http://www.nature.com/nrneurol/journal/v2/n2/full/ncpneuro0113.html
Sindromi da dolore neuropatico: dolore dopo una lesione o dolore periferico o del sistema nervoso centrale, sono clinicamente caratterizzate da tipologie spontanea ed evocata di dolore, che sono sostenuti da vari distinti meccanismi fisiopatologici nel sistema nervoso centrale che periferico.
In alcuni pazienti, la lesione del nervo innesca cambiamenti molecolari nei neuroni nocicettivi, che diventano anormalmente sensibili fino a sviluppare attività spontanea patologica. Reazioni infiammatorie del tronco nervoso lesionato possono indurre l'attività ectopica dei nocicettori, provocando dolore spontaneo. L'iperattività nei nocicettori induce cambiamenti secondari nei segnali elaborati dai neuroni nel midollo spinale e del cervello, in modo che l'input dei meccano-recettori delle fibre tipo A è percepito come dolore. Cambiamenti nei sistemi neuroplastici centrali modulatori del dolore può portare a ulteriori condizioni di ipereccitabilità.
Il trattamento del dolore neuropatico è ancora insoddisfacente, e un nuovo concetto ipotetico è stato proposto, in cui il dolore viene analizzato sulla base dei meccanismi di base. La maggiore conoscenza dei meccanismi che generano il dolore e la loro traduzione in segni e sintomi potrebbero alla fine permettere una dissezione dei meccanismi che operano in ogni paziente. Se una precisa caratterizzazione clinica fenotipica del dolore neuropatico è combinata con una selezione di farmaci che agiscono su quei meccanismi, dovrebbe infine essere possibile progettare trattamenti ottimali per gli individui. Questa recensione descrive il quadro concettuale della classificazione basata sul meccanismo funzionale, incoraggiando il lettore a vedere il dolore neuropatico come entità clinica, piuttosto che una raccolta di stati di malattia unica.
Che cosa è il dolore neuropatico?
Le sindromi da dolore neuropatico sono i disturbi da dolore cronico causato, come diretta conseguenza di una lesione o da una malattia delle parti del sistema nervoso che normalmente veicolano segnali dolorosi. Sono condizioni eterogenee che non possono essere spiegati da una eziologia singolo o lesione specifica. Il dolore cronico neuropatico è comune nella pratica clinica, e si altera notevolmente la qualità della vita dei pazienti. La maggior parte dei pazienti che si dividono in quattro grandi classi:
-lesioni del nervo periferico focale e multifocale (traumatica, ischemica o infiammatorie),
-polineuropatie periferiche generalizzata (tossici, metaboliche, ereditarie o infiammatorie),
-le lesioni del SNC (ad esempio ictus, sclerosi multipla, il midollo spinale infortunio),
-disturbi neuropatici complessi (dolorosa regionale complessa sindromi.
Lesioni multifocali o monofocali del sistema nervoso periferico
Entrapment sindromi
dolore del moncone, arto fantasma,
nevralgia post-traumatica
Nevralgia posterpetica
mononeuropatia diabetica
Neuropatia ischemica
Poliarterite nodosa
Lesioni generalizzate del sistema nervoso periferico (polineuropatie)
Diabete mellito
Alcol
Amiloide
Plasmocitoma
HIV neuropatia
Ipotiroidismo
neuropatie sensoriali ereditarie
malattia di Fabry
La sindrome Bannwarth's (neuroborreliosi)
Carenza di vitamina B
Neuropatie tossiche (arsenico, tallio, cloramfenicolo, metronidazolo, nitrofurantoina, isoniazide, alcaloidi della vinca, taxoids, oro)
Le lesioni del sistema nervoso centrale
Lesioni del midollo spinale
Infarto cerebrale (in particolare il talamo e tronco encefalico)
Spinal infarto
Siringomielia
Sclerosi multipla
Disturbi neuropatici Complessi (CRPS)
Dolorosa regionale complessa sindromi di tipo I e II (distrofia simpatica riflessa, causalgia)
CRPSs (precedentemente chiamato distrofie simpatico-riflesso, atrofia di Sudeck o causalgia) sono disturbi dolorosi che possono svilupparsi a seguito di trauma sproporzionato, e tipicamente influenzare gli arti. CRPS tipo I di solito si sviluppa dopo un trauma estremo, senza lesione del nervo evidente (ad esempio fratture ossee , intervento chirurgico). CRPS tipo II si sviluppa dopo un trauma che è associato con una lesione di un nervo di grandi dimensioni. A differenza di altre sindromi del dolore neuropatico, CRPSs sono caratterizzate da segni aggiuntivi, come una anomala regolazione del flusso di sangue e sudore, e disturbi del movimento attivo e passivo, che indica che CRPSs sono malattie sistemiche del SNC. Inoltre,si osservano cambiamenti periferici, come l'edema dei tessuti cutanei e sottocutanei, i cambiamenti trofici, segni di infiammazione, dolore e una componente che è gestita da innervazione simpatica efferente.
Segni e sintomi del dolore neuropatico
I pazienti con dolore neuropatico mostrano distinti sintomi sensoriali che possono coesistere in varie combinazioni. Il comune esame sensoriale deve includere il tatto, puntura di spillo, pressione, freddo, calore, vibrazioni e sommazione temporale. Le risposte possono essere classificate come normali, diminuite o aumentate per determinare se i fenomeni sensoriali negativi o positivi sono coinvolti. In base allo stimolo-evocato (positivo) i tipi di dolore sono classificati come disestesico, iperalgesia o allodinia, e secondo il carattere dinamico o statico dello stimolo.
La risposta al tocco può essere valutata applicando delicatamente cotone sulla pelle, valutando la sensazione dalla risposta agli stimoli: puntura di spillo acuto, profondo dolore da una leggera pressione su muscoli e articolazioni, e la sensazione di freddo e calore, misurando la risposta ad uno stimolo termico, per esempio thermorollers mantenuta a 20 ° C o 45 ° C. sensazione di freddo può anche essere valutata la risposta all' acetone spray. Le vibrazioni possono essere valutati da un diapason posizionato in punti strategici (ad esempio articolazioni interfalangee). La sommatoria temporale anomala è l'equivalente clinico conseguente l'aumentare l'attività neuronale a seguito di ripetitiva stimolazione delle fibre C a >0.3 Hz. Questo dolore (wind-up-come), può essere prodotto da stimoli meccanici e termici.
Allo stato attuale, è generalmente accettato che la valutazione dovrebbe essere effettuata nella zona di massimo dolore, utilizzando l'area controlaterale come controllo; modifiche controlaterale segmentale a seguito di una lesione del nervo unilaterale o della radice non può essere escluso, comunque, un esame a siti mirror potrebbero non rappresentano necessariamente un controllo efficace.
Una tecnica più sofisticata di test neurofisiologici è la Quantitative Sensory Testing, QST, che utilizza una batteria standardizzata di stimoli meccanici e termici. Quando presenti, allodinia o iperalgesia possono essere quantificati misurando l'intensità, la soglia per l'estrapolazione, la durata e l'area.
Meccanismi patofisiologici del dolore neuropatico
La maggior parte delle idee correnti per quanto riguarda la fisiopatologia del dolore neuropatico si è originata da lavori sperimentali in modelli animali. Questi studi hanno delineato una serie di meccanismi fisiopatologici parzialmente indipendenti. Nelle sezioni che seguono, sono descritti questi meccanismi, seguita da una discussione della possibile traduzione di meccanismi neuropatico in sintomi e segni clinici, e di possibili bersagli per interventi terapeutici.
Sensibilizzazione Periferica
Sensibilizzazione e attività ectopica in nocicettori afferenti primari
Le sensazioni di dolore sono normalmente provocato da attività nelle fibre amieliniche (C-) e scarsamente mieliniche (A-) dei neuroni afferenti primari. Questi nocicettori sono solitamente silenziosi, in assenza di stimolazione, e rispondono meglio a stimoli potenzialmente nocivi. Dopo una lesione del nervo periferico però, questi neuroni diventano anormalmente sensibili e sviluppano attività spontanea patologica. Questi cambiamenti patologici sono sostenuti da drammatici cambiamenti molecolari e cellulari a livello dei nocicettori afferenti primari che vengono attivati dalla lesione del nervo.
Figura 2 Meccanismi di sensibilizzazione periferica e centrale nel dolore neuropatico.
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(A) Percorsi afferenti primari e le loro connessioni nel corno dorsali del midollo spinale. Nocicettivo fibre-C (colore rosso) terminano nei neuroni di proiezione spinotalamico in lamine superiore (neurone arancione), mentre i non-nocicettivo mieliniche A-fibre (blu) proiettano nella parte più profonda della lamina. La proiezione del secondo ordine di neurone è ad ampia gamma dinamica (WDR), cioè, riceve direttamente dai terminali sinaptici input nocicettivo ed anche l'input multisynaptico da fibre mieliniche tipo A- (informazioni non di dolore, sistema dei neuroni-blu). Gli interneuroni a rilascio di acido-aminobutirrico (GABA) (neurone verde) normalmente esercitano una potente inibizione sinaptica sull' ingresso al neurone WDR. Inoltre, si aggiungono le sinapsi modulatorie discendenti a livello dei neuroni WDR, (il terminale verde discendente rappresenta una proiezione inibitoria). Anche le cellule gliali, cellule del midollo spinale, (cellule marrone) possono anche comunicare con il neurone WDR.
(B) Cambiamenti periferici a livello dei neuroni afferenti primari (nocicettivi fibre C, rosso; non-nocicettivo mieliniche A-fibre, blu) dopo lesione del nervo parziale, conducono al meccanismo della conseguente sensibilizzazione periferica. Alcuni assoni sono danneggiati e degenerati (i due assoni superiori), mentre altri (a due assoni in basso) sono ancora intatti e collegate con l'organo periferico fine (la pelle).
La lesione attiva l'espressione dei canali del sodio sulle fibre-C danneggiate. Inoltre, i prodotti come il fattore di crescita nervoso che sono associati alla degenerazione walleriana vengono rilasciati in prossimità delle fibre risparmiate dalla lesione (frecce), elicitando l'espressione dei canali e recettori, (canali del sodio, recettori TRPV1, e recettori adrenergici) sulle fibre illese.
(C) L'attività spontanea in C-nocicettori induce cambiamenti secondari nella elaborazione sensoriale centrale, con conseguente ipereccitabilità del midollo spinale (sensibilizzazione centrale dei neuroni WDR di secondo ordine, indicato dal neurone dalla stella arancione).
Questo fa da ingresso ai meccano-recettori delle A-fibre (tocco leggero e stimoli puntiformi; sistema dei neuroni-blu) per essere percepiti come dolore (dinamici e puntati, cioè allodinia meccanica; '' indica il gating (soglia) a sinapsi via AMPA / KA [-amino-3-idrossi-5 acido-metil-4-isoxasole propionico e kainato recettori])". Diverse strutture molecolari presinaptiche (recettori oppioidi, canali calcio) e postsinaptiche (recettori del glutammato, i recettori NE [noradrenalina], 5-HT [serotonina] recettori, i recettori GABA, canali del sodio) sono coinvolti nella sensibilizzazione centrale. Gli interneuroni inibitori e i sistemi di controllo modulatorio discendente (neuroni verde) sono disfunzionali dopo lesioni nervose, con conseguente disinibizione o facilitazione dei neuroni del corno dorsale del midollo spinale e alla sensibilizzazione ulteriore centrale.
(D) Lesioni dei nervi periferici attivano cellule non neuronali gliali del midollo spinale (cellule marrone), che aumenta ulteriormente l'eccitabilità dei neuroni WDR rilasciando citochine e aumentano i livelli di glutammato. 5-HT, 5-idrossitriptamina (serotonina); GABA acido-aminobutirrico, NE, noradrenalina (meglio usare il termine norepinefrina).
Attività ectopica spontanea a seguito di lesione del nervo è compensata dalla aumentata espressione di RNA messaggero per i canali del sodio voltaggio-dipendenti in neuroni afferenti primari. L'assommarsi dei canali del sodio nei siti di generazione dell'impulso ectopico può essere responsabili per l'abbassamento della soglia d'azione potenziale e conseguente iperattività.
I geni che codificano la tensione di voltaggio dei canali del sodio (Nav1.8 e Nav1.9), sono espressi in modo selettivo in neuroni nocicettivi afferenti primari. Un canale embrionale, Nav1.3, è up-regolato nei nervi periferici danneggiati, e questo è associata con un'aumentata eccitabilità elettrica. Piccole fibre afferenti primarie acquisiscono un unico profilo di espressione di canale sodio (si altera la soglia di voltaggio), dopo lesione del nervo, che li rende un obiettivo interessante terapeutico. La ricerca futura dovrebbe essere finalizzato alla progettazione all'isotipo bloccante specifico dei canali del sodio canali.
Dopo il danno dei nervi periferici, i cluster di sodio-canale non si accumulano solo nel sito della lesione del nervo (Figura 2B), ma anche molto prossimalmente nel ganglio della radice dorsale intatta. Qui, un alternarsi tra un phasically attivare, voltaggio-dipendente, la conduttanza di sodio tetrodotossina-sensitive e un passivo, perdita di potassio voltaggio-indipendente caratteristica genera oscillazioni di potenziale di membrana. ectopica di cottura si attiva quando l'ampiezza di oscillazione sinusoidi raggiunge soglia. proprietà di membrana patologici all'interno dei gangli delle radici dorsali (DRG) sono di particolare interesse terapeutico, in quanto il DRG è risparmiata della barriera emato-encefalica e potrebbe essere facilmente accessibili per le terapie sistemiche.
In amputati umani appena risvegliati con dolore da arto fantasma, registrazioni microneurographic da singola fibra da fibre afferenti proiettanti nel neuroma hanno dimostrato spontanea attività ectopica, così come sbarramenti allo sparo di attività di potenziale. Questi pazienti hanno mostrato spontaneo dolore bruciante e sensazioni a scariche elettriche-simili, per cui è probabile che questi sintomi sono associati a impulsi focali di attività ectopica dei neuroni afferenti primari. Nei pazienti con Eritromelalgia con dolore bruciante, una mutazione è stata trovata nel gene SCN9A, che codifica per il canale Nav1.7 sodio. Ciò ha portato ad un modello di sparo di impulsi alterato nei neuroni afferenti. Prove indirette per attività ectopica afferenti è stata ricavata da un sottoinsieme di pazienti affetti da dolore neuropatico nei quali lidocaina, un bloccante dei canali del sodio produce sollievo dal dolore
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Introduction
Traditionally, clinicians have been taught to examine and classify patients on the basis of lesion topography and underlying pathology, an approach that has proved invaluable for understanding the pathophysiology of many diseases, including bacterial meningitis and osteoarthritis. In most of these disorders, pain is a symptom that rapidly disappears after the relevant therapy has been given, but in other conditions, such as diabetes mellitus, the underlying disease cannot be cured, and pain becomes the primary concern rather than a symptom.
In chronic pain conditions—and particularly in the case of neuropathic pain, which arises from damage or disease within the nervous system—a classification based on disease and anatomy is often insufficient. Despite obvious differences in etiology, many of these conditions share common clinical phenomena: for example, touch-evoked pain in postherpetic neuralgia and painful diabetic neuropathy. Conversely, different signs and symptoms can be present in the same disease: for example, pain paroxysms and stimulus-evoked abnormalities in postherpetic neuralgia. Classification on the basis of location also has its shortcomings, as neuroplastic changes following nervous system lesions often give rise to sensory and pain distributions that do not respect nerve, root, segmental or cortical territories.
These observations have raised the question of whether an entirely different strategy, in which pain is analyzed on the basis of underlying mechanisms,1 could provide an alternative approach for examining and classifying patients, with the ultimate aim of obtaining a better treatment outcome. 2, 3 Our increasing understanding of the mechanisms that underlie chronic pain, together with the discovery of new molecular therapy targets, has strengthened the demand for alternative concepts. In this article, I review some important neural mechanisms in neuropathic pain, drawing parallels between clinically testable sensory symptoms and the pathophysiological mechanisms that might be responsible for these symptoms.
What is neuropathic pain?
Neuropathic pain syndromes are chronic pain disorders caused as a direct consequence of a lesion or by disease of the parts of the nervous system that normally signal pain.4 They are heterogeneous conditions that cannot be explained by a single etiology or specific lesion. Chronic neuropathic pain is common in clinical practice, and it greatly impairs the quality of life of patients. Most patients fall into four broad classes (Box 1): peripheral focal and multifocal nerve lesions (traumatic, ischemic or inflammatory), peripheral generalized polyneuropathies (toxic, metabolic, hereditary or inflammatory), CNS lesions (e.g. stroke, multiple sclerosis, spinal cord injury), and complex neuropathic disorders (complex regional pain syndromes [CRPSs]).
Focal or multifocal lesions of the peripheral nervous system
Entrapment syndromes
Phantom limb pain, stump pain
Post-traumatic neuralgia
Postherpetic neuralgia
Diabetic mononeuropathy
Ischemic neuropathy
Polyarteritis nodosa
Generalized lesions of the peripheral nervous system (polyneuropathies)
Diabetes mellitus
Alcohol
Amyloid
Plasmocytoma
HIV neuropathy
Hypothyroidism
Hereditary sensory neuropathies
Fabry's disease
Bannwarth's syndrome (neuroborreliosis)
Vitamin B deficiency
Toxic neuropathies (arsenic, thallium, chloramphenicol, metronidazole, nitrofurantoin, isoniazid, vinca alkaloids, taxoids, gold)
Lesions of the CNS
Spinal cord injury
Brain infarction (especially the thalamus and brainstem)
Spinal infarction
Syringomyelia
Multiple sclerosis
Complex neuropathic disorders
Complex regional pain syndromes type I and II (reflex sympathetic dystrophy, causalgia)
CRPSs (formerly called reflex sympathetic dystrophies, Sudeck's atrophy or causalgia) are painful disorders that can develop as a disproportionate consequence of trauma, and they typically affect the limbs.5 CRPS type I usually develops after extremity trauma without obvious nerve lesion (e.g. bone fracture, surgery). CRPS type II develops after trauma that is associated with a lesion of a large nerve. In contrast to other neuropathic pain syndromes, CRPSs are characterized by additional signs, such as abnormal regulation of blood flow and sweating, and active and passive movement disorders, indicating that CRPSs are systemic CNS diseases. Furthermore, peripheral changes occur, such as edema of skin and subcutaneous tissues, trophic changes, signs of inflammation, and a pain component that is maintained by efferent sympathetic innervation.
Signs and symptoms in neuropathic pain
Patients with neuropathic pain demonstrate distinct sensory symptoms that can coexist in various combinations. Bedside sensory examination should include touch, pinprick, pressure, cold, heat, vibration and temporal summation. Responses can be graded as normal, decreased or increased to determine whether negative or positive sensory phenomena are involved. The stimulus-evoked (positive) pain types are classified as DYSESTHETIC, HYPERALGESIC or ALLODYNIC, and according to the dynamic or static character of the stimulus.
Touch can be assessed by gently applying cotton wool to the skin, pinprick sensation by the response to sharp pinprick stimuli, deep pain by gentle pressure on muscles and joints, and cold and heat sensation by measuring the response to a thermal stimulus, for example, thermorollers kept at 20 °C or 45 °C. Cold sensation can also be assessed by the response to acetone spray. Vibration can be assessed by a tuning fork placed at strategic points (e.g. interphalangeal joints). Abnormal temporal summation is the clinical equivalent of increasing neuronal activity following repetitive C-fiber stimulation at >0.3 Hz. This wind-up-like pain can be produced by mechanical and thermal stimuli.
At present, it is generally agreed that assessment should be carried out in the area of maximal pain, using the contralateral area as control. Contralateral segmental changes following a unilateral nerve or root lesion cannot be excluded, however, so an examination at mirror sites might not necessarily represent a true control.
A more sophisticated neurophysiological technique (quantitative sensory testing [QST]) uses a battery of standardized mechanical and thermal stimuli. When present, allodynia or hyperalgesia can be quantified by measuring intensity, threshold for elicitation, duration and area.
Table 1 defines several sensory signs and symptoms that can be found in painful neuropathies, and summarizes the appropriate tests to assess these symptoms clinically.
Pathophysiological mechanisms in neuropathic pain
Most of the current ideas regarding the pathophysiology of neuropathic pain originated from experimental work in animal models. These studies delineated a series of partially independent pathophysiological mechanisms. In the sections that follow, these mechanisms are presented, followed by a discussion of the possible translation of neuropathic mechanisms into clinical symptoms and signs, and of possible targets for therapeutic interventions (Figure 1).
Figure 1 Proposed model for the relationship between neuropathic pain mechanisms and clinical symptoms and signs, and possible targets for therapeutic interventions.
5-HT, 5-hydroxytryptamine (serotonin); ASIC, acid-sensing ion channel; GABA, -aminobutyric acid; MAPK, mitogen-activated protein kinase; NK1, neurokinin 1; NMDA, N-methyl-D-aspartate; NSAIDS, nonsteroidal anti-inflammatory drugs; SMP, sympathetically maintained pain; TCA, tricyclic antidepressants; TNF-, tumor-necrosis factor-.
Peripheral sensitization
Sensitization and ectopic activity in primary afferent nociceptors
Pain sensations are normally elicited by activity in unmyelinated (C-) and thinly myelinated (A-) primary afferent neurons. These nociceptors are usually silent in the absence of stimulation, and respond best to stimuli that are potentially noxious. After a peripheral nerve lesion, however, these neurons become abnormally sensitive and develop pathological spontaneous activity. These pathological changes are underpinned by dramatic molecular and cellular changes at the level of the primary afferent nociceptor that are triggered by the nerve lesion (Figure 2).
Figure 2 Mechanisms of peripheral and central sensitization in neuropathic pain.
(A) Primary afferent pathways and their connections in the spinal cord dorsal horn. Nociceptive C-fibers (red) terminate at spinothalamic projection neurons in upper laminae (orange neuron), whereas non-nociceptive myelinated A-fibers (blue) project to deeper laminae. The second-order projection neuron is of the wide dynamic range (WDR) type, that is, it receives direct synaptic input from nociceptive terminals and also multisynaptic input from myelinated A-fibers (non-noxious information, blue neuron system). -aminobutyric acid (GABA)-releasing interneurons (green neuron) normally exert inhibitory synaptic input on the WDR neuron. Furthermore, descending modulatory systems synapse at the WDR neuron (the green descending terminal represents an inhibitory projection). Spinal cord glial cells (brown cell) also communicate with the WDR neuron.
(B) Peripheral changes at primary afferent neurons (nociceptive C-fibers, red; non-nociceptive myelinated A-fibers, blue) after partial nerve lesion, leading to peripheral sensitization. Some axons are damaged and degenerate (upper two axons), whereas others (lower two axons) are still intact and connected with the peripheral end organ (skin). The lesion triggers the expression of sodium channels on damaged C-fibers. Furthermore, products such as nerve growth factor that are associated with Wallerian degeneration are released in the vicinity of spared fibers (arrows), triggering channel and receptor expression (sodium channels, TRPV1 receptors, adrenoceptors) on uninjured fibers.
(C) Spontaneous activity in C-nociceptors induces secondary changes in central sensory processing, leading to spinal cord hyperexcitability (central sensitization of second-order WDR neurons, indicated by star in orange neuron). This causes input from mechanoreceptive A-fibers (light touch and punctate stimuli; blue neuron system) to be perceived as pain (dynamic and punctate mechanical allodynia; '+' indicates gating at synapse via AMPA/KA [-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid and kainate] receptors). Several presynaptic (opioid receptors, calcium channels) and postsynaptic molecular structures (glutamate receptors, NE [norepinephrine] receptors, 5-HT [serotonin] receptors, GABA receptors, sodium channels) are involved in central sensitization. Inhibitory interneurons and descending modulatory control systems (green neurons) are dysfunctional after nerve lesions, leading to disinhibition or facilitation of spinal cord dorsal horn neurons and to further central sensitization.
(D) Peripheral nerve injury activates spinal cord non-neural glial cells (brown cell), which further enhances excitability in WDR neurons by releasing cytokines and increasing glutamate levels. 5-HT, 5-hydroxytryptamine (serotonin); GABA, -aminobutyric acid; NE, norepinephrine.
Ectopic spontaneous activity following nerve injury is matched by increased expression of messenger RNA for voltage-gated sodium channels in primary afferent neurons. Clustering of sodium channels at sites of ectopic impulse generation might be responsible for the lowering of the action-potential threshold and consequent hyperactivity.
The genes that encode the voltage-gated sodium channels Nav1.8 and Nav1.9 are expressed selectively in nociceptive primary afferent neurons. An embryonic channel, Nav1.3, is upregulated in damaged peripheral nerves, and this is associated with increased electrical excitability. Small primary afferent fibers acquire a unique sodium-channel expression profile after nerve lesion, which makes them an interesting therapeutic target. Future research should be aimed at designing isotype-specific sodium-channel blockers.
After peripheral nerve damage, sodium-channel clusters accumulate not only at the site of the nerve lesion (Figure 2B), but also far proximally within the intact dorsal root ganglion. Here, an alternation between a phasically activating, voltage-dependent, TETRODOTOXIN-sensitive sodium conductance and a passive, voltage-independent potassium leak generates characteristic membrane potential oscillations. Ectopic firing is triggered when the amplitude of oscillation sinusoids reaches threshold. Pathological membrane properties within the dorsal root ganglion (DRG) are of particular therapeutic interest, as the DRG is spared of the blood–brain barrier and might be easily accessible for systemic therapies.
In awake human amputees with phantom limb pain, microneurographic single-fiber recordings from afferent fibers projecting into the NEUROMA have demonstrated spontaneous ectopic activity, as well as barrages of action-potential firing. These patients showed spontaneous burning pain and electric-shock-like sensations, so it is likely that these symptoms are associated with ectopic primary afferent firing. In patients with ERYTHROMELALGIA with burning pain, a mutation was found in the SCN9A gene, which encodes the Nav1.7 sodium channel. This led to an altered firing pattern in afferent neurons. Indirect evidence for ectopic afferent activity has been obtained from a subset of neuropathic pain patients in whom lidocaine—a sodium channel blocker—produces pain relief.
DA QUI
Damage to peripheral nerves also induces upregulation of various receptor proteins—some of which are only marginally expressed under physiological conditions—at the membrane of primary afferents. Vanilloid receptors (TRPV1) are located predominantly on nociceptive afferent fibers, and can be activated by CAPSAICIN. Physiologically, this receptor senses noxious heat (>43 °C). After partial nerve injury, and in rats with streptozotocin-induced diabetes, the situation changes dramatically: the lesion triggers a TRPV1 downregulation on many damaged afferents, but novel expression of TRPV1 on uninjured C-fibers and A-fibers (Figure 2B, and see below).
Recent studies also provide evidence for an upregulation of TRPV1 in medium and large injured DRG cells.The observation that TRPV1-deficient mice do not develop heat hyperalgesia after tissue inflammation supports the idea that these changes might contribute to the development of C-nociceptor sensitization and the associated symptom of heat hyperalgesia. TRPV1 does not seem to be the only transduction mechanism for thermal sensitization after nerve injury, however: after partial sciatic nerve ligation, wild-type and TRPV1-null mice exhibited comparable persistent enhancement of mechanical and thermal nociceptive responses.
In taxol-induced small-fiber painful polyneuropathy, TRPV4, which is normally activated by temperatures of >30 °C, seems to play a crucial role in producing taxol-induced mechanical hyperalgesia. Spinal administration of ANTISENSE OLIGODEOXYNUCLEOTIDES to TRPV4, which reduces receptor expression in sensory nerves, abolished mechanical hyperalgesia in rats.
In postherpetic neuralgia patients with heat hyperalgesia, the acute topical application of histamine or capsaicin enhances pain, indicating abnormal sensitivity of nociceptors to capsaicin and histamine in the affected skin area, probably owing to expression of a novel receptor pattern. In a few patients with erythromelalgia and characteristic signs of nociceptor sensitization (burning pain and heat hyperalgesia), microneurographic recordings have confirmed that C-nociceptors are sensitized.
Investigations into temperature-sensitive excitatory ion channels also identified a cold- and menthol-sensitive TRP channel (TRPM8) that is activated in the 8–28 °C range.This receptor is expressed in small-diameter DRG neurons. Upregulation or gating of this channel after injury might lead to the peripheral sensitization of cold-sensitive C-nociceptors, resulting in the sensory phenomenon of cold hyperalgesia.
The transduction process for mechanical stimuli is still unresolved, although acid-sensing ion channels (ASICs) have been proposed as candidates for involvement in static mechanical hyperalgesia.
Experimental nerve injury also triggers the expression of functional 1-adrenoceptors and 2-adrenoceptors on cutaneous afferent fibers (Figure 2B). Consequently, these neurons develop adrenergic sensitivity. The concept of a pathological adrenergic coupling between sympathetic postganglionic fibers and afferent neurons forms the conceptual framework for the use of sympathetic blocks in pain syndromes such as CRPS.
Several observations support the idea that noradrenergic sensitivity of human nociceptors is present after partial or complete nerve lesion. In amputees, the perineuromal administration of norepinephrine induced intense pain. In patients with postherpetic neuralgia, CRPS II and post-traumatic neuralgias, application of norepinephrine in physiological doses into a symptomatic skin area evoked or increased spontaneous pain and dynamic mechanical hyperalgesia. In patients with CRPS I, spontaneous pain and mechanical hyperalgesia were augmented when sympathetic cutaneous vasoconstrictor neurons were activated physiologically by cold stress. By contrast, no adrenergic sensitivity of primary afferent neurons could be found in polyneuropathies.
Novel drugs that specifically block temperature-sensitive receptors or adrenoreceptors on nociceptive neurons would be ideal for tackling specific symptoms, such as temperature-induced and sympathetically-induced pain types.
There is increasing evidence that uninjured fibers that intermingle with degenerating fibers in a partially lesioned nerve might also participate in pain signaling. Products such as nerve growth factor that are associated with WALLERIAN DEGENERATION and are released in the vicinity of spared fibers might trigger the release of tumor-necrosis factor- (TNF-), as well as channel and receptor expression (sodium channels, TRPV1 receptors, adrenoreceptors; Figure 2B) thereby altering the properties of uninjured afferents. Future research should focus on the variety of changes that might occur in uninjured axons, as these neurons are still connected with their peripheral organs and could have a pivotal role in the generation of neuropathic pain.
Inflammation in neuropathic pain
After nerve lesion, activated macrophages infiltrate from endoneural blood vessels into the nerve and DRG, releasing proinflammatory CYTOKINES, in particular TNF-.These mediators induce ectopic activity in both injured and adjacent uninjured primary afferent nociceptors at the lesion site.
In patients with inflammatory neuropathies—such as vasculitic neuropathies or HIV neuropathy—deep proximal aching and paroxysmal pain are characteristic phenomena. COX2 and proinflammatory cytokines were found to be upregulated in nerve biopsy specimens of these patients.41 In the affected extremities of CRPS patients, the fluid of artificially produced skin blisters contain significantly higher levels of IL-6 and TNF- than the uninvolved extremity.
Central sensitization
Sensitization in the spinal cord
As a consequence of peripheral nociceptor hyperactivity, dramatic secondary changes occur in the spinal cord dorsal horn. Peripheral nerve injury leads to an increase in the general excitability of multireceptive spinal cord neurons (wide-dynamic-range neurons with multiple synaptic inputs from the nociceptive as well as the non-nociceptive system [orange neuron in Figure 2C]). This hyperexcitability is manifested by increased neuronal activity in response to noxious stimuli, expansion of neuronal receptive fields and spread of spinal hyperexcitability to other segments. This so-called central sensitization is initiated and maintained by activity in pathologically sensitized C-fibers. These fibers sensitize spinal cord dorsal horn neurons by releasing glutamate, which acts on postsynaptic N-methyl-D-aspartate (NMDA) receptors (Figure 2C), and the neuropeptide substance P. Postsynaptically, second-order dorsal horn neurons abnormally express Nav1.3 after peripheral nerve injury.42 Several intracellular cascades contribute to central sensitization, in particular the mitogen-activated protein kinase system (MAPK).43 If central sensitization is established, normally innocuous tactile stimuli become capable of activating spinal cord pain-signaling neurons via A and A low-threshold mechanoreceptors (blue neurons in Figure 2C).44 Central neuronal voltage-gated N-calcium channels located at the presynaptic sites on terminals of primary afferent nociceptors have an important role in central sensitization, through the facilitation of glutamate and substance P release. These channels are overexpressed after peripheral nerve lesion.45
Dynamic mechanical allodynia in patients is also conveyed by A low-threshold mechanoreceptors, pointing to central sensitization as the underlying mechanism. Reaction-time measurements show that dynamic allodynia in patients is signaled by afferents with conduction velocities that are appropriate for large myelinated axons. Also, transcutaneous or intraneural stimulation of nerves that innervate the allodynic skin can evoke pain at stimulus intensities that only produce tactile sensations in healthy skin.46 Furthermore, differential nerve blocks can abolish dynamic allodynia at time points when tactile sensation is lost but other modalities remain unaffected.
Physiologically, dorsal horn neurons receive a strong inhibitory control by -aminobutyric acid (GABA)-releasing interneurons (Figure 2A,C). In rodents, partial peripheral nerve injury promotes a selective apoptotic loss of GABA-releasing inhibitory neurons in the superficial dorsal horn of the spinal cord,47 a mechanism that further increases central sensitization. An alternative mechanism of intraspinal disinhibition following peripheral nerve injury was recently proposed, however. This mechanism involves a trans-synaptic reduction in the expression of the potassium–chloride exporter KCC2 in lamina I neurons, which disrupts anion homeostasis in these neurons. The resulting shift in the transmembrane anion gradient causes normally inhibitory anionic synaptic currents to be excitatory. The effect is that GABA release from normally inhibitory interneurons now paradoxically exerts an excitatory action on lamina I neurons, again increasing central sensitization.48
Dorsal horn neurons receive a powerful descending modulating control from supraspinal brainstem centers (inhibitory as well as facilitatory)49 (Figure 2A,C). It was hypothesized that a loss of function in descending inhibitory serotonergic and noradrenergic pathways contributes to central sensitization and pain chronification. This idea nicely explained the efficacy of serotonin and noradrenalin reuptake blocking antidepressants in neuropathic pain. In animals, however, mechanical allodynia after peripheral nerve injury depended on tonic activation of descending pathways that facilitate pain transmission, indicating that structures in the mesencephalic reticular formation—possibly the nucleus cuneiformis and the periaqueductal gray—are involved in central sensitization in neuropathic pain.50 Interestingly, advanced functional MRI (fMRI) techniques showed that the same brainstem structures were active in humans with allodynia.51 Because descending facilitation and inhibition are triggered simultaneously in most animal pain models, it will be important to elucidate why inhibition predominates in some neuronal pools, whereas facilitation predominates in others. Therapies that enhance descending inhibition and/or attenuate descending facilitation are an important target for future research.
Central sensitization might also be augmented by non-neural glial cells in the spinal cord. Peripheral nerve injury activates spinal cord glia and causes these cells to enhance pain by releasing neuroexcitatory glial proinflammatory cytokines and glutamate (Figure 2D).52
Changes in the brain
Most animal experiments have concentrated on the dorsal horn as the location of central sensitization. In rodents, however, sensitized neurons are also found in the thalamus and primary somatosensory cortex after partial peripheral nerve injury.53 Furthermore, magneto-encephalography (MEG), positron emission tomography (PET) and fMRI studies demonstrate fundamental changes in the somatosensory cortical representation and excitability in patients with phantom limb pain, CRPS and central pain syndromes,54, 55, 56, 57, 58 as well as in experimental pain models.59, 60 Interestingly, these changes correlated with the intensity of the perceived pain and disappeared after successful treatment of the pain.61, 62
Deafferentation: hyperactivity of central pain transmission neurons
Although the above data convincingly support a role for peripheral and central sensitization in the generation of neuropathic pain, in some patients there is a profound cutaneous deafferentation of the painful area with no significant allodynia. Assuming that the DRG cells and the central afferent connections are lost in such patients, their pain must be the result of intrinsic CNS changes. In animal studies, following complete primary afferent loss of a spinal segment, many dorsal horn cells begin to fire spontaneously at high frequencies,63, 64 and there is some evidence that a similar process might underlie the pain that follows extensive denervating injuries in human. Recordings of spinal neuron activity in a pain patient whose dorsal roots were injured by trauma to the CAUDA EQUINA revealed high-frequency regular and paroxysmal bursting discharges.65 The patient complained of spontaneous burning pain in a skin region that was rendered anesthetized by the lesion (a phenomenon that is termed anesthesia dolorosa).
Quantitative sensory testing as a diagnostic tool in neuropathic pain
The modern theoretical concept of a mechanism-based therapy assumes that a specific symptom predicts a specific underlying mechanism.1, 66 This approach carries certain important caveats, however. Clinical experimental studies indicate that a specific symptom might be generated by several entirely different underlying pathophysiological mechanisms, so a specific symptom profile rather than a single symptom might be required to predict the underlying mechanism. To translate these ideas into the clinical framework, it is important to characterize the somatosensory phenotype of a patient as precisely as possible.
In 2002, the German Research Network on Neuropathic Pain was founded with the aim of building a database of phenotypically characterized patients with various neuropathic pain states, and to perform research studies and clinical trials in this cohort of patients. A standardized QST protocol was introduced, including 13 parameters that encompass thermal as well as mechanical testing procedures for the analysis of the somatosensory phenotype. To judge plus or minus symptoms in patients, an age- and gender-matched database for absolute and relative QST reference data for several body regions in healthy human subjects was established.67
Currently, this nationwide multicenter trial comprises complete sensory profiles of 180 healthy human subjects and more than 1,000 patients with various types of neuropathic pain. For genetic analysis, blood samples of all patients are collected and stored. Skin biopsies to quantify epidermal nerve-fiber density are taken from subgroups of patients.
Precise phenotypic mapping with QST is an important step in determining a future mechanism-based treatment strategy for neuropathic pain. If symptoms are closely related to mechanisms, clinical assessment of the symptoms might give an idea of the interplay between distinct mechanisms that operate in any individual patient. This knowledge might lead to an optimal polypragmatic therapeutic approach, with drugs that address the specific combination of mechanisms occurring in each patient.
Several approaches are particularly interesting, and should be investigated in future trials. First, standardized QST profiling should be used to detect phenotype subgroups in neuropathic pain patients to learn more about pathophysiological mechanisms. Second, precisely classified phenotype subgroups should be entered into proof-of-concept trials. Last, a simplified QST protocol should be elaborated to enable inclusion of simple-to-use QST in large multicenter trials.
Top of pageGenetics of pain perception and response to treatment
It is well known that sensitivity to painful stimuli, the risk of developing chronic pain and the responses to analgesics vary considerably between individuals. Classical genetic techniques have been used to describe differences in pain perception in genetically different mouse strains, and have shown that pain traits are indeed influenced by genetic factors.68 Furthermore, polymorphisms of the endogenous opioid system are likely to account for individual differences in human nociception,69 and differences in the individual response to certain analgesics might be related to polymorphisms in drug-metabolizing enzymes.
Future research should focus on several issues. Genetic studies should be performed to define the influence of the individual genotype on the predisposition to pain chronicity and the response to treatment. It will also be necessary to identify and characterize specific molecular targets (ion channels, enzymes and regulators of gene transcription) and to evaluate the use of biotechnological approaches (gene therapy, stem cells) for pain therapy.
Top of pageConclusion
Neuropathic pain due to lesions or disease of the nervous system represents an important neurological challenge; treatment of patients with neuropathic pain has been largely neglected by neurologists in the past. Existing trials only provide general pain relief values for specific etiologies, which might partially explain the failure to obtain complete pain relief in neuropathic pain conditions. Increased knowledge of pain-generating mechanisms and their translation into symptoms and signs in neuropathic pain patients should allow a dissection of the mechanisms that are at play in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs that act on those particular mechanisms, it should be possible to design optimal treatments for individual patients.
Key points
Neuropathic pain syndromes are chronic pain disorders caused by lesion or disease of the parts of the nervous system that normally signal pain
A disease- and anatomy-based system is often insufficient to classify neuropathic pain conditions, and analysis on the basis of underlying mechanisms provides an alternative approach
Molecular mechanisms that underlie the sensitization of primary afferent nociceptors include upregulation of voltage-gated sodium channels and various receptor proteins, and the release of growth factors from degenerating nerve fibers
As a consequence of peripheral nociceptor hyperactivity, dramatic secondary changes occur in the spinal cord dorsal horn, and there is also evidence of sensitization of neurons in the brain
A single symptom may be generated by several different mechanisms, so a specific symptom profile might be required to predict the underlying mechanism
By combining a systematic clinical examination and a precise phenotypic characterization with a selection of drugs that act on particular mechanisms, it should be possible to design optimal treatments for individual patients
Top of pageAcknowledgments
R Baron is supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921), the German Ministry of Research and Education, German Research Network on Neuropathic Pain (BMBF, 01EM01/04) and an unrestricted educational grant from Pfizer, Germany.
