Research Review by Gary Maguire©

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Date Posted:

November 2010

Study Title:

Central Sensitization: A generator of pain hypersensitivity by central neural plasticity

Authors:

Latremoliere A & Woolf C

Author's Affiliations:

Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Publication Information:

The Journal of Pain 2009; 10(9): 895-926.

Background Information:

Central sensitization (CS) is defined as an augmentation of responsiveness of central neurons to input from unimodal and polymodal (peripheral) receptors. CS is responsible for many of the temporal, spatial, and threshold changes in pain sensitivity observed in acute and chronic clinical pain settings.

The fundamental reason CS occurs is an alteration within the CNS itself, manifesting as an enhancement in the function of neurons and circuits in the nociceptive pathways caused by increases in membrane excitability and synaptic efficiency. The result is multifactorial and includes: altered central processing in the brain, reduced descending anti-nociceptive inhibitory mechanisms, increased pain facilitation, and sensitivity and plasticity of the somatosensory nervous system in response to inflammation, activity, “normal” stimuli and neural injury.

The precursor to the development of CS is acute nociceptive “pain” which is defined as a physiological sensation of hurt that results from activation of the nociceptive pathways by peripheral stimuli of sufficient intensity to lead to, or threaten, tissue damage. This is a protective mechanism to help prevent injury by generating both a reflex withdrawal from the stimulus and a sensation so unpleasant that it results in complex behavioral strategies to avoid further contact of the stimuli.

Our pain perception system is adaptive. For example, sensitization of the nociceptive system can have an important function which occurs after repeated or particularly intense noxious stimuli. This causes the threshold for activation to fall and responses to subsequent inputs to be amplified. As the baseline is reestablished this system becomes adaptive in that it develops a state of being “hyper-alert” and aware of conditions in which a risk of further damage is high.

This phenomenon is the expression of use-dependent synaptic plasticity triggered in the CNS by the nociceptor input resulting from different forms of functional, chemical and structural plasticity. These changes can sensitize the central nociceptive system to produce pain hypersensitivity under both normal and pathological circumstances, some of which are persistent.

Central sensitization provides a mechanistic explanation for many clinical syndromes where pain is no longer protective. The pain is in these situations arises spontaneously, can be elicited by normally innocuous stimuli (referred to as allodynia), is exaggerated and prolonged in response to noxious stimuli (hyperalgesia), and spreads beyond the site of injury (secondary hyperalgesia).

There is a considerable difference between central sensitization and peripheral sensitization. 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 tissues.

Central sensitization creates novel inputs to nociceptive pathways including those that do not normally drive them, such as large, low-threshold mechanoreceptor myelinated fibers to produce A? fiber-mediated pain. Pain hypersensitivity is also produced in noninflamed tissue by changing the sensory response elicited by normal inputs and increasing pain sensitivity long after the initiating cause may have disappeared and when no peripheral pathology may be present (an unnormal state of responsiveness or increased gain of the nociceptive system develops).

As CS develops, a major functional shift occurs in the somatosensory system from high-threshold nociception to low-threshold pain hypersensitivity. When this phenomenon is thought to be present, the target of clinical care is then aimed at the CNS and not the periphery. The receptive field of somatosensory neurons are not fixed or hard wired, but are instead highly malleable. This malleability or plasticity is the substrate for the functional effects of central sensitization, and the means is a change in synaptic efficacy.

Clinically, CS contributes to neuropathic and inflammatory pain in many body regions, and clinical conditions such as migraines or irritable bowel syndrome – producing abnormal responsiveness to noxious and innocuous stimuli and a spread of tenderness beyond lesion sites. There is also evidence to suggest that CS may also play a fundamental role in the abnormal and widespread pain sensitivity in patients with fibromyalgia (1), chronic pain after whiplash injury, and chronic low back pain (3).

Our understanding of this phenomenon is developing rapidly, but further research is needed to understand the mechanisms and triggers that are responsible for the induction and maintenance of the switch in the somatosensory system from the physiological state, in which the sensory experiences evoked by low-intensity stimuli (innocuous sensations) and noxious stimuli (pain) are quite distinct and separate, to a dysfunctional hypersensitive system in which discrimination is lost.

This review will discuss our current state of knowledge on central sensitization. It contains relatively technical information, but will hopefully serve as a reference as we include more reviews on this important topic.

Pertinent Information:

Activity-Dependent Central Sensitization:
  • The first evidence for a central component to acute pain hypersensitivity was provided in 1983 (2). The interpretation of the data collected from the three experiments was that noxious heat stimulation, by activating C-fiber nociceptors, had induced a central plasticity of the nociceptive system, which was thereafter capable of responding to stimuli outside of the injury area and to low-threshold afferents that previously did not activate the nociceptive system. This led to a hypothesis (termed central sensitization) that brief trains of nociceptor C-fiber input could trigger or condition a long-lasting sensitization of the nociceptive system (a production of activity-dependent changes in the functional properties of neurons in the dorsal horn of the spinal cord contributing to both postinjury flexor reflex and pain hypersensitivity).
  • Functional magnetic resonance imaging, positron emission tomography, and magnetoencephalography have revealed in human subjects that several other brain structures involved with pain also exhibit changes compatible with an increase in excitability corresponding to central sensitization (structures involved are: parabrachial nucleus, periaqueductal gray (PAG), superior colliculus and the prefrontal cortex).
  • To induce central sensitization, the noxious stimulus must be intense, repeated, and sustained. There also must be input from many fibers occurring over tens of seconds (a single stimulus, such as a pinch, is insufficient). Another factor is that nociceptor afferents innervating muscles or joints produce a longer-lasting central sensitization than those that innervate skin.
Triggers of Activity-Dependent Central Sensitization:
  • Activation of N-methyl-D-Aspartate (NMDA) receptors is an essential step in both initiating and maintaining activity-dependent central sensitization. NMDA receptors are both a trigger and effector of central sensitization. With NMDA receptor excitability of nociceptive neurons, activation of group I Glutamate receptor subtypes (mGluR) by glutamate also appear important for the development of central sensitization.
  • Substance P, which is co-released with glutamate by unmyelinated peptidergic nociceptors is also involved in the generation of central sensitization.
  • Brain-derived neurotrophic factor (BDNF), released from trigeminal nociceptors (which may contribute to migraine and other primary headaches), is a neurotrophic factor and synaptic modulator that is synthesized by nociceptor neurons and released into the spinal cord (in an activity-dependent manner) and also has a role in the production of central sensitization.
  • Another trigger is the inflammatory kinin bradykinin produced in the spinal cord in response to intense peripheral noxious stimuli and it boosts synaptic strength.
Signaling Pathways and Activity-Dependent Central Sensitization:
  • An increase in intracellular Ca2+ beyond a certain threshold level appears to be the key trigger for initiating activity-dependent central sensitization.
  • Stimulation of amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and group I mGluRs participate with NMDA receptors in the activation of the intracellular pathways sustaining central sensitization.
  • Phosphorylated extracellular signal-regulated kinases (ERK) when present reveals an anatomical distribution of specific neurons whose intracellular signaling has been activated by the nociceptor input and are presumably undergoing the synaptic changes that constitute central sensitization.
  • Once activated, ERK produces translational and post-translational effects that participate in the maintenance of central sensitization in spinal cord neurons.
  • Nitric Oxide (NO) synthesized by either neuronal or inducible NO synthases in the dorsal horn also contributes to central sensitization.
Effectors of Activity-Dependent Central Sensitization:
  • When activated, guanylate cyclase appears to be the major way that NO contributes to the induction of sensitization through increases in neuronal excitability and a reduction in inhibition, although a NO-mediated activation of ADP-ribosyltransferase may participate in the maintenance of central sensitization.
  • AMPAR and NMDA receptor phosphorylation during central sensitization increases the activity/density of these receptors, leading to postsynaptic hyperexcitability.
Global Features of Activity-Dependent Central Sensitization:
  • As previously stated the key features of acute activity-dependent central sensitization are that it is induced with a short latency (seconds) by intense, repeated, or sustained nociceptor inputs and typically lasts for tens of minutes to several hours (in the absence of further nociceptor input).
  • NMDA receptors are required for activation and these also contribute to its maintenance although multiple triggers as mentioned above can contribute to the establishment of this type of central sensitization.
  • The involvement of so many different transmitters, modulators, and their receptors is not because of their specific action being important but rather that they are released directly from, or induced in response to, nociceptor afferent activity. They can separately or together initiate the activation of those multiple intracellular signaling pathways that lead to the establishment of hyperexcitability in dorsal horns.
  • For clarity there is no single defining molecular mechanism of central sensitization but rather it is a general phenomenon. It produces distinct changes in somatosensory processing and can be mediated by several different processes (in response to nociceptor input) and can (1) increase membrane excitability, (2) facilitate synaptic strength, or (3) decrease inhibitory influences in dorsal horn neurons.
  • For longer lasting effects different transcription-dependent changes are required. These effects generally do not occur in response only to nociceptor activity but are the consequence of peripheral inflammation and nerve injury.
  • Activity-dependent central sensitization (even though it increases pain sensitivity) is in most situations an adaptive mechanism.
  • Nociceptive pain warns of potential danger and central sensitization creates a situation in which pain is elicited by innocuous stimuli.
  • Central sensitization becomes pathological, autonomous and is maintained in the absence of active peripheral pathology (e.g. persistent inflammation as with rheumatoid arthritis).
  • The phenomenon of central sensitization represents not only a state in which the central sensitization itself can be maintained but also by a lower level or different kind of input.
  • Although nociceptor input is required to trigger central sensitization, phenotypic changes in myelinated fibers after inflammation and nerve injury can enable these afferents to acquire the capacity to generate central sensitization.
Activity-Dependent Central Sensitization and Synaptic Plasticity:
  • Activity-dependent synaptic plasticity in the dorsal horn is responsible for central sensitization and is reversible. This differs from the permanent activity-dependent synaptic change in the cortex that leads to long-term memory, long-term potentiation (LTP), in which the efficacy only of activated synapses is changed.
  • Heterosynaptic potentiation is the major synaptic alteration underlying activity-dependent central sensitization. This occurs when activity in one set of synapses enhances activity in nonactivated synapses typically by “sensitizing” the entire neuron which is something that never occurs with cortical LTP.
  • Homosynaptic potentiation is a type of use-dependent facilitation of a synapse evoked by activation of that synapse. A form of homosynaptic facilitation in spinal cord neurons is windup. This is when the action potential discharge elicited by a low-frequency (0.5 to 5 Hz) train of identical C-fiber strength stimuli gets larger on each successive stimulus.
  • Repeated C-fiber stimulation is the stimulus that induces windup and can lead to central sensitization. Windup, often considered to be an aspect of central sensitization is instead a reflection of activity-dependent excitability increases in neurons during a nociceptor conditioning paradigm rather than changes that follow such inputs (when central sensitization manifests itself). Windup disappears within ten seconds of the end of the a stimulus train as the membrane potential returns to its normal resting level.
  • Central sensitization constitutes the combination of the homosynaptic potentiation of conditioning nociceptor inputs and the heterosynaptic facilitation of nonconditioned fibers in the nociceptive pathway.
  • Heterosynaptic facilitation represents a form of activity-dependent facilitation where activity in one set of synapses augments subsequent activity in another nonactivated group of synapses. This potentiation appears to dominate the functional sensory manifestations of use-dependent central sensitization.
  • It is likely that both homosynaptic and heterosynaptic facilitations contribute to central sensitization and are triggered by the same process. The major difference is that heterosynaptic potentiation results from the spread of signaling from the conditioning synapse to other synapses in the neuron. Peripheral sensitization is the result of homosynaptic changes and heterosynaptic facilitation alone is responsible for secondary hyperalgesia and allodynia.
  • Another factor is that NO is also a major effector of spinal cord neuronal plasticity and diffuses rapidly from the site of its production to produce multiple effects at a distance via its downstream signaling pathways. In this method it may contribute to the heterosynaptic facilitation characteristic of central sensitization. It appears likely that these and other “spreading” signals cooperate to produce the widespread synaptic facilitation which is part of the characteristic of central sensitization.
Central Sensitization in Pathological Settings:
  • Central sensitization also contributes to the longer-lasting and sometimes persistent pain hypersensitivity present in pathological situations involving inflammation and damage to the nervous system. This occurs from its role in rapidly and reversibly sensitizing the nociceptive system by activity-dependent changes in synaptic strength and excitability.
  • There appear to be molecular and cellular mechanisms involved that include some that are responsible for activity-dependent central sensitization and others that are unique to either inflammation or nerve injury. These various mechanisms (NMDAR, AMPAR, group I mGluR, group II-III mGluR, BDNF, SP, CGRP, NO and bradykinin) have all been shown to contribute both to the development of central sensitization and to pain hypersensitivity in inflammation and neuropathic pain models.
Inflammatory Pain:
  • Peripheral inflammation induces a phenotypic switch in primary sensory neurons and produces a change in their neurochemical character and properties due to alterations in transcription and translation. Some of these changes relate specifically to central sensitization by virtue of changes in the synaptic input produced by the afferents so that anything that increases nociceptor afferent input will also indirectly lead to increased central sensitization.
Neuropathic Pain:
  • Following peripheral nerve injury, damaged and nondamaged A- and C-fibers begin to generate spontaneous action potentials. Since these do not arise from the peripheral terminal, it is a form of ectopic input. This input in C-fibers can initiate and then maintain activity-dependent central sensitization in the dorsal horn. Further, because of chemical and structural changes in A-fibers, input in these afferents can also begin to drive central sensitization. These changes are much greater than in peripheral inflammation and stimulation of non-nociceptive fibers now begins to trigger release of factors.
  • Peripheral nerve injury causes a massive activation of, and change in, glial cells in the spinal cord as well as infiltration of peripheral immune-competent cells, notably macrophages and T-cells. There is a greater extent and duration of the changes in microglia and astrocytes than in response to peripheral inflammation. These activated microglia produce and release oxygen species and appear to play an essential step in the development of pain after nerve injury by triggering central sensitization through their interaction with neurons.
  • Multiple different mechanisms operate after nerve injury to increase excitability and reduce inhibition. Astrocytes also become activated after peripheral nerve injury (with a slower onset and more prolonged time course than microglia) and may play more of a role in the maintenance of neuropathic pain hypersensitivity than microglia.
Scaffolding Proteins, Synaptic Plasticity, and Central Sensitization During Inflammation and After Nerve Injury:
  • The involvement of post synaptic density (PSD) in synaptic plasticity in the cortex is much better established than in the spinal cord and there is increasing evidence for a major role for the PSD in changing synaptic efficacy in response to peripheral inflammation and nerve injury.
  • PSD consists of cytoskeletal proteins, signaling molecules, membrane receptors, and scaffolding proteins. What is interesting is that scaffolding proteins are families of proteins characterized by their ability to interact with numerous partners and these proteins form the dense molecular structure of the postsynaptic component of the synapse.
  • Homer1a is an immediate early gene activated on neuronal activity and participates in remodeling synapses in an activity-dependent manner and may play an important role in the development and maintenance of central sensitization.
PSD Proteins and AMPAR Recycling and Subunit Switch:
  • A kinase-anchoring protein 79/150 (AKAP79/150) is a scaffold for protein kinases and phosphatases and specifically traffics enzymes within PSD to increase (kinases) or reduce (phosphatases) synaptic transmission.
  • AKAP79/150 may function as a “master switch” of central sensitization by promoting phosphorylation or dephosphorylation.

Clinical Application & Conclusions:

Prior to the discovery of central sensitization there were 2 major models of pain:
  1. A label-line system, in which specific “pain pathways” were activated only by particular peripheral “pain stimuli” and that the amplitude and duration of pain was determined solely by the intensity and timing of these inputs.
  2. An evoked “gate controls” system in the CNS. This system consists of opening or closing certain neurochemical/conceptual gates that would enable or prevent pain.
The problem is that neither model takes into account that pain may arise as a result of changes in the properties of neurons in the CNS: central sensitization. It can now be appreciated that there are specific nociceptive pathways and that these are subject to complex facilitating and inhibitory controls.

Changes in the functional properties of the neurons in these pathways are sufficient to reduce pain threshold, increase the magnitude and duration of responses to noxious input, and permit normally innocuous inputs to generate pain sensations. Pain is not simply a reflection of peripheral inputs or pathology but is also a dynamic reflection of central neuronal plasticity. This plasticity profoundly alters sensitivity to an extent that it is a major contributor to many clinical pain syndromes and represents a major target for therapeutic intervention.

There is now great insight into what triggers can induce central sensitization, which signaling pathways are involved and the key neurobiochemical “players”. The complexity persists because central sensitization is a constantly changing mosaic of alterations in membrane excitability, reductions in inhibitory transmission, and increases in synaptic efficacy, mediated by many converging and diverging molecular players on a background of phenotypic switches and structural alterations.

The most appropriate methods for manual therapists to positively affect these changes are still being researched. In the meantime, an understanding of this process can help us understand pain and the responses that we see in our patients.

Study Strengths / Weaknesses:

This critical review of central sensitization is complex and extensive with over 408 reference citations. Due to the length of the report a concise overview was provided to try and highlight the major components involving central sensitization.

A further understanding of the neurobiology described would require consulting the review for more expanded explanations and details and to allow for a better understanding of the complexity of the major triggers that initiate and maintain central sensitization, nociceptor input, inflammation, neuropathic mechanisms and synaptic plasticity.

The review is extremely well researched and provides an in depth understanding of this emerging and complex component associated with pain hypersensitivity. Clinicians should now have a better appreciation and knowledge from this review that central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings.

Additional References:

  1. Ablin J. et al. Pathogenesis of Fibromyalgia: A review. Joint Bone Spine 2008; 75: 273-279.
  2. Woolf C. Evidence for a central component of post-injury pain and plasticity: Nature 1983; 686-688.
  3. Nijs J et al. Recognition of Central Sensitization in Patients with Musculoskeletal Pain: Application of Pain Neurophysiology in Manual Therapy Practice; Manual Therapy 15 (2010) 135-141.