve fibres and their endings must generate a small, but explosively rapid, electrical sodium current known as a nerve impulse (action potential). The sluices for this, the sodium channels, open and close more slowly when cooled and also become more likely to be literally ‘frozen’ in a state known as ‘slow inactivation’. Pain signaling nerves however possess a rather special sodium channel subtype, the NaV1.8, which also becomes more sluggish with cooling but can resist the entry into slow inactivation and thus the channel is in a position to still generate action potentials at 10°C skin temperature.

The NaV1.8 sodium channel is also renowned for being resistant to blockade by a toxin found in the tasty, albeit for Sushi too expensive, Pacific Fugu fish. The bacterially derived substance from the fish´s entrails known as Tetrodotoxin (TTX) blocks most other sodium channels and in doing so can be fatal to the gourmet even at very low doses. A second feature of NaV1.8 is that it is found exclusively in the nerve endings and cell bodies of pain signaling nerves, called ‘nociceptors’. Nociceptors normally use the TTX-sensitive sodium channels to signal pain.

To rescue their function from cold block NaV1.8 channels are recruited so that pain from the extremities can still be registered. Normally, the excitability of these nerve fibres is rather independent of NaV1.8 because its threshold for activation is too high. During cooling however the electrical resistance of the neuronal cell membrane increases. This means that the isolation between the inside and the outside of the cell is better and as such less of the small sodium flow in the nerve ending is lost to a short circuit. In this way, the high threshold of NaV1.8 is reached and its rescue function can be realized.

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