The way of the pain signal – from the periphery to the CNS

Pain pathways

The central nervous system, which consists of the central and peripheral nervous system, can be considered as a network via which the pain stimulus is conveyed within the body.

The following structures are involved:

  • Peripheral nociceptors are activated by painful stimuli
  • Signal is transmitted to spinal cord
  • The ascending pathway transmits pain signals to the brain stem, thalamus and other regions of the brain
  • The descending pathway conveys pain modulating signals to the periphery

Elements of the pain process

Processing of pain signals

The pain process has four elements:

  1. Transduction: pain fibres recognise signals of tissue damage. The term is used for modification of membrane potential at the nociceptor level. Conversion of membrane potentials to action potentials is called transformation.
  2. Transmission: pain stimulus is transmitted via two types of sensory nerve fibres: A-δ nerve fibres (fast, surrounded by thin layer of myelin) and C nerve fibres (slower, non-myelinated). Cells of the dorsal horn are first processing level for pain stimuli. Here, direct activation of motor neurons can result in restrictive and thus protective movement (reflex). After transmission to the second order neuron, the pain stimulus is transmitted to various supra-spinal structures via afferent fibres of the spinothalamic tract.
  3. Modulation: neural activity controls transmission by either inhibiting or enhancing it. Peripheral modulation of pain occurs at the nociceptor level. Different substances can trigger-off or intensify pain in case of tissue damage, e. g. hydrogen ions, potassium ions, histamine, serotonin, acetylcholine, bradykinin, prostaglandins, substance P. Central modulation can either facilitate or inhibit pain as well.
  4. Pain perception: perception of the pain stimulus is processed in the brain in the somatosensory region of the cerebral cortex, and also involves activity in other parts of the brain.

Peripheral nociception

Peripheral nociceptors

In contrast to pain, which is defined as a subjective sensorial or emotional event, nociception means the reception, transmission and central nervous processing of noxious (tissue-damaging or potentially tissue-damaging) stimuli.

  • The painful stimulation referred to as nociceptive stimulation activates specific pain receptors called “nociceptors”.
  • Nociceptors are free nerve endings excited by damaging stimuli arising from various causes.
  • Most nociceptors are polymodal, i.e. they react to several different types of stimuli, e.g. thermal, mechanical and chemical stimuli.
  • They are present in large numbers in the skin, but they are also found in the muscles, periosteum, the capsules of internal organs and the walls of vessels and hollow organs. There are no nociceptors in the brain.

Spinal cord – first processing level of pain

Dorsal horn of the spinal cord

The human spinal cord is protected by the bony spinal column. It consists of nerve cells.

  • The spinal cord conveys the 31 spinal nerve pairs of the peripheral nervous system, as well as central nervous system pathways that innervate skeletal muscles. Inside the spinal cord, there is grey matter surrounded by white matter. The dorsal horn is the dorsal section of the grey substance of the spinal cord.
  • The cells of the dorsal horn of the spinal cord are the first processing level for the pain stimuli. Sensory nerve fibres coming from the periphery end here and neural impulses are switched to the second sensory neuron at excitatory synapses ascending to higher centres of the brain (afferent/ascending pathways).
  • In the other direction, motoneural responses and pain modulating inhibitory signals coming from the higher levels of the CNS are descending the spinal cord (efferent/descending pathways).

Involvement of the brain

Brain structures involved in pain processing

The relevant structures of the CNS in perception are the cerebral cortex, brain stem and the dorsal horn of the spinal cord.

The cortex is the “thinking” part of the brain where the unpleasant pain sensation is generated to cause awareness, while the limbic system generates emotional responses, such as sadness, tears and anger.

Concerning pain, the following structures are of special interest:

  • Cerebral cortex is the part of the brain where the perception as pain takes place.
  • Periaquaeductal grey (PAG; also called the "central grey") is the midbrain grey substance that is located around the cerebral aqueduct. It plays a role in the descending modulation of pain and in defensive behaviour.
  • Thalamus is a symmetric part of the brain. It constitutes the main part of the diencephalon. The thalamus acts as a relay station: dissemination of the signals to various areas of the brain, including transmission to the cerebral cortex.
  • Limbic system is a regulation centre of the pain threshold and of emotional reactions.

From the peripheral nociceptors to higher levels of CNS

Ascending pathways

Peripheral signal transduction
When free nerve endings are excited by damaging stimuli, their membrane potential changes (transduction) and is converted into an action potential (transformation). Afferent (i.e. ascending) A-δ and C fibres of the periphery transmit the pain stimulus to the dorsal horn of the spinal cord.

Synaptic excitation, 2nd order neuron, spinothalamic tract
Transmission of nociceptive information from the first to the second neuron takes place by means of excitatory neurotransmitters. Neurotransmitters bind post-synaptically to various receptors and produce an action potential, which is transmitted to the brain by so-called nociceptive projection neurons. On each segmental level, these neurons cross the spinal cord to the contra-lateral side where they form the ascending spinothalamic tract.

Processing in higher levels of the CNS
Some ascending fibres of the spinothalamic tract induce vegetative reactions by activating the reticular formation and areas of the upper spinal cord (medulla oblongata). They affect consciousness (mild pain increases concentration, severe pain leads to unconsciousness), and lead to cardiovascular and respiratory response to pain stimuli.

Other ascending fibres reach the hypothalamus where endocrine response is triggered (e.g., endorphin release from the pituitary gland).


Feedback loop for modulation of pain signals

Descending pathways

Centrally located grey substance of the midbrain, the periaquaeductal grey (PAG), receives a cortical and subcortical response and initiates inhibitory nerve impulses which descend the CNS in two different tract systems.

  • The medial tract is triggered by the so-called Raphé nuclei and is mainly influenced by the neurotransmitter serotonin which can execute pain inhibitory as well as pain facilitating activity.
  • The lateral tract starts in the Locus coeruleus. In this pathway, the neurotransmitter noradrenaline plays a central role.

Descending inhibition
By sending responses back to the periphery, the CNS can induce the release of neurotransmitters which reduce the transmission of pain signals (feedback loop).
Cortical and subcortical response
Neuronal centres of the cortex and subcortical areas of the brain respond to incoming (ascended) pain signals and can modulate pain signals by activating inhibitory descending efferent pathways.
Inhibitory synapses
Inhibitory impulses descend to the dorsal horn of the spinal cord segment where respective painful stimuli are transmitted to the second order neuron. Activated inhibitory interneurons release inhibitory neurotransmitters such as endorphins, noradrenaline and serotonin.


Quick check

The pain process has four elements:
Transduction, Transmission, Modulation, Perception
Assessment, Movement, Management, Processing
Depression, Anger, Fear, Frustration
Please, select the statement wich does not belong to the ascending pain pathway!
Transmission from Aδ and C nerve fibres to 2nd order neuron in the dorsal horn
Thalamic relay
Cortical impulses
Please, select the wrong statement about ascending pain pathway!
Afferent Aδ and C fibres transmit the pain stimulus to the dorsal horn of the spinal cord
Typical excitatory neurotransmitters are glutamate or substance P
The thalamus is localised in the dorsal horn of the spinal cord


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