The Mysterious Role of Cold Receptors in Pain: Three Thresholds to Consider

Cold is as hot a topic in burning pain as anything right now. Pun intended.

We begin this article with the following reminders:

1) Although Central Pain has had various definitions over the years, the works of S. Weir Mitchell, Dejerine and Roussy, George Riddoch, and David Bowsher have make that they are referring to dysesthetic burning when they referred to pain of central origin.

2) There are other pains which accompany central pain. These include other aspects of superficial sensibilities, including lancinating pains, muscle pains of a cramping, tightening, or burning quality, pins and needles, and in about one third of severe cases gut or bladder burning (over distention sensation) or other pains as well. These additional central pains are not part of the classical definition of central pain. Therefore, they may be referred to as post stroke pains, SCI related pains, MS pains, and the like.

In the more recent literature, ALL of these pains are included as part of the central pains, so we emphasize that the remarks herein about cold allodynia pertain SOLELY to the burning dysesthesia, which for years formed the core definition of what central pain is. Presently, a distinction in CP of spinothalamic tract (ST) pain from lemniscal pain is emerging in much of the literature. Lemniscal central pain usually gives a latency on somatosensory evoked potential testing and tends to respond to treatment and should be addressed aggressively. By contrast, this article deals with a hopeful benefit to ST pain.

3) Dr. David Bowsher was the first to make the “paradoxical” component of cold a definitional part of dysesthetic burning. This paradoxical cold component is now considered part of the standard definition of dysesthetic central pain; however, many patients must be questioned specifically before they themselves realize it is present. Without reflection, the pain feels unitary, and only with time can the sufferer thread out some of the indiviudal parts of the mix.

It is after all the MIX of sensations which is behind our calling the burning dysesthetic. It is the “cold” mixed in which makes the pain burn not capturable by ordinary vocabulary. We are not used to mixed sensations. The term “cenesthetic” has now been coined to denote mixed sensations, but this does not make things clearer than calling the pain “dysesthetic”.

Neither the public nor the garden variety neurologist has much idea of the meaning of “dysesthetic”, let alone “cenesthetic”. If one mixes red and blue, the single color purple emerges, but if one mixes burning and metallic, wet cold, what would we call that? We call it “dysesthesia” but this conceals as much as it illuminates. By having a word, the neurologist looks no further. For most, “dysesthesia” means he/she doesn’t have to try to understand it. The same applies to “allodynia”, which means pain from that which is not normally painful. The illusion of a bracketing word can get in the way of curiosity. “Hyperpathia” means a greater than normal degree of pain from something that IS normally painful. There is no end of words to describe the central pains but hardly a beginning of understanding. Even CP patients give up and just use “nerve pain”, which is impossibly vague.

4) MODERATE COOLING helps the sensation of dysesthesia, but more INTENSE cooling is the most ready evoking stimulus for severe, devastating burning. In the surveys, we have found not a single person who has indicated that heat evokes the burning more quickly than cold. The most commonly experienced cold is a blast on the legs from a car air conditioner. Occlusive light touch is approximately equal to cold as an evoker of the burning. Most have spontaneous burning of a lesser degree even when no cold or touch is present.

5) Based on the articles presented below and our interpretation of the surveys, the EVOCATION of burning from cold which appears after a duration of perhaps twenty seconds (essentially the same delay period as for light touch, which is termed “Mitchell’s Delay”) probably occurs as a result of activation of the TRPV-1 and possibly the TRPV-4 receptors in cell membranes. The TRPV-1 receptor allows sodium and calcium currents to flow.

6) The RELIEF from burning which MODERATE cooling provides for dysesthesia occurs because TRPM8 channels are activated. The TRPM8 channel is a newcomer to the literature, but a knowledge of it allows CP patients to be comfortable in speaking of what goes on in their body, without fear of being accused of making things up.

We owe our awareness of the analgesic effects of TRPM8 in moderate cooling to the absolutely outstanding research by Sue Fleetwood-Walker, an associate of Clare Proudfoot in the U.K. That these fine researchers are aware of the seriousness of the problem is shown by a quote from a recent article “…pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. ” We couldn’t have said it better. This is almost verbatim what the NIH has said, as well.

We are also most grateful to the estimable researchers at the Univ. of Texas Medical Branch, who continue to wow us with their solid advancement on nerve injury pain. We absolutely did not see coming the discovery of cold as an activator of the TRPV-1 channel, which is the “main man” of C fiber induced hypersensitization. U.K. authors