Ouch!! #$@*!! – We Take a Quick Look at the Neuro-Physics of Pain

A cartoon illustrating the phenomenon of physiological pain.Signals and Perception

Prior to the discovery of nociceptors in 1906, scientists believed that animals were like mechanical devices that transformed the energy of sensory stimuli into motor responses.  Pain is one of those stimulated reactions, but it is unlike other sensations.  What is the purpose of pain?

A book frontispiece showing a black and white photographic portrait of Sir Charles Scott Sherrington and the title page of his book 'The Integrative Action of Nervous System Cover'.
Charles Sherrington published his work “The Integrative Action of the Nervous System” in 1906.

Although tissue damage does not always result in pain, and although pain can be felt without tissue damage, pain is vital.

Without it, we would quickly become seriously injured.

Pain is vital.


Without such a mechanism, it is likely that our lives would be radically shorter, with less opportunity to pass on our genetic code.

Feeling pain is an integral part of the defences that enables us to remain alive.

Pain is a psychological response, transmitted by nociceptors – specialized peripheral nerve fibres with bare endings that detect tissue damage.

Two diagrams illustrating the 'top-down' 'bottom-up' pathways of pain perception.Nociceptors were discovered by Charles Scott Sherrington (1857-1952).

Using many different styles of experiments, Sherrington demonstrated that different types of intense stimulation to a nerve’s receptive field led to different responses, such as trigger reflex withdrawal, autonomic responses, and pain.

Nociceptor afferents synapse in the dorsal horn of the spinal cord.

The spinothalamic tract is a sensory pathway from the skin to the thalamus – a midline symmetrical structure of two halves, within the human brain, situated between the cerebral cortex and the midbrain.  Its main functions include relaying sensory and motor signals to the cerebral cortex, and regulating of consciousness, sleep, and alertness.  

The spinothalamic tract consists of two adjacent pathways:

  • the anterior spinothalamic tract carries information about crude touch
  • the lateral spinothalamic tract conveys pain and temperature.

The pain signals pass up the spinothalamic tract on the opposite side of the spinal cord to the afferent input.  Spinothalamic tract activity may be modulated by descending control from the forebrain.


How does a Nociceptor work?

Several diagrams illustrating the reaction to pain caused to a finger, and the firing rate of the somatory system under different stimuli.
When nerve fibres are stimulated, they respond with a sustained discharge that signals stimulus duration.  Source: clinicalgate.com

A nociceptor is is a sensory nerve cell that responds to damaging (or potentially damaging) stimuli by sending signals to the spinal cord and brain.

The process is called nociception, it is usually the cause of pain perception in sentient beings.

Nociceptors respond to potentially damaging stimuli by sending signals to the spinal cord and brain.  They are found in our internal organs, as well as on the surface of our bodies.

Nociceptors can detect different kinds of damaging stimuli or actual damage.  Those that only respond when tissues are damaged are known as “sleeping” or “silent” nociceptors.

We have

  • Thermal nociceptors – activated by noxious heat or cold at various temperatures

  • Mechanical nociceptors – responsive to excess pressure or mechanical deformation

  • Chemical nociceptors – sensitive to a wide variety of chemicals, some of which are signs of tissue damage.  Those nociceptors are involved in the detection of some spices in food.


Stimulus Duration and Stimulated Reaction

Nerve fibres associated with these receptors generally have no background activity while they remain un-stimulated.  When they are stimulated, however, they respond with a sustained discharge that signals stimulus duration.

Pain motivates the individual to withdraw from a damaging situation, to protect a damaged body part while it heals, and avoid similar experiences in the future.

The duration of the stimulus (how long the pain lasts) is normally conveyed by firing patterns of receptors.  These impulses are transmitted to the brain through afferent neurons.

Most pain resolves once the noxious stimulus is removed and the body has healed, but it may persist despite removal of the stimulus and apparent healing of the body.


The Physics of Pain

Physical distortion of the terminal axon membrane, changes in the concentration of various ions in the extracellular fluid or changes in pH are enough to trigger inward sodium (Na+) currents, which generate potentials.  When this electrical potential is large enough, a train of action potentials can result.

A diagram showing the propagation of an action potential along a neural axon.
How an electrical action potential propagates along a neural axon. Source: bioblocks.weebly.com

After a single noxious stimulus, the mechanoreceptors may continue firing action potentials for some time.

Just as a wound does not heal when the injuring stimulus is removed, activated C fibres do not stop firing, and the pain goes on.

These nerve endings are further sensitised by a range of chemicals released in the tissue at the site of injury.

When tissue is injured, there is a rapid release of ‘messenger’ chemicals that stimulate the nerve endings.  Electrical impulses are relayed through the nerves to the spinal column and the brain, which registers the sensation of pain.


The Chemistry of a Skin Lesion

A diagram showing the process at the heart of neurogenic inflammation in the body.
Neurogenic Inflammation: The flare occurs because of vasodilatation (redness) and increased permeability that results in the movement of plasma proteins into the extracellular fluid.

When tissue is damaged, cell walls are ruptured and intra-cellular materials spill out into the extra-cellular space.

A number of chemicals are released in the injured tissue, which can activate free nerve endings or potentiate a response to other physical or chemical stimulation.

Potassium (K+) ions are usually present in the extracellular space, but only at low concentrations.  However, leakage from the damaged cells increase this.  Free nerve endings are activated directly by a rise in extracellular potassium ions.

Tissue damage often leads to an increase in extra-cellular acidity, which activate free nerve endings.

Damaged tissue causes mast cells – a type of white blood cells that is a part of the immune system – to release a number of chemical factors including

  • histamine – an organic nitrogenous compound involved in immune responses

  • ATP (Adenosine Tri-Phosphate) – an energy storage molecule

  • serotonin – a neurotransmitter

  • cytokines, such a Nerve Growth Factor (NGF).

These compounds produce pain or itching, if injected into the skin.

They trigger a cascade of reactions.

A chemical diagram showing the Prostaglandin D2 molecule.
Prostaglandin D2 (PGD2) is a major prostaglandin produced by mast cells – recruits Th2 cells, eosinophils, and basophils. In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells. It is critical to development of allergic diseases, such as asthma. Source: Wikimedia

Factors released by tissue injury can activate enzyme cascades: phospholipase catalyses the conversion of arachidonic acid in cell membranes to arachidonate, which is in turn converted to prostaglandins by the action of the enzyme Cyclo-OxyGenase (COX).

Long story short, the sensation of pain is caused by the release of this particular chemical – prostaglandin – that sensitizes and simulates free nerve endings, and sends an electrical message to the brain.

Prostaglandin is the key!


If the formation of prostaglandin can be inhibited, then pain can be reduced.


Pain Relief

An analgesic or painkiller‘ is any member of the group of drugs used to achieve analgesia, hence achieve pain relief.  Drugs designed to alleviate pain act to interrupt the flow of information along the nerve fibre.

The World Health Organization (WHO) guidelines recommend prompt oral (“by the mouth”) administration of drugs when pain occurs, starting, if the patient is not in severe pain, with non-opioid drugs, such as paracetamol (acetaminophen) or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), including COX-2 inhibitors.

If complete pain relief is not achieved or disease progression necessitates more aggressive treatment, a weak opioid, such as codeine, dihydrocodeine or tramadol, is added to the existing non-opioid regime.

Simple pain medications are useful in 20% to 70% of cases.

Pain Control, Analgesics and Adjuvants

A diagram showing the Analgesic (Pain Relief) Ladder guidance from the World Health Organization (WHO). Mild to moderate pain - Step 1: Non-opioids - aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. Moderate to severe pain - Step 2: Mild opioids (e.g. codeine), with or without non-opioids. Severe pain - Step 3: Strong opioids (e.g. morphine), with or without non-opioids.
If the patient is in severe pain and the painkiller regime is or becomes insufficient, a weak opioid is replaced by a strong opioid, such as morphine, diamorphine, fentanyl, buprenorphine, oxymorphone, oxycodone, or hydromorphone, while continuing the non-opioid therapy, escalating opioid dose until the patient is pain free or at the maximum possible relief without intolerable side effects. If the initial presentation is severe pain, this stepping process should be skipped and a strong opioid should be started immediately in combination with a non-opioid analgesic. Source: WHO

Analgesic drugs (or painkillers) act in various ways on the peripheral and central nervous systems.  Analgesic drugs appear to act centrally in the brain, rather than peripherally in nerve endings.  Their action is distinct from anaesthetics, which reversibly eliminate sensation.


Analgesics include

  • paracetamol (or acetaminophen) and NSAIDs, such as the salicylates,

  • opioid drugs, and

  • local anaesthetics.


Aspirin, Paracetamol and NSAIDs

A diagram illustrating a molecule of Arachidonic acid unable to bind to acetylated COX. The OH group in COX is acetylated, entry of arachidonic acid is blocked. Formation of prostaglandin is prevented.
Arachidonic acid is unable to bind to acetylated COX, due to the action of aspirin. Source: The Open University

Aspirin (acetylsalicylic acid) is a good analgesic for minor injuries because it blocks the enzyme COX and hinders the synthesis of prostaglandins at the site of injury.  Aspirin can release an acetyl group, which bonds to the active site of COX and prevents arachidonic acid from entering the cavity, thus inhibiting the formation of prostaglandin.


NSAIDS (or non-steroidal anti-inflammatory drugs) also inhibit prostaglandin formation.  They can directly targets cyclooxygenase-2 (COX-2) – an enzyme responsible for inflammation and pain.  COX-2 inhibitors are often used in a single dose to treat post-surgery pain.  However, data from clinical trials revealed that prolonged use of COX-2 inhibitors caused a significant increase in heart attacks and strokes, with some drugs in the class having worse risks than others.

Analgesics also include opiates.

Opioid Drugs

A bar chart showing how the number of Deaths per 100,000 population from Opioid Pain Relievers compared to those deaths due to All Illegal Drugs combined.
Deaths From Painkiller Abuse vs. Illicit Drugs Source: getoffmeds.com

Opiates or opioid pain reliever drugs block pain by mimicking the actions of enkephalins – often referred to as ‘neuro-modulators’, as they act by modulating metabolic processes in cells, rather than directly initiating or inhibiting action potentials.

Amongst them, you find morphine and oxycodone.

Recently, the number of prescribed opioid-related deaths has overtaken the number of deaths from abuse of all illegal drugs combined.

Analgesics even include anaesthetics.



Local anaesthetics are medications that cause reversible absence of pain sensation, although other senses are often affected as well.  Clinical local anesthetics belong to one of two classes: aminoamide and aminoester local anesthetics.

Synthetic local anesthetics are structurally related to cocaine.

They include things like lidocaine, articaine, fentanyl and propofol.


Free nerve endings are also activated by peptides – biologically occurring short chains of amino-acid monomers, linked by peptide (amide) bonds.  In particular, there is bradykinin.

Bradykinin is produced at the site of injury.  It can activate nitric oxide synthase in endothelial cells in blood vessels at the site of tissue injury, and generate nitric oxide alongside other factors, and triggers a complex series of reactions leading to inflammation in the tissue.

Still…  Sometimes, pain arises in the absence of any detectable stimulus, damage or disease.


When Pain is Not “Real”

A photograph showing a patient using the "mirror box" technique. Source: EPSON DSC picture
The “mirror box” technique was developed during Vilayanur S. Ramachandran’s studies of cortical remapping, and phantom limb pain.  The technique uses a box, which is halved by a mirror. The participant in the experiment can only see one half of the box. Once the participant puts his “good” arm (or leg) into the box, the mirror produces a “stereo-isomeric image” of the other limb. For example, if the participant had an amputated lower right arm, he would put both arms on opposite sides of the mirror, then the right half would be covered. The mirror mimics the left arm’s actions and the participant perceives this manipulated reflection as his right arm. When participants kept their eyes open, in Ramachandran’s studies, 4 out of 5 amputees claimed that they felt relief from being able to move their once-phantom limb in or out of positions. This would imply that the phantom limb is a creation of the brain and that relief can come from satisfying the brain by manoeuvring the image and making oneself believe that the phantom limb actually does exist. Source: EPSON DSC picture.

Neuropathic pain is due to abnormal patterns of activity in nociceptor relay cells.  Often unresponsive to treatment with analgesic drugs, neuropathic pain poses a considerable clinical problem.
The reticular formation plays a crucial role in the transmission of nociceptive information to the forebrain.  Descending messages to close the pain gate in the spinal cord may originate from here.

Pain is processed in several parts of the forebrain – the forward-most part of the brain that controls body temperature, reproductive functions, eating, sleeping, and any display of emotions.
Overall, the knowledge we have of the forebrain mechanisms mediating pain perception is still limited compared to our knowledge of the peripheral nociceptors and spinal cord mechanisms.

However, it is clear from studies with opiates and agonist drugs that powerful mechanisms exist in the spinal cord to modulate the patterns of spinothalamic activity that are interpreted by the forebrain as pain.  Just as peripheral nociceptors can change their responsiveness, synapses and relay cells can change their connectivity following injury.

New genes are expressed in the afferents and spinal cells.  Synapses may sprout or withdraw.  The reorganization may be temporary and connectivity returns to normal when tissues heals completely… unless a return to normal is impossible, and the changes become permanent.

Such a change can produce abnormal patterns of spinothalamic activity, which may result in pain in a non-existent limb.  In the case of ‘phantom limb’ pain, the unpleasant sensation is caused by the abnormal activity in neurons, rather than actual tissue damage.

A photograph showing a woman undergoing massage by electrical-stimulation (TENs) for upper back pain.
TENS uses low-voltage electrical current for pain relief. Electrical stimulation for pain control is not a new concept, as it was used around 63 A.D in ancient Rome to relieve pain. Throughout history, electrostatic devices have been used to treat headaches and other pains. One well-known proponent of this pain relief method was Benjamin Franklin. Source: massageprocedures.com

For a sufferer of neuropathic pain, the sensation is often intense, and very REAL.  As traditional analgesics are normally less effective, the pain relief often comes from classes of drugs that are not normally considered analgesics, such as tricyclic antidepressants, anti-convulsants and class I antiarrhythmics – Class I agents interfere with the sodium (Na+) channels.  However, the long-term use of such drugs carries a significant risk of serious complications.

TENS (Transcutaneous Electrical Nerve Stimulation) -type electrical stimulation of the spinal cord or thalamus is still a new technique, but the rationale behind the treatment is to attempt and close’ neural gates in the thalamus by activating the appropriate neurons.  However, this is tricky.

A cartoon frame showing character Wyle E. Coyote about to meet once again with his painful predicament. Pain is no laughing matter... unless you're a cartoon character.
Pain is no laughing matter… unless you’re a cartoon character.

Actually, there are nine subtly different voltage-sensitive sodium channels that are critical for nervous system function, and they are extremely hard to manipulate individually… but that’s another article altogether.  Stay tuned.

Whatever the pain though, it is no laughing matter.