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15.9F: Heat, Cold, and Pain Receptors - Biology

15.9F: Heat, Cold, and Pain Receptors - Biology


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This page examines the detection of heat, cold, and pain. Why pain? Because at least some of the receptors of heat and cold, when the stimulus exceeds a certain threshold, transmit signals that the brain interprets as pain.

The Receptors

Few, if any, of the receptors of heat, cold, and pain are specialized transducers (in the way that, for example, the Pacinian corpuscle is). Rather they are sensory neurons whose plasma membrane contains transmembrane proteins that are ion channels that open in response to particular stimuli. A single neuron may contain several types of these ion channels and thus be able to respond to several types of stimuli. Like all sensory spinal neurons, their axons travel to a dorsal root ganglion of the spinal cord, where their cell bodies reside, and then on in to the gray matter of the spinal cord.

Three types of sensory neurons are found in the skin.

  • ("A-delta") fibers
    • These are thinly-myelinated.
    • They transmit signals in response to heat and touch. If the stimulus exceeds a certain threshold, the brain interprets these as acute pain. This is "good pain" because it warns you to do something to take care of the problems, e.g., a hot saucepan.
  • C fibers
    • These are unmyelinated and thus conduct impulses slowly.
    • C fibers also respond to heat and touch. If the stimulus exceeds a certain threshold, the brain interprets these as diffuse, dull, chronic pain. This is "bad pain" because it cannot be alleviated simply by removing the stimulus. It is pain generated by such things as damaged tissue or pain that remains after the stimulus that caused acute pain has been removed.
  • ("A-beta") fibers
    • These are thickly-myelinated fibers.
    • They mostly respond to painless stimuli such as light touch.

Heat

There are several types of ion channels in the skin that respond to temperature. They are all transmembrane proteins in the plasma membrane that open to let in both calcium ions and sodium ions (the latter the source of the action potential). Between them, they cover a range of temperatures.

  • TRPV4
    Warm (~27–34°C)
  • TRPV3
    Warmer (~34–39°C)
  • TRPV1
    Hot (≥43°C). Also activated by capsaicin, the active ingredient of hot chili peppers, by camphor, by acids (protons), and by pain-inducing products of inflammation.
  • TRPV2
    Painfully hot (>52°C)

Knockout mice lacking the TRPV1 receptor not only do not avoid water with capsaicin in it but have a diminished response to heat and to substances that normal elicit itching. Birds also have TRPV1 receptors. Theirs also respond to heat (and acids), but do not respond to capsaicin. This must explain why birds happily eat hot chili peppers (and so disperse their seeds). The vampire bat, Desmodus rotundus, expresses normal TRPV1 receptors in the sensory neurons leading to the dorsal root ganglia, and these respond normally to painful heat (> 43°C). However, these bats express a shortened version of TRPV1 (produced by alternative splicing) in their trigeminal nerves that run from the bat's upper lip and nose. The shortened receptors respond to a lower temperature (~30°C) enabling the bats to detect the warmth radiating from the skin of their victims.

Cold

Two candidate receptors:

  • One, designated TRPM8, is a channel that admits Ca2+ and Na+ in response to moderate cold (<28°C) or menthol (the ingredient that gives mint its "cool" touch and taste). Knockout mice lacking the gene encoding the TRPM8 receptor do not avoid cold places as normal mice do.
  • A second, designated TRPA1, responds to lower temperatures (<18°C). It also responds to several irritant chemicals eliciting signals that the brain interprets at pain. TRPA1 is found in the hair cells of the inner ear that respond to sound and changes in position.) However, TRPA1 knockout mice respond normally to cold and seem to have normal hearing so the precise role of these receptors is still uncertain for those stimuli.

    TRPA1 channels serve a different function in pit vipers like rattlesnakes. These cold-blooded animals detect warm-blooded prey using temperature-sensitive neurons at the base of pits in their head. The neurons contain TRPA1 channels that open wide when radiant heat entering the pit raises their temperature above 27°C.

Pain

When sensory nerve fibers are exposed to extremes, they signal pain. Pain receptors are also called nociceptors.

Processing Pathways

All the neurons in the skin are part of the sensory-somatic branch of the peripheral nervous system. Their axons pass into the dorsal root ganglion, where their cell body is located, and then on in to the gray matter of the spinal cord where they synapse with interneurons.

Several different neurotransmitters have been implicated in pain pathways. Three of them:

  • glutamate. This seems to be the dominant neurotransmitter when the threshold to pain is first crossed. It is associated with acute ("good") pain.
  • substance P. This peptide (containing 11 amino acids) is released by C fibers. It is associated with intense, persistent, chronic - thus "bad" pain.
  • glycine. It suppresses the transmission of pain signals in the dorsal root ganglion. Prostaglandins potentiate the pain of inflammation by blocking its action.

Neuropathic Pain

This is pain caused by injury to the nerves themselves such as by mechanical damage, massive inflammation, and growing tumors.

Visceral Pain

The brain can also register pain from stimuli originating in sensory neurons of the autonomic nervous system. This so-called visceral pain is not felt in a discrete location as pain signals transmitted by the sensory-somatic system are.

Treating pain with drugs

The weapons presently available to reduce pain are many in number but few in types. They are

  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Opioids (also called opiates)

NSAIDs

Inflammation is caused by tissue damage and, among other things, causes pain. Damaged tissue releases prostaglandins and these are potent triggers of pain. Prostaglandins are 20-carbon organic acids synthesized from unsaturated fatty acids.

There are at least three key enzymes that synthesize prostaglandins:

  • Cyclooxygenase 1 (Cox-1)
  • Cyclooxygenase 2 (Cox-2)
  • Cyclooxygenase 3 (Cox-3)

Most NSAIDs block the action of all three cyclooxygenases. They include:

  • aspirin
  • ibuprofen (Advil®, Motrin®)
  • naproxen (Aleve®)
  • and many others

Two NSAIDs celecoxib (Celebrex®) and rofecoxib (Vioxx®) were introduced in 1999 that selectively inhibit Cox-2 while leaving Cox-1 untouched. It was hoped that these would provide pain relief without the gastrointestinal side effects associated with the broad spectrum NSAIDs. However, the manufacturer of Vioxx® removed it from the market on 30 September 2004 because it increases the risk of heart attacks and strokes.

Acetaminophen (Tylenol®)

This is also a nonsteroidal anti-inflammatory drug but its mode of action is different from the others. It selectively inhibits Cox-3 and provides pain relief without irritating the stomach. It is particularly useful for

  • people allergic to aspirin and its relatives
  • avoiding the risk of Reye's syndrome that has been associated with giving aspirin to children with viral infections.

Opioids

Opioids are extremely effective pain killers but are also addictive so their use is surrounded by controversy and regulation.

Some examples:

  • morphine
  • codeine
  • heroin
  • methadone
  • oxycodone

Opioids bind to receptors on interneurons in the pain pathways in the central nervous system. The natural ligands for these receptors are two enkephalins — each a pentapeptide (5 amino acids):

  • Met-enkephalin (Tyr-Gly-Gly-Phe-Met)
  • Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)

The drawing shows how this mechanism might work. The activation of enkephalin synapses suppresses the release of the neurotransmitter (substance P) used by the sensory neurons involved in the perception of chronic and/or intense pain. The ability to perceive pain is vital. However, faced with massive, chronic, intractable pain, it makes sense to have a system that decreases its own sensitivity. Enkephalin synapses provide this intrinsic pain-suppressing system.

Morphine and the other opioids bind these same receptors. This makes them excellent pain killers.

However, they are also highly addictive.

  • By binding to enkephalin receptors, they enhance the pain-killing effects of the enkephalins.
  • A homeostatic reduction in the sensitivity of these synapses compensates for continued exposure to opioids.
  • This produces tolerance, the need for higher doses to achieve the prior effect.
  • If use of the drug ceases, the now relatively insensitive synapses respond less well to the soothing effects of the enkephalins, and the painful symptoms of withdrawal are produced.

Detecting Cold, Feeling Pain: Study Reveals Why Menthol Feels Fresh

Scientists have identified the receptor in cells of the peripheral nervous system that is most responsible for the body's ability to sense cold.

The finding, reported on-line in the journal "Nature" (May 30, 2007), reveals one of the key mechanisms by which the body detects temperature sensation. But in so doing it also illuminates a mechanism that mediates how the body experiences intense stimuli -- temperature, in this case -- that can cause pain.

As such, the receptor -- known as menthol receptor TRPM8 -- provides a target for studying acute and chronic pain, as can result from inflammatory or nerve injury, the researchers say, and a potential new target for treating pain.

"By understanding how sensory receptors work, how thresholds for temperature are determined, we gain insight into how these thresholds change in the setting of injury, such as inflammatory and nerve injury, and how these changes may contribute to chronic pain," says senior author David Julius, PhD, chairman and professor of physiology at UCSF.

The menthol receptor, and other temperature receptors discovered in recent years by the Julius lab, offer potential targets for developing analgesic drugs that act in the peripheral, nervous system, rather than centrally, where opiate receptors act, he says.

The finding is a milestone in an investigation the team began several years ago. In 2002, the researchers discovered that the receptor was activated by chemical cooling agents such as menthol, a natural product of mint, and cool air. They reported their discovery, or "cloning," of the receptor in "Nature" (March 7, 2002), hypothesizing that the receptor would play a key role in sensing cold. However, some subsequent papers questioned this theory.

In the current study, the team confirmed their hypothesis by "knocking out" the gene that synthesizes the receptor, both in sensory neurons in cell culture and in mice. The cells in culture were unresponsive to cooling agents, including menthol. The genetically engineered mice did not discriminate between warm and cold surfaces until the temperature dropped to extremes.

"It's been known for years that menthol and related cooling agents evoke the psychophysical sensation of cold -- somehow by interacting with the aspect of the sensory nervous system that's related to cold detection," says Julius.

The current study, he says -- led by Diana M. Bautista, PhD, and Jan Siemens, PhD, of the Julius lab and Joshua M. Glazer, PhD, of the lab of co-senior author Cheryl Stucky, PhD, of the Medical College of Wisconsin -- puts that question to rest.

As the mice lacking the gene were not completely insensitive to cold -- they avoided contact with surfaces below 10 degrees C, though with reduced efficiency -- the next step, says Julius, will be to illuminate this residual aspect of cold sensation.

The finding is the latest of a series of discoveries led by the Julius lab on the molecular mechanisms of temperature sensation and pain. In 1997, the lab cloned the gene for the capsaicin receptor, the main pungent ingredient in some chili peppers (Nature, Oct. 23, 1997), and in 2000 reported that, in mice, the receptor triggers the nerves to fire pain signals when they are exposed to high ambient heat or the fiery properties of peppery food. (Science, April 14, 2000). The study demonstrated that capsaicin and noxious heat elicit the sensation of burning pain through activation of the same receptor on sensory neurons.

Most recently, they identified the receptor of isothiocyanate compounds, which constitute the pungent ingredients in such plants as wasabi and yellow mustard. In response to high temperatures, the receptor produces pain and irritation.

"All of these studies use natural products to understand pain mechanisms in the periphery of the body, where they are first sensed," says Julius.

Ultimately, pain signals are transmitted from the peripheral nervous system into the body's central nervous system -- moving through nerves in the spinal cord and brain stem up to the brain, which prompts a response, or "feeling." Co-author of the current study Allan Basbaum, PhD, also of UCSF, is a pioneer of research into the mechanism of chronic pain within the central nervous system.

The Julius team's complementary work is focused at the level of the sensory nerve fiber, where the signals are first initiated. "We want to know," Julius says, "how do you detect these stimuli to begin with" How do your sensory nerve endings do this to begin with" And what are the biochemical and biophysical mechanisms that account for this""

All three receptors the Julius lab has discovered are members of the TRP family of ion channels expressed on sensory neurons. The latest finding adds to the evidence, says Julius, that TRP channels are the principal transducers of thermal stimuli in the mammalian periphery nervous system.

Other co-authors of the study were Pamela R. Tsuruda, PhD, of UCSF, and Sven-Eric Jordt, PhD, of Yale University School of Medicine.

The study was funded by the National Institutes of Health, the Burroughs Welcome Fund and the Human Frontiers Science Program Organization.


15.9F: Heat, Cold, and Pain Receptors - Biology

Somatosensory II: Pain and Temperature

  • Describe the physiological and structural characteristics of the two primary sensory neurons that transmit pain and temperature sensations to the central nervous system.
  • Compare the central connections within the spinal cord and the second order projections of A-delta- and C-fibers.
  • Appraise the organization of pars caudalis of the spinal nucleus of trigeminal nerve and the projections to the nucleus.
  • Associate specific higher brain centers with the behavioral responses to acute and chronic pain.
  • Provide examples of how higher brain centers modulate the transmission of pain stimuli within the CNS.

To master the material presented in this lecture:

Purves text, Chapter 10
Haines pp 192, 198.

  • Pain (nociception) has both a sensory/discriminative aspect and a motivational/affective aspect (e.g. suffering). These different aspects of pain are localized to parallel systems that arise in the periphery and enter the spinal cord together but ultimately take separate paths (in part) and activate different systems within the CNS.
  • The sensation of pain and temperature is mediated by free nerve endings.
  • Free nerve endings have no obvious morphological end organ specializations, yet different free nerve endings are selectively sensitive to very different types of stimuli. Nociceptors (pain receptors) may be high threshold mechanoreceptors, high threshold thermoceptors, chemoceptors (sensitive to chemicals applied to the skin), or polymodal. Others are termed "silent", and do not appear to respond to any stimuli (other than shock which activates everything) until frank damage to tissue has occurred. Similarly, low threshold thermoceptors may be sensitive to warmth or coolness, but generally not both. Heat and cold are coded by subtypes of TRP (transient receptor potential) cation channels that are differentially sensitive to warmth or coolness, sensations that can be elicited by either capsaicin or menthol.
  • Cell bodies of the receptors are in the dorsal root ganglia (DRG). The central processes of the afferents enter the spinal cord via the lateral aspect of the dorsal root.
  • The peripheral (primary) afferent fibers of free nerve endings are all small diameter, and all are either thinly myelinated (A &delta , or group III fibers), or unmyelinated (C, or group IV fibers).
    • A &delta = myelinated, fast pain fibers (A &delta - conduction velocity

    • Describe the receptors, nerve, and pathways for perceiving pain on the body and face.
    • Describe the consequences of a lesion in the upper medulla that interrupts the spinal tract of the trigeminal nerve and the spinothalamic tract.
    • Describe the consequences of a lesion on the left side of the spinal cord at mid-thoracic levels with respect to the perception of touch and acute pain on the legs.
    • Describe the impact of myelination upon speed of axon conduction, and characterize the thickness of myelination for: 1. slow pain fibers 2. Golgi tendon organs 3. Pacinian corpuscles.
    • Name the thalamic nucleus receiving the medial lemniscus and spinothalamic tracts, and describe the somatotopic organization of the terminals from these tracts.
    • The secondary axon in an ascending sensory pathway tends to cross to the opposite side. For proprioception, this crossing takes place at what level of CNS? For pain, this crossing takes place at what level of CNS?
    • Describe the consequences of a lesion in the upper medulla that interrupts the spinal tract of the trigeminal nerve and the spinothalamic tract.
    • Describe the origins of the ventral trigeminothalamic tract and the synaptic destination in thalamus.

    Copyright © 1997- 2014 [University of Illinois at Chicago, College of Medicine, Department of Anatomy and Cell Biology]. Last revised: December 30, 2013.


    Sense of Touch Projects

    Is the Glass of Water Hot or Cold?

    With this experiment, test your skin’s ability to perceive whether an object is hot or cold.

    What You Need:

    • Three tall glasses of water, one filled with very warm or hot water (not burning), one filled with room-temperature water, and one filled with ice water
    • A clock to time yourself

    What You Do:

    1. Grab the glass of hot water with one hand, making sure that your palm is touching the glass. Grab the glass of ice water with your other hand, holding the glass in a similar fashion.
    2. Hold the glasses for at least 60 seconds.
    3. After holding the hot and cold glasses for 60 seconds, grab the room-temperature glass with both hands, palms touching the glass.
    4. Does the glass of room-temperature water feel hot or cold?

    What Happened:

    Your brain just received confusing messages from your hands about what the temperature of the third glass was. The hand originally holding the hot glass told you the third glass was cold, whereas the hand originally holding the cold glass told you the third glass was hot. But they were both touching the same glass. How can this be?

    You received these confusing messages because our skin does not perceive the exact temperature of an object. Instead, your skin can sense the difference in temperature of a new object in comparison to the temperature of an object the skin was already used to (“relative temperature”). This is why entering a body of water, such as a pool or lake, seems really cold at first (your body was used to the warmer air) but then gradually “warms up” after being in the water for a while (your body adjusts to the temperature of the water).

    Two-Point Discrimination

    Is your skin equally sensitive all over your body? Try this experiment to find out more about how well your skin perceives touch.

    What You Need:

    • Ruler that measures in millimeters
    • Two toothpicks
    • Partner
    • Blindfold (optional)

    What You Do:

    1. Prepare for this activity by setting up a chart like the one listed above. You may need to go beyond 10 mm in this activity, and you may want to test more areas of the body than what is listed. Some suggestions are: back of finger, back of hand, wrist, neck, stomach, top of foot, sole of foot, calf, thigh, forehead, nose, lip, and ear.
    2. Explain to your partner that you are going to lightly poke her with either one or two toothpicks on various places on her skin. Her job is to tell you whether or not she feels one poke or two pokes. To make sure she is not cheating, she needs to either wear a blindfold or keep her eyes closed.
    3. Without telling your partner this, hold the two toothpicks so that the points measure 1 mm apart and lightly poke her on the palm of her hand. Ask her if she felt one or two points on her skin. If she says one point, separate the two points of the toothpicks so that they measure 2 mm apart and lightly poke her in the palm again. Keep pulling the points apart until she says that she feels two points. Record the measurement at which she felt points on the palm of her hand.
    4. Repeat step 3 with other parts of the body, such as the fingertips, the upper arm, the back, the stomach, the face, the legs, and feet. Make sure to record the smallest distance at which each area of the body felt two distinct points when poked with the toothpicks.

    What Happened:

    The ability to distinguish between one point or two points of sensation depends on how dense mechanoreceptors are in the area of the skin being touched. You most likely found that certain areas of your body are much more sensitive to touch than other areas. Highly sensitive areas such as the fingertips and tongue can have as many as 100 pressure receptors in one cubic centimeter. Less sensitive areas, such as your back, can have as few as 10 pressure receptors in one cubic centimeter. Because of this, areas such as your back are much less responsive to touch and can gather less information about what is touching it than your fingertips can.


    Owww! The science of pain

    Pain is unpleasant &mdash but can save our lives. It informs us of where injuries are and, potentially, how serious they are. And pain reminds us to protect injured areas until they have time to heal.

    Share this:

    Imagine a life without pain. No throbbing headaches. No stinging sunburns. No aching joints. If you think that sounds great, think again.

    Some people can’t feel pain. They’re born that way. They also tend to die young — unlike, say, people who cannot see or hear, notes Luda Diatchenko. “Pain is much more important for survival,” explains the pain researcher at McGill University in Montreal, Canada.

    Pain protects us. When you touch a hot stove, you recoil in pain. That sensation helps you avoid getting a burn that could be dangerous — even deadly. The throbbing of a broken foot tells you to stay off it until it heals, so you don’t do more damage. Without those signals, we’d all be in trouble. Big trouble.

    Educators and Parents, Sign Up for The Cheat Sheet

    Weekly updates to help you use Science News for Students in the learning environment

    Pain from an injury — such as a broken hand — serves an important purpose. That pain warns us to protect the injured tissue from further damage. Alvimann

    Some pain is straightforward. Burn your skin, pull a muscle or break a bone, and you feel discomfort. This short-term effect is called acute pain. Other pain can last months or years. Called chronic pain, its cause often remains a mystery. In fact, “sometimes the nervous system can get it wrong,” says Steve Prescott. “You have pain that shouldn’t be there,” explains this pain researcher at the University of Toronto, Canada, and the local Hospital for Sick Children.

    Scientists are still working out the different causes of pain, and the best treatment for each type. The biology of pain is complex. But the good news: Researchers are learning more about it every day.

    Message sent

    Pain is a kind of perception, similar to smelling, tasting and hearing. However, those senses tell you what’s happening in the world around you. Pain tells you what’s happening within the world of your own body.

    When you suffer an injury, your nervous system is in charge of delivering the news. Imagine that you twist your ankle. Nerve cells in your ankle pick up the signal that something’s wrong. A network of nerve cells relays this message to the spinal cord. From there, it shoots up to the brain. The brain then translates the message and registers the feeling: Ow!

    That’s the simple explanation, at least. There are still a lot of questions about how those messages travel and how the brain turns them into a “feeling.” Piece by piece, scientists are starting to understand how this complicated system works.

    In recent years, researchers have found receptors for different kinds of pain. A receptor is a special protein on a cell. Its job is to pick up signals arriving at the outside of the cell. A receptor called TrpV1, for example, is found on nerve cells.

    TrpV1 detects signals about painful heat. It does that in a couple of ways. For starters, the receptor seems to react to heat itself. That’s not totally surprising as heat also changes the shape of certain compounds in the body. (A compound is a substance formed from two or more chemical elements bound together in a fixed proportion.)

    TrpV1 can detect those altered compounds. When you accidentally touch a hot stove, TrpV1 snaps into action. It takes the too-hot-to-handle message and sends it to the brain. Interestingly, that same receptor also detects the chemical compounds that make spicy chili peppers taste so uncomfortably hot.

    TrpV1 is a receptor on cells that detects signals indicating painful heat. The same receptor also detects capsaicin, the spicy compound that gives chili peppers their heat. MarcoMaru

    Message received

    The search for receptors has become a hot area for scientists too, says Prescott. However, he notes, research hasn’t answered the important question of how those messages are converted to what you actually feel when you experience pain.

    Answering that question could help a lot of people. In the United States alone, more than 100 million Americans suffer from chronic pain, according to the Institute of Medicine. This U.S. health organization is part of the National Academy of Sciences.

    In some cases, doctors know the cause of chronic pain. Inflammation is a common one. Inflammation is one way that the body responds to cellular injury. Beyond pain, it often triggers swelling, redness and heat. Arthritis, for example, is a disease that causes painful inflammation in the joints. The nerves themselves represent a second source of pain. Diabetes is a disease that can damage the nerves in the hands and feet. That damage leads to pain, tingling and numbness. Drugs used to treat cancer also can cause painful nerve damage.

    Many other chronic pain disorders, however, have no easy explanation. Take migraines. These intense headaches aren’t caused by inflammation or injury. They aren’t linked to nerve damage, either.

    For a long time, experts thought of migraines and other episodes of chronic pain as symptoms of another problem, says Theodore Price. He is a pain researcher at the University of Texas at Dallas. More recently, pain researchers have changed their way of thinking. Now, Price says, many scientists believe that chronic pain occurs when the nervous system itself gets broken.

    Pain memories

    Brain cells are surprisingly flexible. When you make new memories or learn something new, your brain cells actually alter shape. “When you learn a math equation, the structure of your brain is literally changing,” Price says.

    It turns out that the same systems involved in learning and memory also are involved in sensing pain. In other words, pain changes nerve cells. Those changes happen both in the brain and in the spinal cord. And they may last even after the initial trigger for pain vanishes. Price calls this a kind of “pain memory.”

    He and other scientists are trying to figure out whether they can reverse those changes. If they could wipe out the “pain memory” stamped onto the cells, maybe they could cure chronic pain. To do so, they’ve tested some drugs that interfere with molecules that transmit messages in the brain. (Molecules are the smallest units of chemical compounds that take part in chemical reactions.) The drugs are newly designed compounds that have not been tested yet in people. They did, though, seem to erase pain memory in mice and rats in Price’s experiments.

    Millions of Americans suffer from chronic headaches, but scientists still don’t understand what causes them. stockarch

    But there remains a worry. Messing with brain cells could have unplanned side effects. “You don’t want to wipe out people’s memories or change who they are,” Price explains. Before he and his colleagues can test their new approach in people, a lot more work will be needed to make sure it’s safe.

    In Toronto, Prescott is working to understand what might go wrong with the nervous system to unleash chronic pain. Part of his research involves figuring out how pain messages travel through the body.

    Some scientists have suggested there are special networks for pain. Such a “circuit” of nerve cells would have only one job: transmit ouch signals. Other experts think pain just borrows the same circuits that relay messages about non-painful sensations. If that second theory is correct, the same network of cells that tells you a cat’s fur feels soft also might tell you that a scratch from its claws really hurts.

    Prescott thinks the second theory is the right one. One clue that it’s right comes from an old illusion, called the thermal grill.

    Just as optical illusions fool the eye, sensory illusions can trick the body into feeling imaginary pain. The thermal grill is made up of metal bars set to different temperatures. The bars alternate: cool, warm, cool, warm. If you touch a single bar, it will feel either cool or warm. But place your hand over the whole grill at once, and it will feel painfully hot. In this way, Prescott says, “You can trick the nervous system into feeling pain.”

    That’s a hint that the same network that picks up normal sensations, including warm and cool, also senses pain. Prescott thinks chronic pain might happen when the nervous system gets confused — just as it does in the thermal grill trick. “There may be parallels between the thermal grill and the way in which the nervous system gets broken to cause pain,” he explains.

    Then again, a confused nervous system may be only one explanation. “Pain is an extremely complex phenomenon,” says Diatchenko. “It can be broken in many different ways.”

    Extra sensitive

    Pain is complicated for lots of reasons. For one thing, there are many different types of pain — a muscle ache is very different from a pinch or a burn. Plus, some people are more sensitive to pain than others.

    Diatchenko at McGill University is trying to understand those differences. She is looking for genes that control pain sensitivity. A gene is a segment of DNA that codes, or holds instructions, for producing a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

    Theodore Price’s team studies mouse nerve cells that detect painful stimuli. This group has engineered the structures to glow green when genes are active. It could help them better understand which genes switch on and off in response to injuries that promote chronic pain. Courtesy of Theodore Price.

    Diatchenko has brought people into her laboratory and asked them to touch a warm surface. Then she turns up the heat, asking them to say when the heat becomes painful. The range is huge, she says. “Some people are really sensitive and some people are really not.”

    The sensitive people aren’t just wimpy or nervous. Areas of the brain involved in pain actually become active earlier in these people. That’s what brain scans using functional magnetic resonance imaging, or fMRI, show. (fMRI uses strong magnetic fields to create pictures of brain regions while they are active.) Some people, in other words, actually feel the pain sooner. They literally can’t take the heat.

    Many different genes are involved in sensing pain. Scientists have identified some that seem to be especially important. One is a gene called COMT.

    Different forms of this gene occur naturally, Diatchenko observes. Some people have a form that is very active. They have a higher threshold for pain. In other people, the gene is less active. These people feel pain more readily. Interestingly, the gene isn’t just involved in pain. Differences in COMT also have been linked to differences in emotions, planning, memory and even personality.

    There are good reasons why understanding a person’s sensitivity to pain is important, Diatchenko says. People who are more sensitive to acute pain are more likely to develop a chronic pain condition. Learning more about what makes their system for processing pain so touchy might help researchers find new ways to treat long-term pain.

    That is the ultimate goal for nearly every scientist who studies pain biology. As these experts fill in the blanks, they are hopeful that their research will help the millions of people who suffer from unexplained pain.

    It might seem like there’s still a lot to learn. In part that is because the work has just begun. Only since the early 2000s have scientists started to understand pain at the level of cells and molecules, Price says. “We’re still in early days” of pain research, he notes. “The next 15 years? Who knows what it will bring.”

    Power Words

    acute An conditions, such as an illness (or its symptoms, including pain), that is typically short in duration but severe.

    arthritis A disease that causes painful inflammation in the joints.

    brain scan The use of an imaging technology, typically using X rays or a magnetic resonance imaging (or MRI) machine, to view structures inside the brain. With MRI technology — especially the type known as functional MRI (or fMRI) — the activity of different brain regions can be viewed during an event, such as viewing pictures, computing sums or listening to music.

    chronic A condition, such as an illness (or its symptoms, including pain), that lasts for a long time.

    circuit A network of that transmit electrical signals. In the body, nerve cells create circuits that relay electrical signals to the brain. In electronics, wires typically route those signals to activate some mechanical, computational or other function.

    compound A compound is a substance formed from two or more chemical elements united in fixed proportions. For example, water is a compound made of two hydrogen atoms bonded to one oxygen atom. Its chemical symbol is H2O.

    COMT A gene that is involved in sensing pain. It has been linked to differences in emotions, planning, memory and personality.

    diabetes A disease where the body either makes too little of the hormone insulin (known as type 1 disease) or ignores the presence of too much insulin (known as type 2 diabetes).

    functional MRI (orfMRI) A type of medical imaging that uses strong magnetic fields to create pictures of brains while they are active.

    gene A segment of DNA that codes, or holds instructions, for producing a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

    inflammation The body’s response to cellular injury. It often involves swelling, redness, heat and pain.

    migraine An intense headache that is often accompanied by nausea and vision changes.

    molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).

    receptor A molecule in cells that serves as a docking station for another molecule. That second molecule can turn on some special activity by the cell.

    TrpV1 A type of pain receptor on cells that detects signals about painful heat.

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    Citations

    S. Ornes. “Mapping the brain’s highways.” Science News for Students. March 7, 2014.

    S. Ornes. “Erasing memories.” Science News for Students.Jan. 14, 2014.

    K. Weir. “Ghosts in your head.” Science News for Students.April 26, 2014.

    Learn more about pain from this National Institutes of Health website.

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    15.9F: Heat, Cold, and Pain Receptors - Biology

    Thermoception or thermoreception is the sense by which an organism perceives temperatures. The details of how temperature receptors work are still being investigated. Ciliopathy is associated with decreased ability to sense heat, thus cilia may aid in the process. Transient receptor potential channels (TRP channels) are believed to play a role in many species in sensation of hot, cold, and pain. Mammals have at least two types of sensor: those that detect heat (i.e., temperatures above body temperature) and those that detect cold (i.e. temperatures below body temperature).

    In addition to Krause end bulbs that detect cold and Ruffini endings that detect warmth, there are different types of cold receptors on some free nerve endings: thermoreceptors, located in the dermis, skeletal muscles, liver, and hypothalamus, that are activated by different temperatures. Their pathways into the brain run from the spinal cord through the thalamus to the primary somatosensory cortex. Warmth and cold information from the face travels through one of the cranial nerves to the brain. You know from experience that a tolerably cold or hot stimulus can quickly progress to a much more intense stimulus that is no longer tolerable. Any stimulus that is too intense can be perceived as pain because temperature sensations are conducted along the same pathways that carry pain sensations

    Pain is the name given to nociception, which is the neural processing of injurious stimuli in response to tissue damage. Pain is caused by true sources of injury, such as contact with a heat source that causes a thermal burn or contact with a corrosive chemical. But pain also can be caused by harmless stimuli that mimic the action of damaging stimuli, such as contact with capsaicins, the compounds that cause peppers to taste hot and which are used in self-defense pepper sprays and certain topical medications. Peppers taste “hot” because the protein receptors that bind capsaicin open the same calcium channels that are activated by warm receptors.

    Nociception starts at the sensory receptors, but pain, inasmuch as it is the perception of nociception, does not start until it is communicated to the brain. There are several nociceptive pathways to and through the brain. Most axons carrying nociceptive information into the brain from the spinal cord project to the thalamus (as do other sensory neurons) and the neural signal undergoes final processing in the primary somatosensory cortex. Interestingly, one nociceptive pathway projects not to the thalamus but directly to the hypothalamus in the forebrain, which modulates the cardiovascular and neuroendocrine functions of the autonomic nervous system. Recall that threatening—or painful—stimuli stimulate the sympathetic branch of the visceral sensory system, readying a fight-or-flight response.


    Sunburn sensitises our heat-detecting channel, lowering the threshold at which we feel pain

    The best understood of them is called TRPV1, and it responds to extreme heat. TRPV1 isn't typically activated until a stimulus reaches 42C (107.6F), which both humans and mice typically regard as painfully hot. Once your skin reaches that threshold the channel becomes activated, which in turn activates the entire nerve, and a signal gets transmitted to the brain with a simple message: ouch!

    "For cold, in principle, the same mechanisms apply," Grandl explains, except the protein in question is called TRPM8, and instead of reacting to extreme cold, this channel instead activates upon exposure to cool, but not painfully cold, temperatures.

    That leaves TRPA1, which is perhaps the least understood of this class of proteins. While researchers have found that it becomes activated in response to extremely cold stimuli, it isn't clear whether it's actually involved in the work of detection itself.

    Stick your finger in a candle flame, and TRPV1 will kick in (Credit: iStock)

    Together these three proteins – TRPV1, TRPM8, and TRPA1 – enable the skin to detect a range of temperatures and the body to respond accordingly. And because they're nociceptors, these proteins' job is to help you avoid certain temperatures rather than to seek them out. Mice with defective versions of the TRPM8 receptor, for example, no longer avoid cool temperatures. That means that mice – and us, probably – don't actively seek pleasant temperatures. Instead, they actively avoid both cold and extreme heat, which explains why they seem to prefer warm, balmy environments.

    While researchers have defined the thermal boundaries at which these TRP receptors become active, that doesn't mean that they can't be modulated. After all, a lukewarm shower can feel excruciatingly hot if you've got a sunburn. "It's been shown that this is specifically because the inflammation in the skin sensitises the TRPV1 channel," says Grandl, lowering the threshold at which these nerves communicate the sensation of pain to the brain.


    Temperature Control in Newborn Infants

    Afferent Thermosensitive Pathways

    The cutaneous thermoreceptors are served by thin myelinated and unmyelinated axons belonging to the slowly conducting group III and group IV nerves. Warm fibers are mostly unmyelinated (group IV). The axons run within the afferent cutaneous nerve bundles, and they enter the spinal cord through the segmental dorsal root ganglia. Those axons cross over to the contralateral side and ascend within the spinothalamic tract in the anterolateral section of the spinal cord. On their way to the thalamus, the ascending thermal fibers join the medial lemniscus and are accompanied by the afferents coming from the trigeminal region. From the medial lemniscus, collaterals diverge and project to the hypothalamus through a pathway not definitively described. Evidence has been obtained that part of the cutaneous thermal input is conveyed through the spinoreticular pathway to the reticular formation from there, it is projected to the hypothalamus through the raphe nuclei and the ventral noradrenergic system, which passes the subcerulean area. 24,27-29

    The spinal cord thermal sensors are connected to the posterior hypothalamus through axons running in an anterolateral pathway of the spinal cord, as has been shown in young guinea pigs 30 and cats. 31,32 The thermosensors of the preoptic area also end in the posterior hypothalamus however, these short pathways have not yet been identified.


    SYMPTOMS OF RESPIRATORY DISEASE | Chest Pain

    Somatosensory Pain

    The anatomical sites of somatosensory chest pain have been described above. The pain receptors are nociceptors. They are known to exist in muscle, joints, and skin. Each nociceptor has selective sensitivity to mechanical (muscle-fiber stretching), chemical (including lactic acid), and thermal stimuli. Whether visceral nociceptors exist is uncertain although it is clear that visceral afferents possess many of the characteristics of nociceptors. This results in electrical stimuli that are transmitted via the sensory nerve fibers that are myelinated and enter the spinal cord via the posterior nerve roots and cross over to the contralateral side of the cord and complex to form the spinothalamic tract. The spinothalamic tract travels in the medial lemniscus to the ventrobasal complex of the thalamus where they synapse. Sensory impulses are integrated in the sensory cortex resulting in the perception of pain and subsequent motor reflex response. Central mechanisms of pain and its modulation appear to be similar for somatic and visceral origin of pain.

    Intercostal nerves are formed from the ventral and dorsal rami of thoracic spine segments T1–T12. They supply the general sensory innervation to the skin and parietal pleura. They also supply the motor innervation to intercostal muscles and carry the postganglionic sympathetic nerve fibers. Intercostal nerves 2–6 are confined to the thorax, whilst the first nerve contributes to the brachial plexus as well as the first intercostal space. Nerves 7–12 leave the intercostal spaces after innervating them and continue to innervate muscles, skin, and parietal peritoneum of the anterior abdominal wall.


    TRPA1 Sensitization Produces Hyperalgesia to Heat but not to Cold Stimuli in Human Volunteers

    Background: Transient receptor potential ion channels play a role in thermal hyperalgesia and are among targets of novel analgesics. However, a role of TRPA1 in either heat or cold hyperalgesia is controversial. In this study, changes in thermal sensitivity were assessed following topical application of a specific sensitizer of TRPA1 and compared with the effects of sensitizers of TRPV1 and TRPM8.

    Methods: Employing a randomized cross-over design, thermal thresholds were assessed in 16 pain-free volunteers before and at 20 minutes after topical application of cinnamaldehyde, capsaicin or menthol stimulating TRPA1, TRPV1, or TRPM8, respectively. Cold or warm detection thresholds and cold or heat pain thresholds were assessed according to the standardized quantitative sensory testing protocol proposed by the German Research Network on Neuropathic Pain.

    Results: The effects of different irritants displayed a cluster structure. Hyperalgesia was induced by capsaicin and cinnamaldehyde on heat pain thresholds and by menthol on cold pain thresholds (Cohen d=2.2035, 0.9932, and 1.256, respectively). A second cluster comprised large effects directed toward hyposensitization, such as cold hyposensitization induced by capsaicin and cinnamaldehyde, or small or absent hyposensitizing effects.

    Conclusions: The observation that the TRPA1 irritant cinnamaldehyde induced heat hyperalgesia at an effect sizes comparable with that of capsaicin attributes TRPA1 a role in human heat-induced pain. Results suggest the inclusion of heat pain as a major efficacy measure in human experimental studies of the effects of TRPA1 antagonists and the development of TRPA1 antagonists for clinical pain settings involving heat hyperalgesia.