By Daniela Pace Nervous System 2 MD 2

Describe the mechanisms that give rise to hyperalgesia

Hyperalgesia is a form of sensitization; heightened sensitivity to stimuli. Hyperalgesia is the

abnormal increase in sensitivity to painful stimuli; stimuli that would normally elicit mildly
painful response is perceived as significantly more so. This effect is due to changes in neuronal
sensitivity at the level of the nociceptors, the receptors responsible for the perception of painful
stimuli, as well as the central targets.

Hyperalgesia is due to peripheral and central sensitization. Peripheral sensitization is due to

the interaction of nociceptors with a mixture of substances released when tissue is damaged,

arising from nociceptors themselves or non-neuronal cells (mast cells, basophils, platelets,

macrophages, neutrophils, endothelial cells, fibroblasts and keratinocytes) that are found

within the damaged tissue or migrate to the area. Nociceptors release peptides and

neurotransmitters such as substance P, calcitonin gene-related peptide (CGRP) and ATP, to

increase inflammatory response such as vasodilation, swelling and release of histamine from

mast cells. Non-neuronal cells release extracellular protons, arachidonic acid and other lipid

metabolites, bradykinin, histamine, serotonin, prostaglandins, nucleotides, nerve growth

factor (NGF) and cytokines (example; interleukin 1- ꞵ (IL-1 ꞵ) and tumour necrosis factor ⍺

(TNF-⍺). Most of these substances interact directly with receptors or ion channels of

nociceptive fibres causing activation. Extracellular protons or lipid metabolites interact with

transient receptor potential vanilloid 1 (TRPV1) receptors to elicit heat sensation. NGF and

bradykinin interact with TrkA and bradykinin receptors to generate an action potential via

stimulation of TRPV1 receptors. Prostaglandins bind to G-protein coupled receptors that

increase cAMP levels within nociceptors and they also reduce the threshold depolarisation

required for generating action potentials via phosphorylation of specific channels found on

nociceptors. Cytokines increase sodium channel activity directly and can also potentiate the

inflammatory response via increased production of prostaglandins, NGF bradykinin and

extracellular protons. All these mechanisms cause an action potential to be generated within

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By Daniela Pace Nervous System 2 MD 2

the peripheral nociceptor which causes signals to travel to the dorsal horn of the spinal cord

and to the anterolateral system within the central nervous system, thus eliciting the sensation

of pain. Peripheral sensitization protects the injured area, promotes healing and guarding

against infection.

Central sensitization is the rapid onset, activity-dependent increase in the excitability of neurons
in the dorsal horn of the spinal cord following high levels of activity in the nociceptive afferents.
This causes activity levels in the nociceptor that were subthreshold prior to the sensitising event
to become sufficient to generate action potentials in dorsal horn neurons, contributing to an
increase in pain sensitivity. There are several mechanisms that contribute to central sensitization;
windup, allodynia, reduction of GABAergic or glycinergic inhibition in spinal cord circuit and
glial cell contributions.

Windup involves a progressive increase in the discharge rate of dorsal horn neurons via

summation of action potentials in response to repeated low-frequency activation of

nociceptive afferents. Involves the activation of voltage-dependent L-type calcium channels

and removal of magnesium block of NMDA receptors, which causes an increase in the

sensitivity of the dorsal horn neuron to the excitatory neurotransmitter glutamate. Windup

only lasts during the period of stimulation, in comparison to the mechanism of allodynia

which lasts longer than the period of sensory stimulation. Allodynia refers to the induction

of pain by normal innocuous stimulus. Mechanisms that last longer than the period of

sensory stimulation involve LTP-like enhancement of postsynaptic potentials, this is

dependent on NMDA receptor-mediated elevations of calcium ions in spinal cord neurons

postsynaptic to nociceptors. Another mechanism is the reduction in the level of GABAergic

or glycinergic inhibition in spinal cord circuits. In conditions promoting central

sensitization, the function and expression of potassium-chloride cotransporter in dorsal horn

neurons may become impaired, causing the concentration of intracellular chloride ions to

increase and the depolarization of dorsal horn neurons postsynaptic to GABAergic

interneurons via GABA release. Furthermore, microglial cells release pro-inflammatory

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By Daniela Pace Nervous System 2 MD 2

cytokines that promote widespread transcription of the COX-2 enzyme responsible for the

production of prostaglandins, and produce TNF- ⍺ and brain-derived neurotrophic factor

which enhance excitatory synaptic transmission and suppress inhibitory synaptic

transmission in nociceptive circulation. Astrocytes produce chemokines to enhance pain

transmission in the spinal cord.

Hyperalgesia declines as tissue begins to heal and the threshold for pain returns to pre-injury
levels. However, when the afferent nerve fibres or central pathways are damaged these processes
can persist and result in a condition called neuropathic pain, constant pain that does not subside
with analgesic medication.

Diagram to be drawn ↑