Mutations in the SCN9A gene and pain sensitivity

The article emphasizes the genetics, but I'm more interested in the implication that the heightened sensitivity relates to the speed at which sodium channels close in nociceptive neurons.

Gene Linked To Pain Perception - Science News: "Gene linked to pain perception
Common genetic variant makes some people more sensitive
By Laura Sanders
Web edition : Monday, March 8th, 2010

[....]
The team found that people who reported higher levels of pain were more likely to carry a particular DNA base, an A instead of a G, at a certain location in the gene SCN9A. The A version is found in an estimated 10 to 30 percent of people, Woods says, though its presence varies in populations of different ancestries.

[....]
The same trend — higher pain levels reported by people who carried the A — held true in cohorts of people with other painful conditions including sciatica, phantom limb syndrome and lumbar discectomy.
[....]

The genetic variation affects the structure of a protein that sits on the outside of nerve cells and allows sodium to enter upon painful stimuli. The sodium influx then spurs the nerve cell to send a pain message to the brain.

This channel protein is a promising target for extremely specific and effective pain drugs, Waxman says: ‘Given that this channel has been indicted, it would be nice if we could develop therapeutic handles that turn it off or down.’

Researchers already knew that people with mutations in SCN9A can have extreme pain syndromes. Genetic changes that render the protein completely inactive can leave a person impervious to pain, although otherwise healthy. Other mutations can lead to conditions such as ‘man on fire’ syndrome, in which people experience relentless, searing pain.
[....]
In additional laboratory studies, the researchers found that nerve cells carrying the A variant of the gene took longer to close their sodium gates, allowing a stronger pain signal to be sent to the brain. Nerve cells carrying the more common G version of the gene snapped shut faster, stopping the pain signal sooner. "

TENS confusion

Given that TENS was part of the discovery of the gate-control theory 40 years ago, it really would be nice if its implications for the distinction between nociception and pain had seeped in. This is from a press release on Science Daily:

Widely used device for pain therapy not recommended for chronic low back pain A new guideline issued by the American Academy of Neurology finds that transcutaneous electric nerve stimulation (TENS), a widely used pain therapy involving a portable device, is not recommended to treat chronic low-back pain that has persisted for three months or longer because research shows it is not effective.... TENS can be effective in treating diabetic nerve pain, also called diabetic neuropathy, but more and better research is needed to compare TENS to other treatments for this type of pain. Research on TENS for chronic low-back pain has produced conflicting results. For the guideline, the authors reviewed all of the evidence for low-back pain lasting three months or longer. Acute low-back pain was not studied. The studies to date show that TENS does not help with chronic low-back pain.

So far so good. But then in the nickel summary of what TENS is they write:

With TENS, a portable, pocket-sized unit applies a mild electrical current to the nerves through electrodes. TENS has been used for pain relief in various disorders for years. Researchers do not know how TENS may provide relief for pain. One theory is that nerves can only carry one signal at a time. The TENS stimulation may confuse the brain and block the real pain signal from getting through.

How about:

Neural signals reporting injury have to pass through a gate in the spine in order to be transmitted to the brain and cause pain. The electric impulse from TENS closes the gate.

That's still inaccurate. But it at least avoids framing the phenomenon as the system stopping the pain before it gets to the brain. Getting people used to distinguishing between nociception and pain is a small but important step in a better public understanding of analgesia and chronic pain conditions.

Why papercuts hurt so damn much

During my bimonthly rereading of Price's Psychological Mechanisms of Pain and Analgesia, I ran across this in the middle of a discussion of the relationship between tissue damage and pain intensity:

the rate of tissue damage is a direct function of protein in activation that, in turn, is a function of temperature. However, the amount of tissue damage is a function of both skin temperature and duration of stimulation. Since heat-induced pain depends only on the temperature attained by the cells of the skin and on duration of stimulation, pain intensity follows the rate of tissue damage and not its total amount. One consequence of this phenomenon is that some extensive wounds may be less painful than slight wounds. Pain from tissues that have suddenly become inflamed, such as a toothache, is an example." [Page 11; italics original]

A role for glial cell-targeting treatments for pain?

The Psychology of Pain blog links to an interesting new study from CU-Boulder. I don't want to steal too much of his post, so here's a tease:

Under normal circumstances glial cells are thought to be like housekeepers, said Watkins. They essentially clean up debris and provide support for neurons.

But, like Gremlins, they have a nasty side too

[the researchers] believe they have figured out how morphine affects glial cells and neurons. 'We've found that different receptors are involved in how morphine suppresses pain through its actions on neurons versus how morphine activates glial cells,' Watkins said. 'What this means is that you should be able to separate the suppressive effects of morphine -- its pain-reducing effects through its action on neurons -- from all of its bad effects when it excites glial cells.'

(Via Psychology of Pain.)

The day after the day after

Question: When I haven't been to judo in a few weeks, I'm more sore 48 hours after practice than I am 24 hours afterward. But after getting back in shape the soreness seems to constantly decrease with time. Other people tell me similar things with other new exercise regimes. So I don't think I'm idiosyncratic. Why does this happen?

My initial thought --and here I reveal the depth of my ignorance-- was that since the tissues have been healing, the worsening allodynia isn't due to increased prostaglandins, bradykinin, leukotrienes, etc, released by the damaged muscle. Rather it's from dorsal horn wind-up, and neurogenic inflammatory factors like substance p and neurokinins A and B. It makes sense that those would continue to increase over time.

But that wouldn't explain why this doesn't seem to happen when I'm already in shape, even when a workout is much harder than usual.

Or is it just the obvious answer that the difference between relative inactivity and a moderate workout is less than the difference between a moderate workout and a really hard one?

Ideas?

Medical News Today News Article

Medical News Today News Article: "Stroking The Skin Sends Signals Direct To The Brain, Deadens Pain Impulses

16 Apr 2009   

The specialised nerve fibres in the skin are called CT nerves (C-tactile) and they travel directly to the areas in the brain that are important in the emergence of feelings.

'Basically the signals that tell the brain that we are being stroked on the skin have their own direct route to the brain, and are not blocked even if the brain is receiving pain impulses from the same area. In fact it's more the opposite, that the stroking impulses are able to deaden the pain impulses,' says Line Löken, postgraduate student in neurophysiology at the Sahlgrenska Academy.
[....]
Each individual nerve fibre is responsible for touch signals from roughly a square centimetre of skin. The research team used a specially-designed robot, which brushed over the exact area of skin for which a particular nerve fibre is responsible. The subjects were also asked to rate how pleasant or unpleasant they found the brushing.

'As the nerve signals that were sent in the CT nerves became more frequent, the subjects reported the experience as being increasingly pleasant. Of the skin nerves that we studied, it was only the CT nerves that had this strong link between the frequency of the signals and how pleasant it felt,' says researcher Johan Wessberg.

Notes:

Journal: Nature Neuroscience
Title of the article: Coding of pleasant touch by unmyelinated afferents in humans
Authors: Line S. Löken, Johan Wessberg, India Morrisson, Francis McGlone, Håkan Olausson
The full text article is available on Nature Neuroscience's web page: http://www.nature.com/neuro/journal/vaop/ncurrent/abs/nn.2312.html

By: Elin Lindström Claessen
"

Translating nociceptive processing into human pain models.

Limits on pain models:

Translating nociceptive processing into human pain models.: "

Exp Brain Res. 2009 Apr 29;
Schmelz M

As volunteers can easily communicate quality and intensity of painful stimuli, human pain models appear to be ideally suited to test analgesic compounds, but also to study pain mechanisms. Acute stimulation of nociceptors under physiologic conditions has proven not to be of particular use as an experimental pain model. In contrast, if the experimental models include sensitization of the peripheral or central pain processing they may indeed mimic certain aspects of chronic pain conditions. Peripheral inflammatory conditions can be induced experimentally with sensitization patterns correlating to clinical inflammatory pain. There are also well-characterized models of central sensitization, which mimic aspects of neuropathic pain patients such as touch evoked allodynia and punctate hyperalgesia. The main complaint of chronic pain patients, however, is spontaneous pain, but currently there is no human model available that would mimic chronic inflammatory or neuropathic pain. Thus, although being helpful for proof of concept studies and dose finding, current human pain models cannot replace patient studies for testing efficacy of analgesic compounds."

(Via HubMed - pain.)

Heat and pain

Hot.

ScienceDaily (Jul. 5, 2006)

The old wives’ tale that heat relieves abdominal pain, such as colic or menstrual pain, has been scientifically proven by a UCL (University College London) scientist, who will present the findings today at the Physiological Society’s annual conference hosted by UCL.
Dr Brian King, of the UCL Department of Physiology, led the research that found the molecular basis for the long-standing theory that heat,such as that from a hot-water bottle applied to the skin, provides relief from internal pains, such as stomach aches, for up to an hour.

Dr King said: “The pain of colic, cystitis and period pain is caused by a temporary reduction in blood flow to or over-distension of hollow organs such as the bowel or uterus, causing local tissue damage and activating pain receptors.

“The heat doesn’t just provide comfort and have a placebo effect – it actually deactivates the pain at a molecular level in much the same way as pharmaceutical painkillers work. We have discovered how this molecular process works.”

If heat over 40 degrees Celsius is applied to the skin near to where internal pain is felt, it switches on heat receptors located at the site of injury. These heat receptors in turn block the effect of chemical messengers that cause pain to be detected by the body.

The team found that the heat receptor, known as TRPV1, can block P2X3 pain receptors. These pain receptors are activated by ATP, the body’s source of energy, when it is released from damaged and dying cells. By blocking the pain receptors, TRPV1 is able to stop the pain being sensed by the body.

(2006, July 5). Heat Halts Pain Inside The Body. ScienceDaily. Retrieved March 19, 2008, from http://www.sciencedaily.com­ /releases/2006/07/060705090603.htm