Pain pathways

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Pain Pathways

Pain (nociception) involves a sequence of events: transduction (at peripheral receptors), transmission (along sensory nerves to the spinal cord and brain), perception (in the cortex), and modulation (descending controls). Here is a complete account of each stage.

1. Peripheral Nociceptors

Nociceptors are free nerve endings that respond only to stimuli strong enough to threaten or damage tissue. They are found in skin, bone, muscle, most internal organs, blood vessels, and meninges - but notably absent from the substance of the brain itself.

Three main classes of nociceptive afferents:

Fiber type	Myelination	Conduction	Pain quality
Aδ (Type I)	Thinly myelinated	~5-30 m/s	Sharp, well-localised "first pain"
Aδ (Type II)	Thinly myelinated	~5-30 m/s	Heat-sensitive
C fibers	Unmyelinated	<2 m/s	Dull, burning, aching "second pain"

The cell bodies of these primary afferents sit in the dorsal root ganglia (DRG). A key channel for nociceptive action potential generation is Na$_v$1.7, a voltage-gated sodium channel encoded by SCN9A. Loss-of-function mutations in SCN9A cause congenital insensitivity to pain.

2. Peripheral Sensitisation and the Inflammatory Soup

When tissue is injured, a cocktail of chemicals - called the inflammatory soup - is released, sensitising nociceptors to produce hyperalgesia and allodynia:

Peripheral chemical mediators of pain and hyperalgesia showing tissue damage triggering release of bradykinin, prostaglandins, serotonin, ATP, K⁺, Substance P, CGRP and histamine from mast cells, all converging on the nociceptive terminal

Peripheral chemical mediators of pain (Neuroscience: Exploring the Brain, 5th Ed.)

Constituents include: glutamate, serotonin, ATP, bradykinin, substance P, CGRP, prostaglandins, endocannabinoids, cytokines, K⁺, H⁺, and neurotrophins.

Primary hyperalgesia - increased sensitivity at the site of injury (peripheral sensitisation)
Secondary hyperalgesia - sensitisation of surrounding uninjured tissue (central sensitisation)
Allodynia - pain from a normally non-painful stimulus

3. Spinal Cord Dorsal Horn (First Synapse)

The central branches of DRG neurons enter the spinal cord and terminate in the dorsal horn in a lamina-specific pattern (Rexed laminae):

Lamina	Input	Function
I (Marginal zone)	Aδ and C fibers	Nociceptive-specific neurons; projects to midbrain and thalamus
II (Substantia gelatinosa)	C fibers	Inhibitory and excitatory interneurons; modulates nociceptive flow
III-IV	Aβ fibers	Light touch; some project supraspinally
V	Wide dynamic range neurons	Convergent noxious + innocuous input; projects to brain stem and thalamus

Key neurotransmitters at the first synapse:

Glutamate (fast, via AMPA receptors) - sharp pain
Substance P (slow neuropeptide, via NK-1 receptors) - prolonged pain, central sensitisation
NMDA receptor activation is central to wind-up and chronic pain development

4. Ascending Pain Pathways

The dominant pathway carrying pain and temperature is the anterolateral system (spinothalamic tract):

The two major ascending pathways - dorsal column-medial lemniscal (touch/vibration/proprioception) vs. anterolateral pathway (pain/temperature) - showing the cross-midline arrangement and respective fiber types

Two major ascending sensory pathways (Neuroscience: Exploring the Brain, 5th Ed.)

Spinothalamic tract route:

First-order neuron: DRG → dorsal horn (laminae I, IV-V)
Axons cross the midline (decussate) in the anterior white commissure at the same spinal level
Ascend in the anterolateral column
Terminate in the thalamus (VPL nucleus and intralaminar nuclei)

Contrast this with the dorsal column-medial lemniscal system (touch, vibration, proprioception), which ascends ipsilaterally and decussates at the level of the medulla.

5. Thalamus and Cortex

Nociceptive axons from the anterolateral system terminate across wider thalamic territory than touch fibers:

Somatic sensory nuclei of the thalamus - VP nucleus (blue) and intralaminar nuclei (red dots) relay nociceptive signals to the cerebral cortex

Thalamic relay nuclei for pain (Neuroscience: Exploring the Brain, 5th Ed.)

VP (ventrobasal) nucleus - projects to primary somatosensory cortex (S1, S2): localisation and intensity coding
Intralaminar nuclei - project diffusely to cortex and striatum: arousal, affective-motivational aspects
The anterior cingulate cortex and insular cortex process the emotional unpleasantness of pain
The prefrontal cortex mediates cognitive appraisal and descending control

This distributed cortical processing accounts for the two dimensions of pain: sensory-discriminative (where? how intense?) and affective-motivational (how unpleasant?).

6. Trigeminal Pain Pathway

Pain from the face and head uses an analogous but parallel route:

Small-diameter Aδ and C fibers in the trigeminal nerve (CN V)
Synapse on second-order neurons in the spinal trigeminal nucleus of the brainstem (equivalent to the substantia gelatinosa)
Axons cross the midline and ascend in the trigeminal lemniscus
Terminate in the VPM nucleus of the thalamus → somatosensory cortex

Neuroscience: Exploring the Brain, 5th Ed.

7. Pain Modulation

Gate Control Theory (Melzack & Wall, 1965)

Gate control theory diagram showing Aβ mechanoreceptor axons activating an inhibitory interneuron that "gates" nociceptive C fiber input to projection neurons of the anterolateral tract

Gate control theory of pain (Neuroscience: Exploring the Brain, 5th Ed.)

Large-diameter Aβ touch fibers activate inhibitory interneurons in the dorsal horn that suppress nociceptive C-fiber signals. This explains why rubbing an injury reduces pain, and is the basis for TENS (transcutaneous electrical nerve stimulation).

Descending Inhibitory Pathway

Descending pain control pathway: PAG (midbrain) → raphe nuclei (medulla) → dorsal horn of spinal cord

Descending pain-control pathway (Neuroscience: Exploring the Brain, 5th Ed.)

Key structures:

Periaqueductal gray (PAG) - midbrain; receives emotional input from cortex, hypothalamus, and amygdala; electrical stimulation produces profound analgesia
Raphe nuclei - medulla; serotonergic neurons project to dorsal horn
Locus coeruleus - pons; noradrenergic neurons project to dorsal horn
These brainstem neurons inhibit (or sometimes facilitate) nociceptive neurons in the dorsal horn

8. Endogenous Opioid System

The brain manufactures its own opioid-like peptides that bind to opioid receptors concentrated in pain-processing areas:

Peptide family	Receptor
Endorphins	μ (mu)
Enkephalins	δ (delta)
Dynorphins	κ (kappa)

Small injections of morphine or endorphins directly into the PAG produce powerful analgesia. Opioid receptors are found at multiple levels: peripheral nociceptors, dorsal horn, PAG, and the rostral ventromedial medulla. Naloxone (an opioid antagonist) blocks both exogenous opioid analgesia and stress-induced analgesia, confirming the role of endogenous opioids in pain modulation.

Summary Flowchart

Noxious stimulus
      ↓
Peripheral nociceptors (Aδ, C fibers) activated
      ↓
Inflammatory soup sensitises receptors → peripheral sensitisation
      ↓
DRG → Dorsal horn (Laminae I, II, V) - first synapse
      Neurotransmitters: glutamate, substance P
      Gate control modulation by Aβ fibers
      ↓
Anterolateral tract (spinothalamic) - crosses midline
      ↓
Thalamus (VPL/intralaminar nuclei)
      ↓
Cortex: S1, S2 (localisation), anterior cingulate + insula (affect)
      ↓
PAIN PERCEPTION

Descending modulation:
Cortex/hypothalamus/amygdala → PAG → Raphe/LC → Dorsal horn
(via serotonin, norepinephrine, endogenous opioids)

Sources: Neuroscience: Exploring the Brain, 5th Ed. | Kandel's Principles of Neural Science, 6th Ed.

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