Nociception and pain modulation

Nociception is the neural process by which potentially or actually tissue-damaging stimuli are detected, transduced, and transmitted within the nervous system. The sensory receptors responsible for detecting such stimuli (nociceptors) are free nerve endings present in nearly all body tissues. They convert mechanical, thermal, or chemical stimuli into electrical impulses, which are conveyed via Aδ and C fibers to the spinal dorsal horn and then ascend through nociceptive pathways to the thalamus and cerebral cortex. It is essential to distinguish nociception, the objective neural activity, from pain, the subjective and emotional experience generated by the brain. This system is dynamically regulated by pain modulation, in which descending pathways can either inhibit or facilitate nociceptive transmission, thereby shaping the final perceptual and behavioral response.
Pain sensitization refers to abnormal pain perception due to increased neuronal sensitivity to noxious stimuli (hyperalgesia) and/or reduced neuronal threshold to normally harmless stimuli (allodynia). Sensitization plays a major role in the generation and maintenance of chronic and neuropathic pain.

Nociception is the neural process by which potentially or actually tissue-damaging stimuli are detected by nociceptors, transduced into electrical signals (action potentials), and transmitted via afferent pain fibers to the CNS for further processing.

Nociceptors

• Definition: primary sensory cells with free nerve endings that react to (potentially) harmful stimuli, thereby initiating the sensation of pain
• Localization: almost in every tissue
  • Highest density in the skin
  • Not present in parenchymatous organs (e.g., brain, lungs, liver)
• Classification: dependent on their sensitivity to certain stimuli
  • Mechanosensitive nociceptors: react to mechanical stimuli
  • Thermosensitive nociceptors: react to extreme thermal stimuli (heat > 45°C or cold < 5°C)
    • Cold and warm sensors are present in the skin in varying densities
      • Highest density of cold spots on the face, lowest density on the acra
  • Polymodal nociceptors: react to thermal (heat > 42°C or cold < 15°C), mechanical, and chemical stimuli
• Adaptation behavior: nociceptors are proportional sensors; they do not adapt to long-lasting, constant pain stimuli

Pain transduction

Nociceptors detect and transduce thermal, mechanical, and chemical stimuli via specialized ion channels and receptors. Activation of these molecular targets alters membrane conductance, leading to depolarization either directly (ionotropic mechanisms) or via intracellular signaling cascades (metabotropic mechanisms). If this depolarization reaches a critical threshold, it triggers the generation of an action potential, the electrical signal that is then transmitted toward the CNS.
For more details, see "Stimulus reception and transmission" in "Sensory physiology."

Nociceptor ion channels and receptors

The capsaicin paradox: Capsaicin initially triggers burning pain by activating TRPV1 cation channels on C-fibers, causing a massive release of the pro-inflammatory neuropeptide Substance P. With chronic use, sustained Ca²⁺ influx leads to the depletion of substance P stores and reversible "defunctionalization" of nociceptors, providing long-term relief in conditions like post-herpetic neuralgia.

Congenital insensitivity to pain
Congenital insensitivity to pain is an extremely rare syndrome, one cause of which is a mutation of the nerve growth factor (NGF) gene. This growth factor is critical during prenatal development, as it normally binds to its specific tyrosine kinase A (TrkA) receptor to stimulate the development and survival of nociceptors. If a mutation in the NGF gene prevents this signaling from occurring, pain fibers fail to form. As a result of this profound insensitivity to pain, individuals often sustain severe, unnoticed injuries, such as burns or bone fractures. The condition is typically evident within the first year of life.

Pain transmission

Nociceptive afferents

Nociceptors carry the electrical signal to the CNS via two types of afferent fibers: a large population of slow-conducting C-fibers and a smaller amount of faster-conducting Aδ-fibers. Depending on which fibers are excited, an initial, sharp, fast pain ("early pain") and a delayed, duller, and more persistent slow pain ("late pain") can be distinguished.

Myelin increases speed via saltatory conduction.

The withdrawal reflex is a polysynaptic spinal reflex initiated by Aδ-fibers that causes a part of the body to move away from a painful stimulus (e.g., a hot object) via contraction of flexor muscles and relaxation of extensor muscles.

Ascending nociceptive pathways

• Organized as a three-neuron chain with two main synaptic relays:
  1. Dorsal horn of the spinal cord (between the nociceptor and the second-order neuron)
  2. Thalamus (between the second-order and third-order neurons)
• Transmission is heavily influenced by modulating interneurons, especially at the first synaptic junction in the dorsal horn (see descending inhibitory pathways below)

Second-order neurons of the spinothalamic tract decussate (cross over) immediately at the spinal level via the anterior white commissure before ascending. Consequently, a unilateral spinal lesion (Brown-Séquard syndrome) causes contralateral loss of pain and temperature sensation 1–2 segments below the injury, as the ascending information from the opposite side of the body is interrupted.

Transmitters

Synaptic transmission onto the next neuron is either direct (excitatory) or modulated by inhibitory interneurons.

• Excitatory transmitter (from nociceptors)
  • Primary transmitter: glutamate
  • Cotransmitters: substance P and CGRP
  • Mechanism of action: activation of AMPA and NMDA receptors in the postsynaptic membrane → depolarization and pain transmission
• Inhibitory transmitters (from interneurons)
  • Primary transmitters: GABA and glycine
  • Neuropeptide transmitters: endogenous opioids (= endorphins)
    • Mechanism of action: opioid receptor activation → activation of an inhibitory G-protein → inhibition of adenylate cyclase → ↓ cAMP → potassium channels open (↓ cellular excitability) and calcium channels close (↓ glutamate release)

Synthetic opioids
The primary indication for synthetic opioids is pain therapy, although other uses, such as cough suppression, also exist. They function, just like endogenous opioids, by binding to inhibitory G-protein-coupled receptors. The three classical receptor types (μ-, δ-, and κ-receptors) bind these ligands with varying affinities, mediating not only analgesia but also a range of adverse effects. These receptors are densely expressed in the central nervous system and are also found in peripheral tissues, such as the gastrointestinal tract. Clinically, opioid analgesics are differentiated by their analgesic strength (e.g., low-potency vs. high-potency). Common and serious side effects include respiratory depression, constipation, and a high potential for dependence.

Nociceptive pathways of the head

The pain transmission from the head region differs in its circuitry at the brainstem level from that of the rest of the body.

Sensory information from the body travels to the VPL nucleus of the thalamus (think "L" for limb), while information from the face (via the trigeminal nerve) travels to the VPM nucleus (think "M" for mouth/makeup). Crucially, while both pathways eventually cross over, head pain fibers descend to the medulla before decussating, whereas body fibers decussate immediately at the spinal level.

Because the trigeminal pain fibers and the spinothalamic tract are close to each other in the medulla, a stroke here causes ipsilateral loss of pain/temperature on the face (spinal trigeminal nucleus) AND contralateral loss of pain/temperature on the body (lateral spinothalamic tract).

Pain modulation is the process by which the nervous system inhibits or amplifies nociceptive signal transmission at various levels through the action of inhibitory and excitatory mechanisms.

Descending modulatory pathways

• Regulate nociceptive signal transmission, primarily in the dorsal horn, by inhibiting (or, in some cases, facilitating) pain signals
• 1st order neuron: located in the periaqueductal gray of the midbrain → axons travel to the brainstem
• 2nd order neuron: located in brainstem nuclei → axons travel caudally via the dorsolateral funiculus to the dorsal horn of the spinal cord
  • Nucleus raphe magnus provides serotonergic (5-HT) efferents
  • Locus coeruleus provides noradrenergic (NE) efferents
• Spinal mechanism
  • Descending efferents terminate on dorsal horn synapses (on presynaptic nociceptor terminals, postsynaptic second-order neurons, and local interneurons)
  • Indirect inhibition: norepinephrine and serotonin activate inhibitory interneurons → release of GABA, glycine, and endogenous opioids (enkephalins/endorphins) → decrease in glutamate release, thereby reducing nociceptive transmission
  • Direct modulation:
    • Norepinephrine directly inhibits excitatory transmission via α₂-adrenergic receptors.
    • Serotonin has bidirectional effects (inhibitory or facilitatory) depending on the 5-HT receptor subtype activated .

The periaqueductal gray has a high density of μ-opioid receptors and is the primary target for opioid-induced analgesia.

SNRIs and TCAs treat neuropathic pain by inhibiting the reuptake of norepinephrine at the spinal synapse of the descending inhibitory pathway.

Stress-induced analgesia
Endogenous pain inhibition is a constantly active process, mediated by descending pathways and the body's own opioids. During acute stressful situations, such as after an accident, this system is significantly upregulated, causing pain to be perceived only weakly or not at all, a phenomenon known as stress-induced analgesia.

Pain sensitization

• Definition: abnormal pain perception due to increased neuronal sensitivity to noxious stimuli (hyperalgesia) and/or reduced neuronal threshold to otherwise normal stimuli (allodynia) in response to local injury, inflammation, and/or repetitive stimulation
• Plays a major role in the generation and maintenance of chronic pain and neuropathic pain (e.g., postherpetic neuralgia)
• Although not completely understood, the pathophysiology is thought to involve the following two mechanisms:
  • Peripheral sensitization
    • Injury, inflammation, or repetitive stimulation of the peripheral nociceptive neurons → local release of inflammatory mediators (e.g., cytokines, nerve growth factors, histamine, prostaglandins) → repeated or prolonged exposure to these mediators upregulates the ion channels in the nociceptors → increases sensitivity and/or reduces threshold to chemical mediators even further → increased action potential firing → abnormal pain signaling
    • Axon reflex: release of neuropeptides (CGRP, substance P) from damaged or activated nociceptors
      • Phosphorylation of ion channels in nociceptors (especially TRPV1) → reduces activation threshold and increases excitability of nociceptors
      • CGRP causes vasodilation and substance P increases capillary permeability.
      • Activation of mast cells and keratinocytes → additional release of inflammatory mediators and further potentiation of nociceptor sensitivity
  • Usually ceases once the tissue injury or inflammation heals
• Central sensitization (nociplastic pain)
  • Injury and/or inflammation of the CNS (e.g., dorsal horn of the spinal cord, brain) → increased release of glutamate → increased excitability of postsynaptic nociceptive neurons → long-term changes, such as:
    • Genetic changes in nociceptive neurons
    • Recruitment of non-nociceptive fibers (e.g., Aβ fibers) into the nociceptive pathway
  • Chronic peripheral pain disorders can be a significant driver to the sensitization of central nociceptive neurons
  • Persists after initial injury has healed (maladaptive)

While peripheral sensitization is a normal, temporary response to local inflammation (mediated by prostaglandins and substance P), central sensitization is a maladaptive "functional rewiring" of the CNS. It is driven by excessive glutamate release and leads to allodynia (pain from light touch), explaining why patients with conditions like fibromyalgia or postherpetic neuralgia feel pain even after the original tissue damage has cleared.

For the classification of pain by duration and type, please see "Principles of pain management."