Pain: Can’t live with it, can’t live without it

Imagine what life would be like with no pain.  'He stubbed-my-toe yell sounds a lot like his chest-pounding victory yell.'No headaches or sore throats.  You would never experience the anguish of a papercut or a stubbed toe or a sprained ankle.  No stomach cramps or muscle soreness.  Childbirth or getting kicked in the balls?  Piece of cake.  Thrown from a moving car?  Don’t feel a thing.  Basically the best superpower ever!

Not quite.  Pain is essential to our survival.  If you didn’t feel pain, you might consistently get third degree burns from leaving your hands on a hot pan.  Your unnoticed strep throat could turn into rheumatic fever.  You could die from appendicitis with little forewarning. You might mistakenly rub a chemical in your eye or absent-mindedly chew your tongue to a pulp.

There is, in fact, a genetic disorder that strips its patients of pain’s vital alarm system.  Those with CIPA (congenital insensitivity to pain with anhidrosis) cannot feel pain or temperature and do not sweat in response to heat [1].  While naked mole rats seem unbothered by their inability to feel pain, for humans the deficit is incredibly debilitating.  Children with CIPA often have frequent burn-related injuries, bone infections from multiple instances of bone trauma, and mutilated tongues and fingers from self-biting.  For their entire lives, those with CIPA must undergo constant medical monitoring to catch illnesses or injuries that are usually diagnosed with reports of pain.  Imagining a life without pain suddenly makes me want to stub my toe just for reassurance.

Your Brain on Pain

Perception of pain is a lot like any other sensory system.  Just as there are cells in your tongue that transmit information about the molecular content of the food you eat and cells in your retina that gather information about light and color, cells in your skin and in some internal organs can respond to physical damage, extreme temperature, and noxious chemicals.  These cells are called nociceptors.

There are two types of nociceptors, A-delta (Aδ) fibers and C fibers.  Aδ fibers send information extremely quickly with the purpose of alerting the brain to the location of the insult.  Imagine touching a hot pan—it is important that this stimulus be understood by the brain immediately so that you can remove your hand from the hot surface.  Aδ fibers are responsible for this “first pain” which is often first-and-second-painstrong, sharp, and localized.  After you remove your hand from the hot surface, another kind of pain sets in shortly after, a more prolonged aching or burning.  While “first pain” acts as an alert system, “second pain” makes sure you do something about the injury—run the hand under cold water, cover the burn with cream and a band-aid, use the hand more gingerly for a while.  C fibers transmit “second pain.”  Aδ fibers are covered in myelin, a substance that insulates the fiber and makes the signal travel faster (see figure).  C fibers are unmyelinated, which is why second pain is slower and more prolonged.  The signal travels along A-delta or C fibers to the spinal cord, where the fibers signal to another cell that reaches up to the thalamus, a region of the brain that relays all types of sensory information to higher level brain structures.  These higher brain structures then create the perception of pain [2].

pain-pathway

Have you ever wondered why pain in the left arm can be a sign of a heart attack?  The answer is related to nociceptive signaling.
referred-painThe fibers that sense noxious stimuli in the left arm and fibers that receive nociceptive information from the heart happen to converge on the same spinal cord cell.  The brain doesn’t know where the original signal came from, so it creates the perception of pain in the skin because it figures that’s the more likely source.  This is an example of “referred pain’–when an injury to an internal organ is perceived as coming from the surface of the body [2].

All of this cell communication occurs with a common signaling molecule, glutamate, but the aforementioned C fibers often co-release another molecule along with glutamate: Substance P.  Substance P acts on the cells in the signaling pathway, causing the effect of the original signal to be stronger and more prolonged.  Substance P is the reason that, after an injury, the injured location is more sensitive.  How do we know for sure?  A group of scientists concocted a new compound: a toxin attached to Substance P, and they injected this compound into mice.  It selectively killed any cells in the mice’s spinal cords that could respond to Substance P.  With these cells eliminated, the mice could still feel pain but did not become more sensitive to pain after the first injury [3]!  Substance P is also the reason for inflammation symptoms.  When released from C fibers, Substance P causes dilation of the blood vessels, leading to redness.  It also can break the structural integrity of blood vessels, leading to leakage of cells and fluid from the blood into the tissue, a.k.a. swelling [2].

Persistent Pain

An incredibly high number of people (about 1 in 10 Americans!) suffer from chronic pain.  Chronic pain does not come with the life-saving perks of acute pain and in many cases severely impacts quality of life.  Persistent pain can be “nociceptive” (caused by inflamed or damaged tissue such as sprains, strains, arthritis, tumors) or “neuropathic” (caused by direct damage to nerves, usually characterized by a burning or electric sensation). phantom-limb A fascinating example of neuropathic chronic pain is phantom limb pain in which people feel pain (or tingling, heat, cold) in a limb that has been amputated.  How does it happen?!  The amputation procedure can damage the nociceptive fibers running through the limb.  These cells, although damaged, remain alive and continue sending signals to the brain.  The brain interprets these signals as a pain stimulus coming from the limb rather than the amputation site, leading to the perception that the limb is still there.  Phantom limb pain is difficult to treat; one creative approach is mirror therapy in which the brain is tricked into perceiving a healthy, painless limb instead of an amputated or painful one.  

Chronic pain is often treated with opioids such as morphine, which decrease pain by reducing the strength of cell signaling in the pain pathway.  Unfortunately, patients often develop a tolerance to opioids, necessitating higher and higher doses and leading to addiction.  According to the CDC, 91 Americans die every day from opioid overdose [4], and last year the CDC released new guidelines urging physicians to think twice before prescribing opioids for chronic pain [5].  

The mechanisms underlying chronic pain is an area of active research.  Hopefully, with a clearer understanding of what causes it, scientists and doctors can find better ways to diagnose and treat it.  There are already some fascinating alternatives to pain medications.  For example, in biofeedback training, patients learn to exert some control over the activity patterns in their brains!

Love your Pain

Just as with any other sensory system, when pain perception goes haywire, the results can be devastating.  Chronic pain is one example.  However, we desperately rely on pain signals to alert us when a part of our body is damaged or sick.  I, for one, am happy that I can feel pain.  Maybe you should express just a little bit of gratitude the next time you stub your toe.  

pain-scale-chart

References

  1. https://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain#genes    
  2. Basbaum, Allan I., and Thomas M. Jessell. “Pain.” Principals of Neural Science. Ed. Eric R. Kandel, James H. Schwartz, Thomas M. Jessell, Steven A. Siegelbaum, and A. J. Hudspeth. 5th ed. N.p.: McGraw Hill Companies, 2013. 530-55. Print.
  3. Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, Simone DA. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science. 1997 Oct 10;278(5336):275-9. PubMed PMID: 9323204.
  4. https://www.cdc.gov/drugoverdose/epidemic/index.html
  5. https://www.cdc.gov/media/modules/dpk/2016/dpk-pod/rr6501e1er-ebook.pdf

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