Physiology Of Pain

Pain is one of the commonest reasons for an ED visit and is universally recognised as a sign of disease. Frankly, uncontrolled pain should be dealt with as a medical emergency.

Harrison’s Principles of Internal Medicine (21st ed.) defines pain as :

“ Pain is an unpleasant sensation localised to a part of the body, often described as a penetrating or tissue-destructive process and/or a bodily or emotional reaction”

But honestly, the IASP 2020 definition is simpler (and makes more sense):

“Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”

Whether this definition is adequate is a whole different issue, and we are not going into that today.

Pain Perception

It is broadly divided into central and peripheral mechanisms.

1. Peripheral Mechanism

Or simply — nociceptors.

So what are they?

“ Unspecialized, free, unmyelinated nerve endings that convert a variety of stimuli into nerve impulses”

“Free" nerve ending means that it does not synapse with anything else and forms a finely branched meshwork (terminal arbor). The cell body of the nociceptor lies in the dorsal root ganglion, and its peripheral processes end as free nerve endings.

This mostly refers to - Aδ and C fibres. They respond to painful stimuli, producing the sensation of pain and are hence called primary afferent nociceptors.

Large myelinated Aδ fibres → Rapid action potential propagation, hence responsible for the pain felt first.

Type I Aδ fibres usually respond to high-intensity mechanical stimuli
Type II Aδ fibres respond mainly to extremes of heat and cold

Thin unmyelinated C fibres → Can be triggered by anything - mechanical, heat, chemical changes, etc. They are responsible for the deep throbbing pain felt later.

If we block these fibres, pain perception is abolished.

Noxious stimuli sensed by these endings include:

Mechanical deformation

Acidity

Temperature (heat and cold)

Inflammatory mediators (eg, prostaglandins, bradykinin)

Contents from damaged cells (eg, ATP and Potassium)

Sensitisation

Nociceptors have this slightly annoying feature called sensitisation:

Repeated / prolonged/intense stimuli cause a lower activation threshold and higher firing rate. In simpler words, the same stimulus causes more pain when applied repeatedly. This explains the concept of hyperalgesia (Abnormally increased sensitivity to pain) and allodynia ( Pain due to stimuli that do not normally provoke pain).

Silent nociceptors

A lot of visceral nociceptors are inactive in normal tissue and are not triggered by usual stimuli. But in inflammation, in the presence of inflammatory mediators, they suddenly become active.

These are silent nociceptors.

This explains why deep structures suddenly become very painful in disease states

2. Central Mechanisms

Primary afferent (first-order neurons) enter the spinal cord via the dorsal root and synapse in the dorsal horn. From here, signals are transmitted to higher centres (more in the pain pathway), but multiple inputs may converge on single neurons, causing referred pain.

For example,

The afferents supplying the central diaphragm arise from the C3–C4 dorsal root ganglia. Because these same segments also receive input from the shoulder region, irritation of the diaphragm is felt as shoulder pain.

Spinothalamic tract

The majority of fibres from the second-order neurons in the dorsal horn cross over and ascend as the spinothalamic tract. They reach the thalamus and then project to multiple cortical areas (more in the pain pathway)

It projects into the cingulate cortex and insula, eliciting an emotional response. This is possibly why pain has an emotional component and why fear often accompanies pain

Pain Modulation

The brain behaves strangely. The same injury can have very different pain experiences.

A classic example is WWII soldiers who had severe injuries and experienced minimal pain perception

Why?

This is because of endogenous opioid systems. This is activated by strong emotions, distraction or even expectation of relief (placebo effect) (more in the descending pathway)

Pain Pathway

1. Ascending Pathway

Signals from nociceptors are transmitted to the dorsal horn of the spinal cord via primary afferent fibres (first-order neurons)

Aδ fibres predominantly terminate in Rexed laminae I, where they mainly release the neurotransmitter, glutamate.

C fibres predominantly terminate in Rexed laminae II (known as substantia gelatinosa) and release the neurotransmitter substance P.

The second-order neurons in the dorsal horn cross midline and ascend in the spinothalamic tract to terminate in the thalamus. In the thalamus, third-order neurons send projections to the prefrontal cortex, somatosensory cortex and cingulate cortex.

Somatosensory cortex → where pain is felt (location, intensity)

Prefrontal cortex → interpretation

Cingulate cortex → emotional aspect of pain

Cortex
(S1, Cingulate, Pre- Frontal)
↑
Thalamus
↑
Spinothalamic Tract
↑
(Crosses to opposite side)
↑
Dorsal Horn
↑
Dorsal Root Ganglion
↑
Nociceptor
(Injury)

2. Descending Pathway / Pain Modulation

The descending pain modulatory system originates in the periaqueductal grey (PAG) of the midbrain. The PAG receives inputs from higher centres, including the limbic system, hypothalamus, prefrontal cortex, and amygdala.

From the PAG, signals are transmitted to the rostroventromedial medulla (RVM) in the brainstem. The RVM then projects to the dorsal horn of the spinal cord, where it modulates nociceptive transmission at the level of primary afferent terminals (the end of the first-order neuron where it meets the second-order neuron)

The RVM has both:

Inhibitory effects (OFF cells) → suppress pain transmission

Facilitatory effects (ON cells) → enhance pain transmission

Pain inhibition occurs via endogenous opioid peptides, including Endorphins, Enkephalins and Dynorphins. These bind to opioid receptors (μ, κ, δ) located in the dorsal horn and brainstem. They reduce postsynaptic neuronal excitability, causing overall suppression of pain transmission.

Frontal Cortex / Hypothalamus
↓
Midbrain (PAG)
↓
Medulla
↓
Spinal Cord
↓
Inhibits dorsal horn neurons