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Pathophysiology

Modes Of Sensitization

Nociception, the detection of noxious stimuli, is a protective process that helps prevent injury by generating both a reflex withdrawal from the stimulus and as a sensation so unpleasant that it results in complex behavioral strategies to avoid further contact with such stimuli.

An additional important phenomenon that further enhances this protective function is the sensitization of the nociceptive system that occurs after repeated or particularly intense noxious stimuli, so that the threshold for its activation falls and responses to subsequent inputs are amplified1

Pain sensitization is considered a key process in chronic pain conditions that are characterized by exaggerated responses to innocuous or only mildly noxious stimuli (hyperalgesia and allodynia). Two types of sensitization (peripheral sensitization [PS] and central sensitization [CS]) have been reported to affect chronicity and treatment resistance. 2

What Is Peripheral Sensitization?

Inflammatory mediators, intense, repeated, or prolonged noxious stimulation, or both can sensitize nociceptors. Sensitized nociceptors exhibit a lowered threshold for activation and an increased rate of firing.

In other words, they generate nerve impulses more readily and more often.

Peripheral (nociceptor) sensitization plays an important role in central sensitization and clinical pain states such as hyperalgesia (increased response to a painful stimulus) and allodynia (pain caused by a normally innocuous stimulus).3

peripheral-sensitization
central-sensitization

What Is Central Sensitization?

Central sensitization refers to a state of spinal neuron hyperexcitability.

Tissue injury (inflammation), nerve injury (i.e., aberrant neural input), or both may cause it, and ongoing nociceptive input from the periphery is needed to maintain it.

Repeated stimulation of nociceptors initially causes a gradual increase in the frequency of dorsal horns neuron firing known as “wind-up”.

The clinical correlate of wind-up temporal summation-refers to a progressive increase in pain experienced over the course of a repeated stimulus.3

Although phenomenologically central sensitization may appear to be comparable to peripheral sensitization, it differs substantially, in terms of both the molecular mechanisms responsible and its manifestation. Peripheral sensitization represents a reduction in threshold and an amplification in the responsiveness of nociceptors that occurs when the peripheral terminals of these high-threshold primary sensory neurons are exposed to inflammatory mediators and damaged tissue and, in consequence, is restricted to the site of tissue injury. Central sensitization, in contrast to peripheral sensitization, co-opts novel inputs to nociceptive pathways including those that do not normally drive them. 1

Key Points4

Pain chronicity may be the result of changes in Central Nervous System neuron properties by central sensitization phenomenon.

Nociceptive pathways are subject to excitatory and inhibitory modulations.

Changes in the balance of such modulations may change neuronal functional properties and decrease pain threshold, increase magnitude and duration of responses to nociceptive afferences allowing that normally painless afferences start to generate painful sensations.

MC-I305-13-2024
Data preparation: January 2024

  1. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 Sep;10(9):895-926. doi: 10.1016/j.jpain.2009.06.012. PMID: 19712899; PMCID: PMC2750819.
  2. Ohashi Y, Uchida K, Fukushima K, Inoue G, Takaso M. Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain. Cureus. 2023 Feb 22;15(2):e35331. doi: 10.7759/cureus.35331. PMID: 36846635; PMCID: PMC9949992.
  3. Pain: Current Understanding of Assessment, Management and Treatments. Developed by NPC as part of a collaborative project with JCAHO (2001)
  4. Ashmawi, H.A. and Freire, G.M.G., 2016. Peripheral and central sensitization. Revista Dor, 17, pp.31-34

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