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CRONICIZZAZIONI E DECRONICIZZAZIONE DELL’EMICRANIA

CRONICIZZAZIONE E DECRONICIZZAZIONE DELL’EMICRANIA
DEFINIZIONE DI EMICRANIA CRONICA
Secondo i criteri stabiliti dalla Classificazione della International Headache Society -seconda edizione- si indica emicrania cronica come una condizione ove siano presenti 15 o più giorni al mese con emicrania. In questo caso non si fa menzione di superuso di medicamenti per il controllo in acuto. Tale diagnosi può essere estesa quando la condizione dura immutata da 3 mesi o più. E’ stata proposta una revisione che dovrà con ogni probabilità, essere inserita nella prossima edizione: 15 o più giorni con cefalea al mese di cui almeno 8 abbiano ad essere emicrania. Questo verrebbe a chiarire almeno un punto: quello della trappola per cui talvolta forme emicraniche vengono diagnosticate come non emicraniche e quindi trattate in modo non adeguato alla loro natura e meccanismo
In realtà statisticamente la gran parte delle forme croniche è una forma associata a superuso di analgesici e triptani destinati a controllare il dolore in acuto.

VI SONO DELLE CAUSE CHIARE A MONTE DELLA FORMA CRONICA?
O MEGLIO PERCHE’ ALCUNI CRONICIZZANO ED ALTRI NO?
Vediamo qui di seguito fattori di rischio che come tali vanno accepiti e non come sicuri prodromi di cefalea cronica

• Storia di trauma cranico o trauma a livello del rachide cervicale
• Sesso femminile
• Apnee notturne e disturbi del sonno
• Obesità
• Elevato consumo di caffeina
• Superuso di medicamenti diretti a contenere l’acuzie del dolore, specie gli oppiacei
• Eventi cosiddetti stressanti (dal cambiar residenza allo sposarsi )
• Fattori genetici
Critiche che si possono muovere a quest’elenco è che alcuni fattori possono far scattare una forma cronica ma altri risultano indicatori estremamente generici, sia fatta ad esempio menzione del sesso femminile che poco risulta di rilievo in una patologia che interessa le donne fino a 5 volte più dei maschi. Sia fatta menzione ad esempio dell’obesità , fattore calcolato per paesi dove questa patologia sta diventando un problema sociale ed è quindi molto diffuso (fino al 79% per il marcato sovrappeso , secondo studi dell’OMS), Questo senza contare una cosa assai rilevante e cioè che pregresse terapie antiemicraniche possono avere indotto incremento ponderale; è difatti non insolito che terapie antiemicraniche possano indurre incremento dell’appetito.
Reference
Bigal M, Sheftell F, Rapoport A, Lipton R, Tepper S. Chronic Daily Headache in A Tertiary Care Population: Correlation Between the International Headache Society Diagnostic Criteria and Proposed Revisions of Criteria for Chronic Daily Headache. Cephalalgia. 2002:432 -438. Available at: http://cep.sagepub.com/content/22/6/432.abstract [Accessed July 17, 2010].
Qual’è il meccanismo dell’emicrania cronica?
Si potrebbe sinteticamente rispondere: quello di tutti i dolori cronici che, comunque originatisi, se severi e ripetitivi portano a modificazioni del sistema nervoso centrale chr si manifestano al fine con reazioni dolorose e prolungate a fronte di stimoli sensitivi innocui per il soggetto sano esente da dolore primario

Ma scendiamo un poco nei dettagli

DALLA CRONICIZZAZIONE ALLA DECRONICIZZAZIONE

Mechanism of chronic migraine.
Aurora SK, Kulthia A, Barrodale PM.
Source
Swedish Headache Center, Swedish Neurosciences Institute, 1221 Madison Street, Seattle, WA 98116, USA. sheena.aurora@swedish.org
Abstract
Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. Results of electrophysiologic and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brainstem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiologic and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine, in which relatively permanent and pervasive central changes that warrant novel and tolerable treatments have occurred, is emerging. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.

Exploration of NMDA receptors in migraine: therapeutic and theoretic implications.
Nicolodi M, Sicuteri F.
Source
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence University, Italy.
Abstract
Pain intensity was observed before and after the subcutaneous (s.c.) administration of ketamine hydrochloride (80 micrograms/kg/s.c.) or saline (0.9% NaCl given by the same route) in 17 migraine (M) sufferers as an acute treatment of their M attacks. The same parameter was observed in another group of 17 M-sufferers complaining of very severe and frequent M attacks; these subjects were completely refractory to the prophylactic treatments currently used in M. In this second group, ketamine 80 micrograms/kg/s.c./three times a day) or saline was randomly assigned in a short (3-week) chronic treatment. A randomized, double-blind, cross-over study design was used both when testing ketamine as an acute administration for relieving M attack and when comparing its effect to that of the placebo in a chronic treatment for preventing M-pain. Ketamine, but not placebo, produced a marked relief of pain both as an acute treatment and as a prophylactic therapy. Mild specific side-effects were observed in the majority of the patients treated with ketamine. Moreover in the placebo group, the majority of these patients also complained of side-effects. The present results support the hypothesis that N-methyl-D-aspartic acid (NMDA) receptors play an important role in the mechanisms of M.

Int J Clin Pharmacol Res. 1998;18(2):93-100.
Negative modultors of excitatory amino acids in episodic and chronic migraine: preventing and reverting chronic migraine. Special lecture 7th INWIN Congress.
Nicolodi M, Sicuteri F.
Source
Interuniversity Center of Neurochemistry, Florence University, Italy.
Abstract
The mechanism capable of transforming episodic migraine into chronic migraine is attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly long-term potentiation, due to the action of excitatory amino acids, chiefly the ones acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to ‘third hyperalgesia’, a newly observed type of hyperalgesia which is inheritable and can act as a ground for the above-mentioned mechanism of ‘chronicization’ of migraine. The role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin, inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far considered refractory to prophylactic therapies, gives indirect but evident support to the mechanism suggested above. The antinociceptive role of the above-mentioned negative modulators of excitatory amino acids and the possible interplay between ionotropic and metabotropic receptors are also taken into consideration.
PMID:
9675627
[PubMed - indexed for MEDLINE]

The use of NMDA-receptor antagonists in the treatment of chronic pain.
(PMID:10870744)
Hewitt DJ
Department of Neurology, Emory University Medical Center, Atlanta, Georgia, USA. David_Hewitt@emory.org
The Clinical Journal of Pain [2000, 16(2 Suppl):S73-9]
Type: Journal Article, Review
Abstract Highlight Terms
Gene Ontology(5) Diseases(1) Chemicals(11)

Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.

Br J Pharmacol. 2009 June; 157(3): 464–473.
Published online 2009 March 20. doi: 10.1111/j.1476-5381.2009.00142.x
PMCID: PMC2707992
Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation
AP Andreou, PR Holland, and PJ Goadsby
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
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Abstract
Background and purpose:
Migraine is a disabling neurological disorder involving activation, or the perception of activation, of trigeminovascular afferents containing calcitonin gene-related peptide (CGRP). Released CGRP from peripheral trigeminal afferents causes dilatation of dural blood vessel, and this is used to measure trigeminal nerve activation. Kainate receptors with the GluR5 subunit (iGluR5, ionotropic glutamate receptor) are present in the trigeminal ganglion and may be involved in nociception. We investigated the possible involvement of prejunctional iGluR5 kainate receptors on CGRP release from trigeminal afferents.
Experimental approach:
We used neurogenic dural vasodilatation, which involves reproducible vasodilatation in response to CGRP release after electrical stimulation of the dura mater surrounding the middle meningeal artery. The effects of the specific iGluR5 receptor antagonist UBP 302 and agonist (S)-(-)-5-iodowillardiine were investigated on neurogenic and CGRP-induced dural vasodilatation in rats, by using intravital microscopy.
Key results:
Administration of 10 and 20 mg•kg−1 of iodowillardiine inhibited electrically induced dural vessel dilatation, an effect blocked by pretreatment with 50 mg•kg−1 UBP 302. Administration of the iGluR5 receptor antagonist UBP 302 alone had no significant effect. CGRP (1 mg•kg−1)-induced dural vasodilatation was not inhibited by the iGluR5 receptor agonist iodowillardiine.
Conclusions and implications:
This study demonstrates that activation of the iGluR5 kainate receptors with the selective agonist iodowillardiine is able to inhibit neurogenic dural vasodilatation probably by inhibition of prejunctional release of CGRP from trigeminal afferents. Taken together with recent clinical studies the data reinforce CGRP mechanisms in primary headaches and demonstrate a novel role for kainate receptor modulation of trigeminovascular activation.

Fibromyalgia and headache. Failure of serotonergic analgesia and N-methyl-D-aspartate-mediated neuronal plasticity: their common clues.
(PMID:9533670)
• Abstract
• Citations
• BioEntities
• Related Articles
Nicolodi M, Volpe AR, Sicuteri F
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence, Italy.
Cephalalgia : an International Journal of Headache [1998, 18 Suppl 21:41-44]
Type: Journal Article, Review, Research Support, Non-U.S. Gov’t
Abstract Highlight Terms
Diseases(3) Genes/Proteins(1) Chemicals(1)

A defect in serotonergic analgesia and a hyperalgesic state are proposed as features common to headache and fibromyalgia. The benefit to both migraine and fibromyalgia from inhibiting ionotropic N-methyl-D-aspartate receptor activity implies that redundant hyperalgesia-related neuroplastic changes are crucial for severe or chronic migraine and primary fibromyalgia. The fact that migraine and primary fibromyalgia share some pivotal set-up of serotonergic and excitatory amino acid systems led us to analyse epidemiological data supporting the hypothesis that analgesic disruption and a consequent hyperalgesic state are mechanisms of both migraine and fibromyalgia. Beyond demonstrating the comorbidity between migraine and primary fibromyalgia, the data suggest that migraine may represent a risk factor for fibromyalgia.

La teoria centrale dell’ emicrania e della sua cronicizzazione – La teoria serotoninergica- aminoacidergica nella lettura della fenomenologia acuta e cronica dell’ emicrania. In Zeneca (Ed.) XXX Congresso Nazionale della Società Italiana di Neurologia, Roma: Edizioni Internazionali CIC , pp 15-20, 1997
Nicolodi M., Sicuteri F. From migraine to primary fibromyalgia: LTP the common clue. Int. J. Clin. Pharmacol. Res., XVIII (2): 93-100, 1998

Nicolodi M, Sicuteri F. Planet Pain: Focus on chronic migraine . J Headache Pain 1: S11-S16, 2000

LA CENTRAL SENSITIZATION, LA LONG TERM POTENTION, E IL TANDEM GLUTAMMATO-NMDA
Il dolore che si sperimenta nella vita quotidiana (ad esempio per l’aver battuto un ginocchio) ha un meccanismo d’origine profondamente diverso dal dolore cronico neurogeno che è poi quello che ha il maggior impatto nella clinica e sulla qualità di vita.
Normalmente nel dolore acuto periferico la trasmissione del dolore è promossa da stimoli ad alta soglia, al contrario il dolore neurogeno centrale è indotto da stimoli a bassa soglia.
Accade così che stimoli sensitive innocui nel soggetto integro ed esente rispetto a condizioni di dolore centrale vengano a manifestarsi fenomeni di allodinia, cioè di dolore per stimolo innocui.
E’ inoltre caratteristica nota del dolore neurogeno centrale la cosiddetta overreaction fenomeno che determina il perdurare del dolore ben oltre il momento dell’applicazione dello stimolo fino a costituire un episodio doloroso di buona durata e severità.
Il dolore neurogeno centrale può avere degli acmi ma è fondamentalmente un fenomeno cronico. Il dolore cronico ha come caratteristica fondamentale e permissiva la plasticità che conduce alla cosiddetta “sensitization”, fenomeno per cui il sistema di trasmissione sensitivo/algogeno risponde a stimoli nocivi ed innocui. La rilevanza della sensitization fu sperimentalmente dimostrata negli anni ’90 ablando proprio I neuroni che , a livello spinale, andavano incontro a tale fenomeno. Il risultato fu che senza sensitization il dolore cronico non comparve.
E’ da sottolineare che i neuroni spinali e del sistema nervosa centrali in genere dimostrano un particolare tipo di plasticità detto long-term potentiation che assomiglia al meccanismo fisiologico con cui di instaurano i circuiti della memoria. In altre parole si assiste a una condizione patofisiologica in cui si edificano le vie del mantenimento del dolore.
Il glutammato , aminoacido presente in molti organi ed anche conosciuto come un esaltatore del sapore con il nome di monoglutammato di sodio, fa parte degli aminoacidi eccitatori ed è il neurotrasmettitore attivo nelle sinapsi più plastiche del nostro cervello, ovvero a livello di quelle che manifestano LTP. I recettori per il glutammato sono quattro e si trovano soprattutto condensati sul versante post-sinaptico. Tre sono i cosiddetti recettori ionotropici cioè l’AMPA, l’NMDA ed il kainato. Il quarto tipo è metabotropico ed è definito con la sigla mGluR. Tutti i tipi hanno importanza per la plasticità sinaptica, ma i recettori AMPA e NMDA sono quelli meglio conosciuti e vengono spesso ritenuti responsabili della memoria molecolare.
LA CENTRAL SENSITIZATION NELL’AMIGDALA E NELLA CORTECCIA CINGOLATA ANTERIORE
La central sensitization si estende anche ad aree che non fanno parte del sistema di trasmissione dell’input sensitivo/algogeno. In condizioni di dolore cronico si assiste alla sensitization dell’ amigdala nocicettiva, area connessa alle emozioni ed alla paura, e dei neuroni della corteccia cingolata anteriore, area che determina le componenti affettive del dolore. Questo giustifica una risonanza emotiva peculiare del dolore cronico poiché aree cerebrali come l’amigdala e la corteccia cingolata anteriore, coinvolte nell’esprimersi delle emozioni, diventano iperattive se si è in condizioni di dolore cronico.

Neuroscientist June 2004 vol. 10 no. 3 221-234
The Amygdala and Persistent Pain
1. Volker Neugebauer1,
2. Weidong Li2,
3. Gary C. Bird3 and
4. Jeong S. Han4
+ Author Affiliations
1. 1Department of Anatomy & Neurosciences, University of Texas Medical Branch, voneugeb@utmb.edu
2. 2Department of Anatomy & Neurosciences, University of Texas Medical Branch
3. 3Department of Anatomy & Neurosciences, University of Texas Medical Branch
4. 4Department of Anatomy & Neurosciences, University of Texas Medical Branch
Abstract
A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the “nociceptive amygdala” and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.

RVM E PAG
L’INIBIZIONE E LA FACILITAZIONE AL DOLORE
Il grigio periacqueduttale (PAG) ed il midollo rostrale ventromediale (RVM) son parte di un sistema modulatori della trasmissione nocicettiva, produce quindi analgesia. RVM può d’altra parte determinare un effetto la “facilitazione” per cui è anche provvisto della capacità di dare un effetto di promozione del dolore detto descending facilitation

Neuroscience 140 (2006) 1311–1320
DESCENDING FACILITATION FROM THE ROSTRAL VENTROMEDIAL
MEDULLA MAINTAINS NERVE INJURY-INDUCED CENTRAL
SENSITIZATION
L. P. VERA-PORTOCARRERO, E.-T. ZHANG,
M. H. OSSIPOV, J. Y. XIE, T. KING, J. LAI
AND F. PORRECA*

LA DECRONICIZZAZIONE
E’ d’interesse rilevare come interferire regolando negativamente la trasmissione dei recettori NMDA possa mettere capo a decronicizzazione interrompendo un circuito neurobiochimico che sostiene la central sensitization.
Pur essendo questo un risultato sperabile poiché gli antagonisti NMDA son da decenni impiegati negli USA come intervento di prima scelta per il trattamento di dolori primari quali la deafferentazione , abbiamo potuto constatare che dosi molto basse e ben tollerate di questi principi inducevano rapida decronicizzazione in circa
il 91% dei pazienti con emicrania cronica (n= 1250) , indipendentemente dalla durata dello stato patologico.
Il follow-up a 2 mesi vedeva un declino del beneficio nel 15% dei casi che comunque non tornavano allo stato iniziale ma peggioravano di circa il 20% rispetto ai valori post-trattamento
Il follow-up a 1 anno indicava la cessazione di stato di cronicità nell’ 85% dei casi trattati
M Nicolodi, A Torrini. Chronic Migraine and NMDA antagonists: what is effective, what is puzzling: a twelve years experience. Cephalalgia 16, 1347, 2006

DALLA DECRONICIZZAZIONE ALLA CURA DELL’ATTACCO IN ACUTO: UN CIRCOLO VIRTUOSO
E’ interessante notare come gli agenti neurobiochimici utili nella decronicizzazione del dolore possano essere usati anche come sintomatici e questo avrebbe il doppio scopo di decronicizzare le forme ormai croniche come quello di inibire il singolo attacco inibendo, simultaneamente il percorso verso la cronicità
FEATURE ARTICLE
Tapping Into the Migraine Pipeline—A Review of New Drugs on the Horizon
2010;18(1):20.
New acute and preventive migraine treatments target novel mechanisms and show promise for relieving symptoms.

Glutamate Receptor Antagonists
Another therapeutic target is glutamate, an excitatory neurotransmitter that has been shown to play a key role in both migraine and epilepsy pathophysiology. Ionotropic glutamate receptor agonists NMDA, kainate, and AMPA are involved in trigeminovascular activation, central sensitization, and cortical spreading depression. Drugs aimed at blocking their action are showing promise in treating acute attacks and have potential for preventing future attacks, according to Dr. Goadsby.

Glutamate receptor antagonists in the pipeline include tezampanel (LY-293558), an AMPA and kainate receptor antagonist; LY-466195, a GLUK5 receptor antagonist; ADX10059, an mGluR5 modulator that shows promise as a prophylactic agent; and perampanel, an AMPA receptor antagonist that is also being investigated as a preventive treatment for migraines.

CRONICIZZAZIONE E DECRONICIZZAZIONE DELL’EMICRANIA
DEFINIZIONE DI EMICRANIA CRONICA
Secondo i criteri stabiliti dalla Classificazione della International Headache Society -seconda edizione- si indica emicrania cronica come una condizione ove siano presenti 15 o più giorni al mese con emicrania. In questo caso non si fa menzione di superuso di medicamenti per il controllo in acuto. Tale diagnosi può essere estesa quando la condizione dura immutata da 3 mesi o più. E’ stata proposta una revisione che dovrà con ogni probabilità, essere inserita nella prossima edizione: 15 o più giorni con cefalea al mese di cui almeno 8 abbiano ad essere emicrania. Questo verrebbe a chiarire almeno un punto: quello della trappola per cui talvolta forme emicraniche vengono diagnosticate come non emicraniche e quindi trattate in modo non adeguato alla loro natura e meccanismo
In realtà statisticamente la gran parte delle forme croniche è una forma associata a superuso di analgesici e triptani destinati a controllare il dolore in acuto.

VI SONO DELLE CAUSE CHIARE A MONTE DELLA FORMA CRONICA?
O MEGLIO PERCHE’ ALCUNI CRONICIZZANO ED ALTRI NO?
Vediamo qui di seguito fattori di rischio che come tali vanno accepiti e non come sicuri prodromi di cefalea cronica

• Storia di trauma cranico o trauma a livello del rachide cervicale
• Sesso femminile
• Apnee notturne e disturbi del sonno
• Obesità
• Elevato consumo di caffeina
• Superuso di medicamenti diretti a contenere l’acuzie del dolore, specie gli oppiacei
• Eventi cosiddetti stressanti (dal cambiar residenza allo sposarsi )
• Fattori genetici
Critiche che si possono muovere a quest’elenco è che alcuni fattori possono far scattare una forma cronica ma altri risultano indicatori estremamente generici, sia fatta ad esempio menzione del sesso femminile che poco risulta di rilievo in una patologia che interessa le donne fino a 5 volte più dei maschi. Sia fatta menzione ad esempio dell’obesità , fattore calcolato per paesi dove questa patologia sta diventando un problema sociale ed è quindi molto diffuso (fino al 79% per il marcato sovrappeso , secondo studi dell’OMS), Questo senza contare una cosa assai rilevante e cioè che pregresse terapie antiemicraniche possono avere indotto incremento ponderale; è difatti non insolito che terapie antiemicraniche possano indurre incremento dell’appetito.
Reference
Bigal M, Sheftell F, Rapoport A, Lipton R, Tepper S. Chronic Daily Headache in A Tertiary Care Population: Correlation Between the International Headache Society Diagnostic Criteria and Proposed Revisions of Criteria for Chronic Daily Headache. Cephalalgia. 2002:432 -438. Available at: http://cep.sagepub.com/content/22/6/432.abstract [Accessed July 17, 2010].
Qual’è il meccanismo dell’emicrania cronica?
Si potrebbe sinteticamente rispondere: quello di tutti i dolori cronici che, comunque originatisi, se severi e ripetitivi portano a modificazioni del sistema nervoso centrale chr si manifestano al fine con reazioni dolorose e prolungate a fronte di stimoli sensitivi innocui per il soggetto sano esente da dolore primario

Ma scendiamo un poco nei dettagli

DALLA CRONICIZZAZIONE ALLA DECRONICIZZAZIONE

Mechanism of chronic migraine.
Aurora SK, Kulthia A, Barrodale PM.
Source
Swedish Headache Center, Swedish Neurosciences Institute, 1221 Madison Street, Seattle, WA 98116, USA. sheena.aurora@swedish.org
Abstract
Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. Results of electrophysiologic and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brainstem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiologic and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine, in which relatively permanent and pervasive central changes that warrant novel and tolerable treatments have occurred, is emerging. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.

Exploration of NMDA receptors in migraine: therapeutic and theoretic implications.
Nicolodi M, Sicuteri F.
Source
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence University, Italy.
Abstract
Pain intensity was observed before and after the subcutaneous (s.c.) administration of ketamine hydrochloride (80 micrograms/kg/s.c.) or saline (0.9% NaCl given by the same route) in 17 migraine (M) sufferers as an acute treatment of their M attacks. The same parameter was observed in another group of 17 M-sufferers complaining of very severe and frequent M attacks; these subjects were completely refractory to the prophylactic treatments currently used in M. In this second group, ketamine 80 micrograms/kg/s.c./three times a day) or saline was randomly assigned in a short (3-week) chronic treatment. A randomized, double-blind, cross-over study design was used both when testing ketamine as an acute administration for relieving M attack and when comparing its effect to that of the placebo in a chronic treatment for preventing M-pain. Ketamine, but not placebo, produced a marked relief of pain both as an acute treatment and as a prophylactic therapy. Mild specific side-effects were observed in the majority of the patients treated with ketamine. Moreover in the placebo group, the majority of these patients also complained of side-effects. The present results support the hypothesis that N-methyl-D-aspartic acid (NMDA) receptors play an important role in the mechanisms of M.

Int J Clin Pharmacol Res. 1998;18(2):93-100.
Negative modultors of excitatory amino acids in episodic and chronic migraine: preventing and reverting chronic migraine. Special lecture 7th INWIN Congress.
Nicolodi M, Sicuteri F.
Source
Interuniversity Center of Neurochemistry, Florence University, Italy.
Abstract
The mechanism capable of transforming episodic migraine into chronic migraine is attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly long-term potentiation, due to the action of excitatory amino acids, chiefly the ones acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to ‘third hyperalgesia’, a newly observed type of hyperalgesia which is inheritable and can act as a ground for the above-mentioned mechanism of ‘chronicization’ of migraine. The role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin, inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far considered refractory to prophylactic therapies, gives indirect but evident support to the mechanism suggested above. The antinociceptive role of the above-mentioned negative modulators of excitatory amino acids and the possible interplay between ionotropic and metabotropic receptors are also taken into consideration.
PMID:
9675627
[PubMed - indexed for MEDLINE]

The use of NMDA-receptor antagonists in the treatment of chronic pain.
(PMID:10870744)
Hewitt DJ
Department of Neurology, Emory University Medical Center, Atlanta, Georgia, USA. David_Hewitt@emory.org
The Clinical Journal of Pain [2000, 16(2 Suppl):S73-9]
Type: Journal Article, Review
Abstract Highlight Terms
Gene Ontology(5) Diseases(1) Chemicals(11)

Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.

Br J Pharmacol. 2009 June; 157(3): 464–473.
Published online 2009 March 20. doi: 10.1111/j.1476-5381.2009.00142.x
PMCID: PMC2707992
Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation
AP Andreou, PR Holland, and PJ Goadsby
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
Background and purpose:
Migraine is a disabling neurological disorder involving activation, or the perception of activation, of trigeminovascular afferents containing calcitonin gene-related peptide (CGRP). Released CGRP from peripheral trigeminal afferents causes dilatation of dural blood vessel, and this is used to measure trigeminal nerve activation. Kainate receptors with the GluR5 subunit (iGluR5, ionotropic glutamate receptor) are present in the trigeminal ganglion and may be involved in nociception. We investigated the possible involvement of prejunctional iGluR5 kainate receptors on CGRP release from trigeminal afferents.
Experimental approach:
We used neurogenic dural vasodilatation, which involves reproducible vasodilatation in response to CGRP release after electrical stimulation of the dura mater surrounding the middle meningeal artery. The effects of the specific iGluR5 receptor antagonist UBP 302 and agonist (S)-(-)-5-iodowillardiine were investigated on neurogenic and CGRP-induced dural vasodilatation in rats, by using intravital microscopy.
Key results:
Administration of 10 and 20 mg•kg−1 of iodowillardiine inhibited electrically induced dural vessel dilatation, an effect blocked by pretreatment with 50 mg•kg−1 UBP 302. Administration of the iGluR5 receptor antagonist UBP 302 alone had no significant effect. CGRP (1 mg•kg−1)-induced dural vasodilatation was not inhibited by the iGluR5 receptor agonist iodowillardiine.
Conclusions and implications:
This study demonstrates that activation of the iGluR5 kainate receptors with the selective agonist iodowillardiine is able to inhibit neurogenic dural vasodilatation probably by inhibition of prejunctional release of CGRP from trigeminal afferents. Taken together with recent clinical studies the data reinforce CGRP mechanisms in primary headaches and demonstrate a novel role for kainate receptor modulation of trigeminovascular activation.

Fibromyalgia and headache. Failure of serotonergic analgesia and N-methyl-D-aspartate-mediated neuronal plasticity: their common clues.
(PMID:9533670)
• Abstract
• Citations
• BioEntities
• Related Articles
Nicolodi M, Volpe AR, Sicuteri F
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence, Italy.
Cephalalgia : an International Journal of Headache [1998, 18 Suppl 21:41-44]
Type: Journal Article, Review, Research Support, Non-U.S. Gov’t
Abstract Highlight Terms
Diseases(3) Genes/Proteins(1) Chemicals(1)

A defect in serotonergic analgesia and a hyperalgesic state are proposed as features common to headache and fibromyalgia. The benefit to both migraine and fibromyalgia from inhibiting ionotropic N-methyl-D-aspartate receptor activity implies that redundant hyperalgesia-related neuroplastic changes are crucial for severe or chronic migraine and primary fibromyalgia. The fact that migraine and primary fibromyalgia share some pivotal set-up of serotonergic and excitatory amino acid systems led us to analyse epidemiological data supporting the hypothesis that analgesic disruption and a consequent hyperalgesic state are mechanisms of both migraine and fibromyalgia. Beyond demonstrating the comorbidity between migraine and primary fibromyalgia, the data suggest that migraine may represent a risk factor for fibromyalgia.

La teoria centrale dell’ emicrania e della sua cronicizzazione – La teoria serotoninergica- aminoacidergica nella lettura della fenomenologia acuta e cronica dell’ emicrania. In Zeneca (Ed.) XXX Congresso Nazionale della Società Italiana di Neurologia, Roma: Edizioni Internazionali CIC , pp 15-20, 1997
Nicolodi M., Sicuteri F. From migraine to primary fibromyalgia: LTP the common clue. Int. J. Clin. Pharmacol. Res., XVIII (2): 93-100, 1998

Nicolodi M, Sicuteri F. Planet Pain: Focus on chronic migraine . J Headache Pain 1: S11-S16, 2000

LA CENTRAL SENSITIZATION, LA LONG TERM POTENTION, E IL TANDEM GLUTAMMATO-NMDA
Il dolore che si sperimenta nella vita quotidiana (ad esempio per l’aver battuto un ginocchio) ha un meccanismo d’origine profondamente diverso dal dolore cronico neurogeno che è poi quello che ha il maggior impatto nella clinica e sulla qualità di vita.
Normalmente nel dolore acuto periferico la trasmissione del dolore è promossa da stimoli ad alta soglia, al contrario il dolore neurogeno centrale è indotto da stimoli a bassa soglia.
Accade così che stimoli sensitive innocui nel soggetto integro ed esente rispetto a condizioni di dolore centrale vengano a manifestarsi fenomeni di allodinia, cioè di dolore per stimolo innocui.
E’ inoltre caratteristica nota del dolore neurogeno centrale la cosiddetta overreaction fenomeno che determina il perdurare del dolore ben oltre il momento dell’applicazione dello stimolo fino a costituire un episodio doloroso di buona durata e severità.
Il dolore neurogeno centrale può avere degli acmi ma è fondamentalmente un fenomeno cronico. Il dolore cronico ha come caratteristica fondamentale e permissiva la plasticità che conduce alla cosiddetta “sensitization”, fenomeno per cui il sistema di trasmissione sensitivo/algogeno risponde a stimoli nocivi ed innocui. La rilevanza della sensitization fu sperimentalmente dimostrata negli anni ’90 ablando proprio I neuroni che , a livello spinale, andavano incontro a tale fenomeno. Il risultato fu che senza sensitization il dolore cronico non comparve.
E’ da sottolineare che i neuroni spinali e del sistema nervosa centrali in genere dimostrano un particolare tipo di plasticità detto long-term potentiation che assomiglia al meccanismo fisiologico con cui di instaurano i circuiti della memoria. In altre parole si assiste a una condizione patofisiologica in cui si edificano le vie del mantenimento del dolore.
Il glutammato , aminoacido presente in molti organi ed anche conosciuto come un esaltatore del sapore con il nome di monoglutammato di sodio, fa parte degli aminoacidi eccitatori ed è il neurotrasmettitore attivo nelle sinapsi più plastiche del nostro cervello, ovvero a livello di quelle che manifestano LTP. I recettori per il glutammato sono quattro e si trovano soprattutto condensati sul versante post-sinaptico. Tre sono i cosiddetti recettori ionotropici cioè l’AMPA, l’NMDA ed il kainato. Il quarto tipo è metabotropico ed è definito con la sigla mGluR. Tutti i tipi hanno importanza per la plasticità sinaptica, ma i recettori AMPA e NMDA sono quelli meglio conosciuti e vengono spesso ritenuti responsabili della memoria molecolare.
LA CENTRAL SENSITIZATION NELL’AMIGDALA E NELLA CORTECCIA CINGOLATA ANTERIORE
La central sensitization si estende anche ad aree che non fanno parte del sistema di trasmissione dell’input sensitivo/algogeno. In condizioni di dolore cronico si assiste alla sensitization dell’ amigdala nocicettiva, area connessa alle emozioni ed alla paura, e dei neuroni della corteccia cingolata anteriore, area che determina le componenti affettive del dolore. Questo giustifica una risonanza emotiva peculiare del dolore cronico poiché aree cerebrali come l’amigdala e la corteccia cingolata anteriore, coinvolte nell’esprimersi delle emozioni, diventano iperattive se si è in condizioni di dolore cronico.

Neuroscientist June 2004 vol. 10 no. 3 221-234
The Amygdala and Persistent Pain
1. Volker Neugebauer1,
2. Weidong Li2,
3. Gary C. Bird3 and
4. Jeong S. Han4
+ Author Affiliations
1. 1Department of Anatomy & Neurosciences, University of Texas Medical Branch, voneugeb@utmb.edu
2. 2Department of Anatomy & Neurosciences, University of Texas Medical Branch
3. 3Department of Anatomy & Neurosciences, University of Texas Medical Branch
4. 4Department of Anatomy & Neurosciences, University of Texas Medical Branch
Abstract
A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the “nociceptive amygdala” and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.

RVM E PAG
L’INIBIZIONE E LA FACILITAZIONE AL DOLORE
Il grigio periacqueduttale (PAG) ed il midollo rostrale ventromediale (RVM) son parte di un sistema modulatori della trasmissione nocicettiva, produce quindi analgesia. RVM può d’altra parte determinare un effetto la “facilitazione” per cui è anche provvisto della capacità di dare un effetto di promozione del dolore detto descending facilitation

Neuroscience 140 (2006) 1311–1320
DESCENDING FACILITATION FROM THE ROSTRAL VENTROMEDIAL
MEDULLA MAINTAINS NERVE INJURY-INDUCED CENTRAL
SENSITIZATION
L. P. VERA-PORTOCARRERO, E.-T. ZHANG,
M. H. OSSIPOV, J. Y. XIE, T. KING, J. LAI
AND F. PORRECA*

LA DECRONICIZZAZIONE
E’ d’interesse rilevare come interferire regolando negativamente la trasmissione dei recettori NMDA possa mettere capo a decronicizzazione interrompendo un circuito neurobiochimico che sostiene la central sensitization.
Pur essendo questo un risultato sperabile poiché gli antagonisti NMDA son da decenni impiegati negli USA come intervento di prima scelta per il trattamento di dolori primari quali la deafferentazione , abbiamo potuto constatare che dosi molto basse e ben tollerate di questi principi inducevano rapida decronicizzazione in circa
il 91% dei pazienti con emicrania cronica (n= 1250) , indipendentemente dalla durata dello stato patologico.
Il follow-up a 2 mesi vedeva un declino del beneficio nel 15% dei casi che comunque non tornavano allo stato iniziale ma peggioravano di circa il 20% rispetto ai valori post-trattamento
Il follow-up a 1 anno indicava la cessazione di stato di cronicità nell’ 85% dei casi trattati
M Nicolodi, A Torrini. Chronic Migraine and NMDA antagonists: what is effective, what is puzzling: a twelve years experience. Cephalalgia 16, 1347, 2006

DALLA DECRONICIZZAZIONE ALLA CURA DELL’ATTACCO IN ACUTO: UN CIRCOLO VIRTUOSO
E’ interessante notare come gli agenti neurobiochimici utili nella decronicizzazione del dolore possano essere usati anche come sintomatici e questo avrebbe il doppio scopo di decronicizzare le forme ormai croniche come quello di inibire il singolo attacco inibendo, simultaneamente il percorso verso la cronicità
FEATURE ARTICLE
Tapping Into the Migraine Pipeline—A Review of New Drugs on the Horizon
2010;18(1):20.
New acute and preventive migraine treatments target novel mechanisms and show promise for relieving symptoms.

Glutamate Receptor Antagonists
Another therapeutic target is glutamate, an excitatory neurotransmitter that has been shown to play a key role in both migraine and epilepsy pathophysiology. Ionotropic glutamate receptor agonists NMDA, kainate, and AMPA are involved in trigeminovascular activation, central sensitization, and cortical spreading depression. Drugs aimed at blocking their action are showing promise in treating acute attacks and have potential for preventing future attacks, according to Dr. Goadsby.

Glutamate receptor antagonists in the pipeline include tezampanel (LY-293558), an AMPA and kainate receptor antagonist; LY-466195, a GLUK5 receptor antagonist; ADX10059, an mGluR5 modulator that shows promise as a prophylactic agent; and perampanel, an AMPA receptor antagonist that is also being investigated as a preventive treatment for migraines.

CRONICIZZAZIONE E DECRONICIZZAZIONE DELL’EMICRANIA
DEFINIZIONE DI EMICRANIA CRONICA
Secondo i criteri stabiliti dalla Classificazione della International Headache Society -seconda edizione- si indica emicrania cronica come una condizione ove siano presenti 15 o più giorni al mese con emicrania. In questo caso non si fa menzione di superuso di medicamenti per il controllo in acuto. Tale diagnosi può essere estesa quando la condizione dura immutata da 3 mesi o più. E’ stata proposta una revisione che dovrà con ogni probabilità, essere inserita nella prossima edizione: 15 o più giorni con cefalea al mese di cui almeno 8 abbiano ad essere emicrania. Questo verrebbe a chiarire almeno un punto: quello della trappola per cui talvolta forme emicraniche vengono diagnosticate come non emicraniche e quindi trattate in modo non adeguato alla loro natura e meccanismo
In realtà statisticamente la gran parte delle forme croniche è una forma associata a superuso di analgesici e triptani destinati a controllare il dolore in acuto.

VI SONO DELLE CAUSE CHIARE A MONTE DELLA FORMA CRONICA?
O MEGLIO PERCHE’ ALCUNI CRONICIZZANO ED ALTRI NO?
Vediamo qui di seguito fattori di rischio che come tali vanno accepiti e non come sicuri prodromi di cefalea cronica

• Storia di trauma cranico o trauma a livello del rachide cervicale
• Sesso femminile
• Apnee notturne e disturbi del sonno
• Obesità
• Elevato consumo di caffeina
• Superuso di medicamenti diretti a contenere l’acuzie del dolore, specie gli oppiacei
• Eventi cosiddetti stressanti (dal cambiar residenza allo sposarsi )
• Fattori genetici
Critiche che si possono muovere a quest’elenco è che alcuni fattori possono far scattare una forma cronica ma altri risultano indicatori estremamente generici, sia fatta ad esempio menzione del sesso femminile che poco risulta di rilievo in una patologia che interessa le donne fino a 5 volte più dei maschi. Sia fatta menzione ad esempio dell’obesità , fattore calcolato per paesi dove questa patologia sta diventando un problema sociale ed è quindi molto diffuso (fino al 79% per il marcato sovrappeso , secondo studi dell’OMS), Questo senza contare una cosa assai rilevante e cioè che pregresse terapie antiemicraniche possono avere indotto incremento ponderale; è difatti non insolito che terapie antiemicraniche possano indurre incremento dell’appetito.
Reference
Bigal M, Sheftell F, Rapoport A, Lipton R, Tepper S. Chronic Daily Headache in A Tertiary Care Population: Correlation Between the International Headache Society Diagnostic Criteria and Proposed Revisions of Criteria for Chronic Daily Headache. Cephalalgia. 2002:432 -438. Available at: http://cep.sagepub.com/content/22/6/432.abstract [Accessed July 17, 2010].
Qual’è il meccanismo dell’emicrania cronica?
Si potrebbe sinteticamente rispondere: quello di tutti i dolori cronici che, comunque originatisi, se severi e ripetitivi portano a modificazioni del sistema nervoso centrale chr si manifestano al fine con reazioni dolorose e prolungate a fronte di stimoli sensitivi innocui per il soggetto sano esente da dolore primario

Ma scendiamo un poco nei dettagli

DALLA CRONICIZZAZIONE ALLA DECRONICIZZAZIONE

Mechanism of chronic migraine.
Aurora SK, Kulthia A, Barrodale PM.
Source
Swedish Headache Center, Swedish Neurosciences Institute, 1221 Madison Street, Seattle, WA 98116, USA. sheena.aurora@swedish.org
Abstract
Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. Results of electrophysiologic and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brainstem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiologic and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine, in which relatively permanent and pervasive central changes that warrant novel and tolerable treatments have occurred, is emerging. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.

Exploration of NMDA receptors in migraine: therapeutic and theoretic implications.
Nicolodi M, Sicuteri F.
Source
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence University, Italy.
Abstract
Pain intensity was observed before and after the subcutaneous (s.c.) administration of ketamine hydrochloride (80 micrograms/kg/s.c.) or saline (0.9% NaCl given by the same route) in 17 migraine (M) sufferers as an acute treatment of their M attacks. The same parameter was observed in another group of 17 M-sufferers complaining of very severe and frequent M attacks; these subjects were completely refractory to the prophylactic treatments currently used in M. In this second group, ketamine 80 micrograms/kg/s.c./three times a day) or saline was randomly assigned in a short (3-week) chronic treatment. A randomized, double-blind, cross-over study design was used both when testing ketamine as an acute administration for relieving M attack and when comparing its effect to that of the placebo in a chronic treatment for preventing M-pain. Ketamine, but not placebo, produced a marked relief of pain both as an acute treatment and as a prophylactic therapy. Mild specific side-effects were observed in the majority of the patients treated with ketamine. Moreover in the placebo group, the majority of these patients also complained of side-effects. The present results support the hypothesis that N-methyl-D-aspartic acid (NMDA) receptors play an important role in the mechanisms of M.

Int J Clin Pharmacol Res. 1998;18(2):93-100.
Negative modultors of excitatory amino acids in episodic and chronic migraine: preventing and reverting chronic migraine. Special lecture 7th INWIN Congress.
Nicolodi M, Sicuteri F.
Source
Interuniversity Center of Neurochemistry, Florence University, Italy.
Abstract
The mechanism capable of transforming episodic migraine into chronic migraine is attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly long-term potentiation, due to the action of excitatory amino acids, chiefly the ones acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to ‘third hyperalgesia’, a newly observed type of hyperalgesia which is inheritable and can act as a ground for the above-mentioned mechanism of ‘chronicization’ of migraine. The role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin, inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far considered refractory to prophylactic therapies, gives indirect but evident support to the mechanism suggested above. The antinociceptive role of the above-mentioned negative modulators of excitatory amino acids and the possible interplay between ionotropic and metabotropic receptors are also taken into consideration.
PMID:
9675627
[PubMed - indexed for MEDLINE]

The use of NMDA-receptor antagonists in the treatment of chronic pain.
(PMID:10870744)
Hewitt DJ
Department of Neurology, Emory University Medical Center, Atlanta, Georgia, USA. David_Hewitt@emory.org
The Clinical Journal of Pain [2000, 16(2 Suppl):S73-9]
Type: Journal Article, Review
Abstract Highlight Terms
Gene Ontology(5) Diseases(1) Chemicals(11)

Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.

Br J Pharmacol. 2009 June; 157(3): 464–473.
Published online 2009 March 20. doi: 10.1111/j.1476-5381.2009.00142.x
PMCID: PMC2707992
Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation
AP Andreou, PR Holland, and PJ Goadsby
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
Background and purpose:
Migraine is a disabling neurological disorder involving activation, or the perception of activation, of trigeminovascular afferents containing calcitonin gene-related peptide (CGRP). Released CGRP from peripheral trigeminal afferents causes dilatation of dural blood vessel, and this is used to measure trigeminal nerve activation. Kainate receptors with the GluR5 subunit (iGluR5, ionotropic glutamate receptor) are present in the trigeminal ganglion and may be involved in nociception. We investigated the possible involvement of prejunctional iGluR5 kainate receptors on CGRP release from trigeminal afferents.
Experimental approach:
We used neurogenic dural vasodilatation, which involves reproducible vasodilatation in response to CGRP release after electrical stimulation of the dura mater surrounding the middle meningeal artery. The effects of the specific iGluR5 receptor antagonist UBP 302 and agonist (S)-(-)-5-iodowillardiine were investigated on neurogenic and CGRP-induced dural vasodilatation in rats, by using intravital microscopy.
Key results:
Administration of 10 and 20 mg•kg−1 of iodowillardiine inhibited electrically induced dural vessel dilatation, an effect blocked by pretreatment with 50 mg•kg−1 UBP 302. Administration of the iGluR5 receptor antagonist UBP 302 alone had no significant effect. CGRP (1 mg•kg−1)-induced dural vasodilatation was not inhibited by the iGluR5 receptor agonist iodowillardiine.
Conclusions and implications:
This study demonstrates that activation of the iGluR5 kainate receptors with the selective agonist iodowillardiine is able to inhibit neurogenic dural vasodilatation probably by inhibition of prejunctional release of CGRP from trigeminal afferents. Taken together with recent clinical studies the data reinforce CGRP mechanisms in primary headaches and demonstrate a novel role for kainate receptor modulation of trigeminovascular activation.

Fibromyalgia and headache. Failure of serotonergic analgesia and N-methyl-D-aspartate-mediated neuronal plasticity: their common clues.
(PMID:9533670)
• Abstract
• Citations
• BioEntities
• Related Articles
Nicolodi M, Volpe AR, Sicuteri F
Interuniversity Centre of Neurochemistry and Clinical Pharmacology of Idiopathic Headache, Florence, Italy.
Cephalalgia : an International Journal of Headache [1998, 18 Suppl 21:41-44]
Type: Journal Article, Review, Research Support, Non-U.S. Gov’t
Abstract Highlight Terms
Diseases(3) Genes/Proteins(1) Chemicals(1)

A defect in serotonergic analgesia and a hyperalgesic state are proposed as features common to headache and fibromyalgia. The benefit to both migraine and fibromyalgia from inhibiting ionotropic N-methyl-D-aspartate receptor activity implies that redundant hyperalgesia-related neuroplastic changes are crucial for severe or chronic migraine and primary fibromyalgia. The fact that migraine and primary fibromyalgia share some pivotal set-up of serotonergic and excitatory amino acid systems led us to analyse epidemiological data supporting the hypothesis that analgesic disruption and a consequent hyperalgesic state are mechanisms of both migraine and fibromyalgia. Beyond demonstrating the comorbidity between migraine and primary fibromyalgia, the data suggest that migraine may represent a risk factor for fibromyalgia.

La teoria centrale dell’ emicrania e della sua cronicizzazione – La teoria serotoninergica- aminoacidergica nella lettura della fenomenologia acuta e cronica dell’ emicrania. In Zeneca (Ed.) XXX Congresso Nazionale della Società Italiana di Neurologia, Roma: Edizioni Internazionali CIC , pp 15-20, 1997
Nicolodi M., Sicuteri F. From migraine to primary fibromyalgia: LTP the common clue. Int. J. Clin. Pharmacol. Res., XVIII (2): 93-100, 1998

Nicolodi M, Sicuteri F. Planet Pain: Focus on chronic migraine . J Headache Pain 1: S11-S16, 2000

LA CENTRAL SENSITIZATION, LA LONG TERM POTENTION, E IL TANDEM GLUTAMMATO-NMDA
Il dolore che si sperimenta nella vita quotidiana (ad esempio per l’aver battuto un ginocchio) ha un meccanismo d’origine profondamente diverso dal dolore cronico neurogeno che è poi quello che ha il maggior impatto nella clinica e sulla qualità di vita.
Normalmente nel dolore acuto periferico la trasmissione del dolore è promossa da stimoli ad alta soglia, al contrario il dolore neurogeno centrale è indotto da stimoli a bassa soglia.
Accade così che stimoli sensitive innocui nel soggetto integro ed esente rispetto a condizioni di dolore centrale vengano a manifestarsi fenomeni di allodinia, cioè di dolore per stimolo innocui.
E’ inoltre caratteristica nota del dolore neurogeno centrale la cosiddetta overreaction fenomeno che determina il perdurare del dolore ben oltre il momento dell’applicazione dello stimolo fino a costituire un episodio doloroso di buona durata e severità.
Il dolore neurogeno centrale può avere degli acmi ma è fondamentalmente un fenomeno cronico. Il dolore cronico ha come caratteristica fondamentale e permissiva la plasticità che conduce alla cosiddetta “sensitization”, fenomeno per cui il sistema di trasmissione sensitivo/algogeno risponde a stimoli nocivi ed innocui. La rilevanza della sensitization fu sperimentalmente dimostrata negli anni ’90 ablando proprio I neuroni che , a livello spinale, andavano incontro a tale fenomeno. Il risultato fu che senza sensitization il dolore cronico non comparve.
E’ da sottolineare che i neuroni spinali e del sistema nervosa centrali in genere dimostrano un particolare tipo di plasticità detto long-term potentiation che assomiglia al meccanismo fisiologico con cui di instaurano i circuiti della memoria. In altre parole si assiste a una condizione patofisiologica in cui si edificano le vie del mantenimento del dolore.
Il glutammato , aminoacido presente in molti organi ed anche conosciuto come un esaltatore del sapore con il nome di monoglutammato di sodio, fa parte degli aminoacidi eccitatori ed è il neurotrasmettitore attivo nelle sinapsi più plastiche del nostro cervello, ovvero a livello di quelle che manifestano LTP. I recettori per il glutammato sono quattro e si trovano soprattutto condensati sul versante post-sinaptico. Tre sono i cosiddetti recettori ionotropici cioè l’AMPA, l’NMDA ed il kainato. Il quarto tipo è metabotropico ed è definito con la sigla mGluR. Tutti i tipi hanno importanza per la plasticità sinaptica, ma i recettori AMPA e NMDA sono quelli meglio conosciuti e vengono spesso ritenuti responsabili della memoria molecolare.
LA CENTRAL SENSITIZATION NELL’AMIGDALA E NELLA CORTECCIA CINGOLATA ANTERIORE
La central sensitization si estende anche ad aree che non fanno parte del sistema di trasmissione dell’input sensitivo/algogeno. In condizioni di dolore cronico si assiste alla sensitization dell’ amigdala nocicettiva, area connessa alle emozioni ed alla paura, e dei neuroni della corteccia cingolata anteriore, area che determina le componenti affettive del dolore. Questo giustifica una risonanza emotiva peculiare del dolore cronico poiché aree cerebrali come l’amigdala e la corteccia cingolata anteriore, coinvolte nell’esprimersi delle emozioni, diventano iperattive se si è in condizioni di dolore cronico.

Neuroscientist June 2004 vol. 10 no. 3 221-234
The Amygdala and Persistent Pain
1. Volker Neugebauer1,
2. Weidong Li2,
3. Gary C. Bird3 and
4. Jeong S. Han4
+ Author Affiliations
1. 1Department of Anatomy & Neurosciences, University of Texas Medical Branch, voneugeb@utmb.edu
2. 2Department of Anatomy & Neurosciences, University of Texas Medical Branch
3. 3Department of Anatomy & Neurosciences, University of Texas Medical Branch
4. 4Department of Anatomy & Neurosciences, University of Texas Medical Branch
Abstract
A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the “nociceptive amygdala” and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.

RVM E PAG
L’INIBIZIONE E LA FACILITAZIONE AL DOLORE
Il grigio periacqueduttale (PAG) ed il midollo rostrale ventromediale (RVM) son parte di un sistema modulatori della trasmissione nocicettiva, produce quindi analgesia. RVM può d’altra parte determinare un effetto la “facilitazione” per cui è anche provvisto della capacità di dare un effetto di promozione del dolore detto descending facilitation

Neuroscience 140 (2006) 1311–1320
DESCENDING FACILITATION FROM THE ROSTRAL VENTROMEDIAL
MEDULLA MAINTAINS NERVE INJURY-INDUCED CENTRAL
SENSITIZATION
L. P. VERA-PORTOCARRERO, E.-T. ZHANG,
M. H. OSSIPOV, J. Y. XIE, T. KING, J. LAI
AND F. PORRECA*

LA DECRONICIZZAZIONE
E’ d’interesse rilevare come interferire regolando negativamente la trasmissione dei recettori NMDA possa mettere capo a decronicizzazione interrompendo un circuito neurobiochimico che sostiene la central sensitization.
Pur essendo questo un risultato sperabile poiché gli antagonisti NMDA son da decenni impiegati negli USA come intervento di prima scelta per il trattamento di dolori primari quali la deafferentazione , abbiamo potuto constatare che dosi molto basse e ben tollerate di questi principi inducevano rapida decronicizzazione in circa
il 91% dei pazienti con emicrania cronica (n= 1250) , indipendentemente dalla durata dello stato patologico.
Il follow-up a 2 mesi vedeva un declino del beneficio nel 15% dei casi che comunque non tornavano allo stato iniziale ma peggioravano di circa il 20% rispetto ai valori post-trattamento
Il follow-up a 1 anno indicava la cessazione di stato di cronicità nell’ 85% dei casi trattati
M Nicolodi, A Torrini. Chronic Migraine and NMDA antagonists: what is effective, what is puzzling: a twelve years experience. Cephalalgia 16, 1347, 2006

DALLA DECRONICIZZAZIONE ALLA CURA DELL’ATTACCO IN ACUTO: UN CIRCOLO VIRTUOSO
E’ interessante notare come gli agenti neurobiochimici utili nella decronicizzazione del dolore possano essere usati anche come sintomatici e questo avrebbe il doppio scopo di decronicizzare le forme ormai croniche come quello di inibire il singolo attacco inibendo, simultaneamente il percorso verso la cronicità
FEATURE ARTICLE
Tapping Into the Migraine Pipeline—A Review of New Drugs on the Horizon
2010;18(1):20.
New acute and preventive migraine treatments target novel mechanisms and show promise for relieving symptoms.

Glutamate Receptor Antagonists
Another therapeutic target is glutamate, an excitatory neurotransmitter that has been shown to play a key role in both migraine and epilepsy pathophysiology. Ionotropic glutamate receptor agonists NMDA, kainate, and AMPA are involved in trigeminovascular activation, central sensitization, and cortical spreading depression. Drugs aimed at blocking their action are showing promise in treating acute attacks and have potential for preventing future attacks, according to Dr. Goadsby.

Glutamate receptor antagonists in the pipeline include tezampanel (LY-293558), an AMPA and kainate receptor antagonist; LY-466195, a GLUK5 receptor antagonist; ADX10059, an mGluR5 modulator that shows promise as a prophylactic agent; and perampanel, an AMPA receptor antagonist that is also being investigated as a preventive treatment for migraines.

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