Mechanism of Central Sensitisation

Mechanism of Central Sensitisation
The first evidence that in the acute pain hypersensitivity there is a central component described by
Wolf in 1983. Though the concept of central sanitation has been introduced by Liebeck in 2002 in a
review who describe that in the physiology of pain are included booth peripheral and central
mechanisms in pain modulation.
Furthermore, Liebeck focused on dysfunctional central pain modulation and its importance for the
development of chronic pain. According to his review after trauma or inflammation, not only a
peripheral nociceptive sensitization occurs (hyperexcitability - primary hyperalgesia), but a central
sensitization may develop due to continuous noxious stimulation. This most commonly occur in the
level of dorsal horn neurons leading to long standing pain disorder (secondary hyperalgesia).
Alternatively, in the central nerve system another dysfunctional process can occur in the descending
nociceptive inhibition causing dysfunctional inhibition.
Central sensitization, in contrast to peripheral sensitization, produces pain hypersensitivity after the
inflammation or injury process have terminated by changing the sensory response to normal inputs.
Central sensitization involves pre-synaptic, post -synaptic changes, inter-neuron changes and
changes in descending modulation, and finally immune mechanisms resulting in an increased release
of excitatory neurotransmitters or enhanced synaptic activity.
In the pathophysiological process of central sensitization, the nervous system gets in a persistent
state of high reactivity. This process is called wind-up and take place in the dorsal horn after
repetitive noxious stimulus due to tissue damage or inflammation. These stimulations progressively
result in an increase in the C-fibre evoked responses or the activation (depolarization) of N-methyl-
D-aspartate (NMDA) receptors, leading to increased neuronal sensitivity. Liebeck 2002. Wolf has also
found that even the large low-threshold mechanoreceptor myelinated fibres involved in sensitisation
by producing Aβ fibre–mediated pain.
In the central sensitization process, there is a number of substances interactions in the spinal cord
where glutamate plays an important role binding to several receptors on postsynaptic neurons in the
dorsal horn. Latremoliere & Woolf (2009) in their review have described in detail these processes
and interactions. In summary, glutamate is the primary afferent neurons transmitter and in spinal
cord, interacts with ionotropic amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-
D-Aspartate (NMDA), Kainate (KA) receptors and several metabotropic (G-protein
coupled)receptors. The AMPAR and NMDAR are found in all the synapses in the superficial laminae
of the dorsal horn. Another receptor group is glutamate receptor subtypes (mGluR), are found in the
extremities of the postsynaptic density zone (PSD).
The central sensitization mechanism has been categorized in three phases, depending on the
functional synaptic activity that leads in pain hypersensitivity. The first phase is the early
phosphorylation-dependent phase were glutamate phosphorylation play important role. Secondly is
the transcription-independent phase which occurs due to rapid changes in glutamate receptors and
ion channel. The last phase is the transcription-dependent phase that usually last longer and drives
synthesis of the responsible proteins that involved in central sensitization.
So, in the central sensitisation occur several changes in the nerve system, manifesting neuroplasticity
changes of the somatosensory nervous system. There is an increase of neurons activity, increased
membrane excitability and synaptic efficacy which reducing inhibition. The pathways reactivity alters
the synaptic input to nociceptive neurons, creating an increased action potential output. That results
to facilitation, potentiation, augmentation or amplification of the pain signals which contributes to
the generation of pain hypersensitivity. (Pricher 2007)
Clinical central sensitisation can become apparent with two main pain characteristics; allodynia and
hyperalgesia. Allodynia result from increased reactivity and is defined as pain experience from a
stimulus that usually is an innocuous sensation and doesn’t cause pain. It can be categorized
according to the sensory modality (touch, pressure, pinprick, cold, and heat), and it affects 15-50% of
patients with neuropathic pain (Jensen, 2003). Hyperalgesia is an amplification of pain and is defined
as painful stimuli that cause pain in greater extend compare to the stimuli (Wolfe, 2009),
In many peripheral neuropathies and central pain, the prominent symptoms disorders are allodynia
and hyperalgesia. Lidbeck in his study describes that many chronic musculoskeletal pain syndromes
caused from abnormalities in central pain modulation, like regional myofascial pain syndromes,
whiplash pain syndromes, refractory work-related neck-shoulder pain, chronic low back pain,
fibromyalgia and others (Lidbeck,2002).
Although, this pathophysiology mechanism that focuses on the properties of primary afferent and
dorsal horn nociceptive neurons and ascending pathways explains part of the central sensitization
the process in many chronic pain conditions can be more complex (Hladnik et all 2015).
Currently the central sensitization is recognized to play significant role in many chronic pain
disorders, such as chronic low back pain, chronic neck pain, whiplash injuries, chronic tension
headaches, migraine headaches, rheumatoid arthritis, osteoarthritis of the knee, endometriosis,
irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, after motor vehicle accident
injuries and post surgeries. (Wolf 2011)
1. Woolf CJ;(1983) Evidence for a central component of post-injury pain hypersensitivity.; Nature.
1983 Dec 15-21; 306(5944):686-8.
2. Lidbeck, J. (2009). Central hyperexcitability in chronic musculoskeletal pain: a conceptual
breakthrough with multiple clinical implications.
https://www.ncbi.nlm.nih.gov/pubmed/12185372
Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: a generator of pain hypersensitivity
by central neural plasticity. The journal of pain: official journal of the American Pain Society,
10(9), 895-926.
3. Pitcher MH, Ribeiro-da-Silva A, Coderre TJ; (2007) Effects of inflammation on the ultrastructural
localization of spinal cord dorsal horn group I metabotropic glutamate receptors; J Comp Neurol.
2007 Dec 1; 505(4):412-23.
4. Jensen, T.S. and Baron, R., 2003. Translation of symptoms and signs into mechanisms in
neuropathic pain. Pain, 102(1), pp.1-8.
5. Woolf, C et al. (2009). Central Sensitization: A Generator of Pain Hypersensitivity by Central
Neural Plasticity.
https://www.ncbi.nlm.nih.gov/pubmed/12185372
6. Hladnik, A., Bičanić, I ., Petanjek, Z. (2015) Functional neuroanatomy of nociception and pain.;
Periodicum Biologorum Vol. 117, No 2, 195–204
7. Woolf, C.J., (2011.) Central sensitization: implications for the diagnosis and treatment of pain.
Pain, 152(3), pp. S2-S15.

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