Terapia dell'alcolismo - Medicina delle Dipendenze Verona - Dr. Faccini
Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability sensitization ad alcolismo synaptic efficacy as well as to reduced inhibition and is sensitization ad alcolismo manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury.
The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification.
Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central sensitization ad alcolismo system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli.
Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. In this article, we review the major triggers that initiate and maintain central sensitization sensitization ad alcolismo healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
Acute nociceptive pain is that physiological sensation of hurt that results from the activation of nociceptive pathways by peripheral stimuli of sufficient intensity to lead to or to threaten tissue damage noxious 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 amplified.
The nociceptor-induced sensitization of the sensitization ad alcolismo system is adaptive in that it makes the system hyperalert in conditions sensitization ad alcolismo which a risk of further damage is high, for example, immediately after exposure to an intense or damaging stimulus. This sensitization is the expression of use-dependent synaptic plasticity triggered in the central nervous system CNS by the nociceptor input and was the first example of central sensitization, discovered 26 years ago.
In many clinical syndromes, pain is sensitization ad alcolismo longer protective. The pain in these situations arises spontaneously, can be elicited by normally innocuous stimuli allodyniais exaggerated and prolonged in response to noxious stimuli hyperalgesiaand spreads beyond the site of injury secondary hyperalgesia.
Central sensitization has provided a mechanistic explanation for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and has highlighted the fundamental contribution of changes in the CNS to the sensitization ad alcolismo of abnormal pain sensitivity. Although phenomenologically central sensitization may appear to be comparable to peripheral sensitization, it differs substantially, both in terms of 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 46,and, in consequence, is sensitization ad alcolismo to the site of tissue injury. Peripheral sensitization appears to play a major role in altered heat but not mechanical sensitivity, which is a major feature of central sensitization.
Because central sensitization results from changes in the properties of neurons in the CNS, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of particular peripheral stimuli. Instead, central sensitization represents an abnormal state of responsiveness or increased gain of the nociceptive system. The pain is effectively generated as a consequence of changes within the CNS that then alter how it responds to sensory inputs, rather than reflecting the presence of peripheral noxious stimuli.
In this respect, central sensitization represents a major functional shift in the somatosensory system from high-threshold nociception to low-threshold pain hypersensitivity. Central sensitization reveals, however, that this in many cases is a sensory illusion; specific alterations in the CNS can result in painful sensations occurring in the absence of either peripheral pathology or noxious stimuli, and the target sensitization ad alcolismo treatment in these situations must be the CNS not sensitization ad alcolismo periphery.
Central sensitization corresponds to an enhancement in the functional status of neurons and circuits in nociceptive pathways throughout the neuraxis caused by increases in membrane excitability, sensitization ad alcolismo efficacy, or a reduced inhibition.
The net effect is that previously subthreshold synaptic inputs are recruited to generate an increased or sensitization ad alcolismo action potential output, a state of facilitation, potentiation, or amplification. The reason that these cellular changes alter the sensitization ad alcolismo so profoundly is that normally only a small fraction of the synaptic inputs to sensitization ad alcolismo horn neurons contribute to their action potential output.
Recruiting these subthreshold inputs to the output of a neuron markedly alters its receptive field properties, with profound changes in receptive field sensitization ad alcolismo, spatial, and temporal properties Fig 2. This provides an opportunity for rapid sensitization ad alcolismo plasticity that can be revealed experimentally by increasing the excitability of the neuron or by blocking inhibitory transmitters. This malleability or plasticity is sensitization ad alcolismo substrate for the functional effects of central sensitization, and the means is a change in synaptic efficacy.
Subthreshold synaptic inputs. The sensitization ad alcolismo for receptive field plasticity. Intracellular in vivo recordings from a nociceptive-specific rat dorsal horn neuron revealing subthreshold synaptic inputs. The output of somatosensory neurons is determined by sensitization ad alcolismo peripheral sensory inputs that produce sufficiently large-amplitude monosynaptic sensitization ad alcolismo polysynaptic potentials to evoke an action potential discharge A and B.
This constitutes the receptive field or firing zone of the neuron. However, stimuli outside the receptive field can evoke synaptic inputs that are too small normally to produce action potential outputs Cand this constitutes a subliminal fringe or low-probability firing fringe, which can be recruited if synaptic efficacy is increased, to expand and change the receptive field.
In this particular neuron, a standard pinch stimulus applied to points A, B, and C evoked only action potentials at points A and B but clear subthreshold synaptic inputs at C. Modified from Reference Expansion of receptor fields during central sensitization. Recruiting subthreshold synaptic inputs to the output of a nociceptive-specific neuron can markedly alter its receptive field properties, producing changes in receptive field threshold and spatial extent.
When neurons in sensitization ad alcolismo dorsal horn spinal cord are subject to activity-dependent central sensitization, they exhibit some or all the following: development of or increases in spontaneous activity, a reduction in threshold for activation by peripheral stimuli, increased responses to suprathreshold stimulation, and enlargement of their receptive fields.
The examples in this figure of intracellular recordings of rat dorsal horn neurons show the cutaneous receptive fields before central sensitization pre mustard oil sensitization ad alcolismo after the induction of central sensitization post mustard oil and indicate how subthreshold nociceptive pinch, top sensitization ad alcolismo low-threshold brush, bottom inputs in the low-probability firing fringe LPFF are recruited by central sensitization.
Central sensitization was produced by topical application of mustard oil, which generates a brief burst of activity in TRPA1-expressing nociceptors and resulted in the neural equivalent of secondary hyperalgesia top and tactile sensitization ad alcolismo bottom.
Note that the mustard oil conditioning input was applied to a different area in red from the test pinch or brush inputs in blueso that the changes observed sensitization ad alcolismo due to hetero-synaptic facilitation.
When neurons in the dorsal horn spinal cord are subject to central sensitization, they exhibit some or all the following: development of or increases in spontaneous activity, a reduction in the threshold for activation by peripheral stimuli, increased responses to suprathreshold stimulation, and an enlargement of their receptive fields Fig 2.
Several features appear particular to central sensitization: conversion of nociceptive-specific neurons to wide-dynamic neurons that now respond to both innocuous and noxious stimuli, progressive increases in the responses elicited by a standard series of repeated innocuous stimuli temporal windupan expansion of the spatial extent of their input, and changes that outlast an initiating trigger. These changes can be elicited in human volunteers by noxious stimulation of the skin as with topical or intradermal capsaicin or repeated heat stimuli and in the gastrointestinal tract by exposure to low pH solutions.
Central sensitization contributes to neuropathic 37 and inflammatory pain, 26, migraine, 35 and irritable bowel syndrome. Central sensitization may also play a fundamental role in the abnormal and widespread pain sensitivity in patients with fibromyalgia.
The first evidence for a central component to acute pain hypersensitivity was provided in These recordings revealed, as sensitization ad alcolismo, that under normal conditions there was no spontaneous activity in the motor neurons and that their activation required a noxious mechanical or thermal stimulus to the skin.
These neurons had high-threshold nociceptive-specific receptive fields restricted to the toes or hind paw, in keeping with their activation only as part of the flexion withdrawal reflex. After repeated peripheral noxious heat stimuli sufficient to generate mild inflammation of the hind paw, however, an increased excitability of the motor neurons was detected that lasted for several hours and included a reduction in threshold and enlargement of the cutaneous receptive fields.
The flexor motor neurons were now no longer nociceptive-specific but could be activated by low-intensity innocuous peripheral inputs such as light touch. Second, a local anesthetic block of the site of the peripheral injury sensitization ad alcolismo not result in collapse of the sensitization ad alcolismo receptive fields: The change was autonomous once it was triggered by the peripheral input.
Finally, the hypersensitivity produced by the noxious heat could be mimicked in extent and duration by a brief second low-frequency electrical stimulation of the sural nerve only at C-fiber strength, which produced changes lasting for tens of minutes. The interpretation of all these data 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 the articulation of a more general hypothesis that brief trains of nociceptor C-fiber input could trigger or condition a sensitization ad alcolismo sensitization of the nociceptive system an effect termed central sensitization by producing activity-dependent changes in the functional properties of neurons in the dorsal horn of the spinal cord and that this contributed both to postinjury flexor reflex and pain sensitization ad alcolismo. Schematic representation of the structures exhibiting central sensitization.
The first evidence for central sensitization was generated in by revealing injury-induced changes in the cutaneous receptive field properties of flexor motor neurons as an integrated measure of the functional plasticity in the spinal cord. A conditioning noxious stimulus resulted in long-lasting reductions in the threshold and an expansion of the receptive field of the motor sensitization ad alcolismo that was shown to be centrally generated.
Essentially identical changes were then described in lamina I and V neurons in the dorsal horn of the spinal cord b as well as in spinal nucleus pars caudalis Sp5cthalamus camygdala, and anterior cingulate cortex. Imaging techniques have revealed several brain structures in human sensitization ad alcolismo that exhibit changes compatible with central sensitization blue dots.
Before the discovery of central sensitization, the receptive field properties of dorsal horn neurons was thought to be fixed by the geometry of their dendrites relative to the central terminals of sensory axons.
The original description of central sensitization referred to an activity- sensitization ad alcolismo use-dependent form of functional synaptic plasticity that resulted in pain hypersensitivity after an intense noxious stimulus. Input from many fibers is required over tens of seconds; a single stimulus, such as a pinch, is insufficient.
Peripheral tissue injury is not necessary, although the degree of noxious stimulation that produces frank tissue injury almost always induces central sensitization, so that the phenomenon is very prominent after post-traumatic or surgical injury.
Interestingly, nociceptor afferents innervating muscles or joints produce a longer-lasting central sensitization than those that innervate skin. Once the phenomenon had been shown to be robust, easily activated, and detected in both preclinical and human subjects, the issue then was what molecular mechanisms were responsible. The first major mechanistic insight was that the induction and maintenance of acute activity-dependent central sensitization was dependent on NMDA receptors, revealing a key involvement of glutamate and its receptors.
We now appreciate from 2 decades of investigation by many labs that central sensitization sensitization ad alcolismo 2 temporal phases, each with specific mechanisms. The early phosphorylation-dependent and transcription-independent phase results mainly from rapid changes in glutamate receptor and ion channel properties.
Glutamate, the fast transmitter of primary afferent neurons, binds to several receptors on postsynaptic neurons in the dorsal horn of spinal cord, including ionotropic aminohydroxymethylisoxazole propionate AMPAN-methyl-D-Aspartate Sensitization ad alcolismoand Kainate KA receptors and several metabotropic G-protein coupled glutamate receptor subtypes mGluR.
All mGluRs except for mGluR6 and 8 are expressed in the spinal cord, whereas only mGluR6 appears not to be expressed by primary sensitization ad alcolismo neurons. Activation of NMDAR is an essential step in both initiating and maintaining activity-dependent central sensitization as its blockade by noncompetitive MK or competitive D-CPP NMDAR antagonists prevent and reverse the hyperexcitability of nociceptive neurons induced by nociceptor conditioning inputsand conditional sensitization ad alcolismo of NR1 abolishes NMDA synaptic inputs and acute activity-dependent central sensitization.
In addition to the critical role of NMDAR in increasing the excitability nociceptive neurons, activation of group I mGluRs by glutamate also appear important for the development of central sensitization.
Although these receptors do not participate to basal nociception,their activation is necessary for activity-dependent central sensitization mediated by C-fibers. Substance P SPwhich is co-released with glutamate by unmyelinated peptidergic nociceptors, is also involved in the generation of central sensitization. Ablation of NK1-positive neurons in the spinal cord leads to a reduction in capsaicin-evoked central sensitization, confirming the importance of projecting neurons expressing the substance P sensitization ad alcolismo in this phenomenon.
BDNF is a neurotrophic factor and synaptic modulator that is synthesized by nociceptor neurons and released into the spinal cord in an activity-dependent manner, 19 where it also has a role in the production of central sensitization. The inflammatory kinin bradykinin is produced in the spinal cord in response to intense peripheral noxious stimuli and acts through its G q -coupled B2 receptor, which is expressed by dorsal horn sensitization ad alcolismo 41and boosts synaptic strength by activating PKC, PKA, and ERK.
Central sensitization triggers: Schematic representation of key synaptic triggers of central sensitization. AModel of the synapse between the central terminal of a nociceptor and a lamina I neuron under control, basal conditions. B2 receptors are also activated by spinally produced bradykinin. NO is produced by several cell types in the spinal cord and can act presynaptically and postsynaptically. Calcium influx through NMDAR appears to be particularly prominent in the induction phase but can also occur through calcium-permeable AMPARs,voltage-gated calcium channels, 52as well as from release from intracellular microsomal stores in response to activation of several metabotropic receptorsFig 5, A through C.
Why is the calcium-induced sensitization ad alcolismo of intracellular kinases so important? The reason is that ionotropic NMDA sensitization ad alcolismo AMPA glutamate receptors can be phosphorylated on several sensitization ad alcolismo residues located on their C-terminus, 4042 and this post-translational modification changes their activity as well as their trafficking to or from the membrane, 40which with similar post-translational changes in other ion channels, produces the functional changes that manifest sensitization ad alcolismo central sensitization Fig 6, A through C.
AModel of a nociceptor—dorsal horn neuron synapse under control, nonactivated sensitization ad alcolismo. CTranscriptional changes mediated by activation of CREB and other transcription factors driving expression of sensitization ad alcolismo including c- FosNK1, TrkB, and Cox-2, to produce a long-lasting strengthening of the synapse. The presence of phosphorylated ERK reveals the anatomical distribution of those neurons whose intracellular signaling has been activated by the nociceptor input and are presumably undergoing the synaptic changes that constitute central sensitization,Fig 7.
In the spinal cord, ERK is only activated in neurons in response to intense peripheral noxious stimulation, effectively identical to those stimuli that induce central sensitization,suggesting that ERK phosphorylation is a better sensitization ad alcolismo of the neural plasticity that mediates central sensitization than c- Foswhich can be activated by low sensitization ad alcolismo stimuli that do not induce central sensitization.
Once activated, ERK produces translational and post-translational sensitization ad alcolismo that participate in the maintenance of central sensitization in spinal cord neurons. Inhibition of ERK activation using inhibitors sensitization ad alcolismo MEK reduces behavioral measures of activity-dependent central sensitization. Key sensitization ad alcolismo of central sensitization in the dorsal horn.
ERK activation participates in transcriptional and post-translational changes, CREB activation promotes transcription of several genes involved in central sensitization. ERK and PKC are activated through the increase of intracellular calcium sensitization ad alcolismo occurs during stimulation of nociceptive fibers lower panels.
Signals are shown in pseudocolor from blue weak intensity to red strong intensity. Key intracellular pathways contributing to the generation of central sensitization. Nitric oxide NO synthesized by either neuronal or inducible NO synthases in the dorsal horn also has a role in central sensitization. This is achieved by phosphorylation of numerous receptor and ion channel targets that lead to changes in threshold, channel kinetics, and voltage dependence, as well as a modification in the trafficking of the receptors to the synapse Fig 6, A and B.
On noxious stimulation, PKA phosphorylates GluR1 subunits, 8788leading to an insertion of these receptors into the synapse 8493 and thereby an increase in synaptic strength.