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About inflammatory pain Anatomy, physiology, and pharmacology of acute inflammatory pain

Paola Sacerdote
Professor of Pharmacology
Department of Pharmacological and Biomolecular Sciences
University of Milano, Italy

Anatomy, physiology, and pharmacology of acute inflammatory pain
Acute inflammatory pain derives from the action of inflammatory mediators produced by several types of cells including those of the immune system in response to tissue injury.  Heightening sensory sensitivity after unavoidable tissue damage, this pain assists in the healing of the injured body part by creating a situation that discourages physical contact and movement. Pain hypersensitivity, or tenderness, reduces further risk of damage and promotes recovery, as after a surgical wound or in an inflamed joint, where normally innocuous stimuli now elicit pain. While this pain is adaptive, it needs to be reduced in patients with persistent inflammation.

Nociceptive signals are generated by peripheral sensory fibres called nociceptors: these fibres belong to neurons with cell bodies in the dorsal root ganglia (DRG) located outside the spinal cord. These neurons present two branches: one is innervating skin, viscera, muscles, and joints, and one reaches the dorsal horn of the spinal cord (Figure).



There are in turn two distinct types of these small-diameters nerve fibres (nociceptors): 

  • A-delta (lightly myelinated)
  • C-fibres (unmyelinated)

These fibres generally fail to adapt to stimulation so they keep firing until the stimulus is removed or escaped from.

Nociceptors alert us to potentially damaging stimuli by detecting extremes in temperature, pressure, acid, and injury-related chemicals, and transducing these stimuli into electrical signals that are relayed to spinal cord and then to brain centers. The nociceptors are extremely rich in specialized receptors that are either transducers, i.e. structures capable of converting a physical stimulus into a depolarizing current that runs through the cell membrane, or different type of receptors that can increase the sensitivity of the transducer receptors. 


There are a large number of chemical mediators, produced during inflammatory reactions, capable of activating, sensitizing, or arousing nociceptors. These  include  bradykinins, prostanoids (prostaglandin E2), histamine, serotonin, adenosine triphosphate (ATP), lipooxygenases,  growth factors (nerve growth factor, NGF, and brain-derived neurothrophic factor, BDNF), neuropeptides, nitric oxide (NO), tumor necrosis factor α (TNFα), interleukin 1β (IL-1), IL-6, and IL-8.

These mediators bind to specific receptors expressed in nociceptive sensory neurons and produce changes in the periphery and in the nervous system that result in hyperalgesia and allodynia. 

Amplification of nociceptive messages is produced not only by the substances released within the site of inflammation, but also by mediators released by the sensory fibres itself; for example, Substance P contributes to the recruitment of adjacent activated or sensitized fibres via a phenomenon known as neurogenic inflammation.

Hyperalgesia is an increased or amplified response to a noxious stimulus caused by sensitisation of peripheral nociceptors and/or central neurons that carry nociceptive information. Amplification of pain response can occur in the periphery, in the spinal cord and in some cases also in higher brain centres.  Primary hyperalgesia, which develops at the site of tissue injury, is associated with an increased sensitivity of the peripheral nerve fibres involved in pain transmission while secondary hyperalgesia, which develops in uninjured tissue surrounding the site of injury, is caused by an enhanced neural responsiveness in the CNS.

Allodynia differs from hyperalgesia in that it involves a noxious response to an innocuous stimulus; in particular, a tactile stimulus is now perceived as pain.

Hyperalgesia and allodynia are typical features of acute inflammatory pain and active agents able to modulate the mechanisms involved in the development of these phenomena provide the most useful therapeutic approach to clinical conditions characterized by the presence of this kind of pain.


Coutaux A. et al. Hyperalgesia and allodynia: peripheral mechanisms. Joint Bone Spine 72: 359-371, 2005

Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci  15: 1063-1967, 2012 

Dubin ED, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest 120: 3760-3772, 2010

Okuse K. Pain signaling pathways: from cytokines to ion channels. Int J Biochem Cell Biol 39: 490-496, 2007

Woolf CJ. What is this thing called pain? J Clin Invest 120: 3742-3744, 2010



Inflammatory pain - Pain associated with tissue injury and inflammation characterized by reduced threshold and increased responsiveness of sensory neurons

Nociceptor - A peripherally localized neuron preferentially sensitive to a noxious stimulus or to a stimulus that would become noxious if prolonged

Allodynia - Pain evoked by a normally innocuous stimulus

Hyperalgesia - Increase in the perception of pain elicited by a noxious stimulus

Primary hyperalgesia - Increased pain perception in area of injury (inflammation)

Secondary hyperalgesia - Increased pain perception in the region surrounding the area of injury (inflammation)

Neurogenic inflammation - General term used to describe the effects of the local release of inflammatory mediators such as substance P and CGRP from afferent nerve terminals. It plays a crucial role in the activation of peripheral mechanisms involved in the development of hyperalgesia

HELSINN Last Update: 22.02.2013
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