Physiology of pain

Vivian Imbriotis | March 14, 2026

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

Nociceptive pain is created by

Peripheral nociceptors respond to physical and chemical stimuli $\to$ depolarize 1° nociceptor
Synaptic transmission in dorsal horn, modulated by gating and descending inhibition
2° nociceptor decussates and travels in contralateral spinothalamic tract
Transmission to the thalamus $\to$ sensory and affective features

Nociception and peripheral sensitization

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Nociceptors are unmyelinated free nerve endings which respond to a range of noxious stimuli.

Mechanosensitive (pressure) $\to$Type I A$\delta$

Thermosensitive ($\Delta$Temp) $\to$Type II A$\delta$

Polymodal (pressure, $\Delta$Temp, chemical*) $\to$C-fiber

*$\downarrow$pH, intracellular contents (ATP), inflammatory mediators (prostaglandins/leukotrienes)

APs travel via axon to the primary nociceptive soma in the dorsal root ganglion, then to the dorsal horn

A$\delta$: myelinated, thick, fast

C-fiber: unmyelinated, thin, slow

In absense of stimulus, electrically silent

Maximal firing rate ~100, firing rate $\propto$ stimulus intensity

Peripheral sensitization

In response to activation, release substance P $\to$ local inflammation

Local inflammation $\to$ Substance P, serotonin, leukotrienes, cytokines

$\to$ decreased activation threshold

Lesion $\to$ ectopic discharges $\to$ neuropathic pain

Spinal pain pathways

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In dorsal horn, 3 mechanisms for synaptic transmission of pain stimulus

1° Nociceptive afferent $\to$ glumtate $\to$ AMPAr $\to$ fast depolarization

1° Nociceptive afferent $\to$ substance P $\to$ NK1r $\to$ second messages, slow depolarization

Repeated depolarization + further glutamate $\to$ NMDAr $\to$ second messenges $\to$ potentiation ($\to$ wind-up, central sensitization)

Gating of pain in dorsal horn

$$\require{AMScd}$$

$$\begin{CD} {\text{1° nociceptor}} @>{inhibits}>> {\text{Interneuron}} @<{excites}<< {A\delta\text{ touch fiber}} \\ @. @V{inhibits}VV @. \\ @. \text{2° nociceptor} @. \end{CD}$$

Interneuron system facilitates withdrawal reflex

Also descending modulation (noradrenergic, sertonergic, GABA) from medulla.

2° nociceptors then decussate and travel in contralateral spinothalamic tract.

CNS processing of pain + descending control

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Thalamus

Lateral $\to$ sensatory-discriminatory component $\to$ parietal cortex
Medial $\to$ affective-behavioral component $\to$ frontal cortex + cingulate gyrus

Medulla: Physiological component (tachycardia, HTN)

Periaqueductal grey: Descending pain inhibition