Archive for agosto 2012

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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FARMACI PER IL DOLORE CRONICO E LA CEFALEA: NOVITA’ IN CANTIERE

FARMACI IN CANTIERE
BASI PER I NUOVI FARMACI CONTRO IL DOLORE CRONICO E L’EMICRANIA

Contributi dai membri della Fondazione

Nicolodi M., Volpe AR. , Torcia S., Spillantini MG. Fibromialgia: Aspetti Clinici , Meccanismi Neurobiochimici/Ormonali – Un circuito di interconnessioni. Proceedings XXIV Congresso SISC, Caserta 2010

Nicolodi M., Spillantini M. G.,Sicuteri F. & Del Bianco E. NGF and SP in the saliva of migraine sufferers using FANs daily Cephalalgia Vol. 23 (7) pp. 641, 2003
Nicolodi M. Interaction of EAAs and gabaergic system. Int. J. Clin. Pharmacol. Res., XVIII (2): 79-85, 1998
Nicolodi M. Nostril capsaicin application as a model of trigeminal primary sensory neurons activation. Cephalalgia 14:134-138, 1994
Nicolodi M, Volpe AR, Porcelli G, Sicuteri R, , Curradi C, Sicuteri F. Coupling between nitric oxide level and inheritable hyperalgesia characterizes migraine diathesis. In: F Clifford Rose (ed) Advances in Headache Research: 4, London: Smith-Gordon p 115-120, 1994
Nicolodi M. Neurogenic inflammation speculated through the changes of salivary substance P and calcitonin gene-related Peptide. The semantic ford of idiopathic headaches. Catania 10-12 ottobre 1991, p 37

Nicolodi M., Del Bianco E. Sensory neuropeptides (substance P, calcitonin gene-related peptide) and vasoactive intestinal polypeptide in human saliva: their pattern in migraine and cluster headache. Cephalalgia 10: 39-50,1990

Caleri D, Nicolodi M, Andreini R, Curradi C, Sicuteri F. Effects of glucagon on plasma cyclic AMP in headache. Cephalalgia 7(6): 151-153, 1987

Contributi dall’estero

HCN2 CHANNELS E AMP CICLICO
DOLORI CRONICI NEUROPATICI

Science. 2011 Sep 9;333(6048):1462-6.
HCN2 ion channels play a central role in inflammatory and neuropathic pain.
Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA.
Source
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Abstract
The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.

CGRP E ANTAGONISTI CGRP
SPECIFICI CONTRO LA CEFALEA, SVILUPPATI COME ANTIEMICRANICI

The Lancet, Volume 372, Issue 9656, Pages 2115 – 2123, 20 December 2008
doi:10.1016/S0140-6736(08)616g26-8 Cite or Link Using DOI
This article can be found in the following collections: Neurology (Headache & migraine)
Published Online: 25 November 2008
Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial
Dr Tony W Ho MD a , Prof Michel D Ferrari MD b, Prof David W Dodick MD c, Vince Galet PhD a, James Kost PhD a, Xiaoyin Fan PhD a, Heather Leibensperger BS a, Samar Froman BS a, Christopher Assaid PhD a, Christopher Lines PhD a, Hille Koppen MD b, Paul K Winner DO d

The antagonists-CGRP receptors, are a new class of drugs which is expected in a short time the availability for the acute treatment of migraine. The GCRP can probably play an important role in the pathophysiology of migraine and cluster headache. Occurs in the trigeminal ganglia and has a dilation of cerebral and dural vessels. During attacks of migraine and headache in clusters, were measured high concentrations of GCRP in jugular venous blood and saliva. GCRP-receptor antagonists have been developped for the treatment of migraine chiefly; they do not act as vasoconstrictive compounds. Thus, they may represent a treatment option for patients with comorbid vascular diseases.
Mechanism of action
The manuscript by Goadsby and co-workers presents results that indicate that CGRP has a role in mediating nociceptive information in the cerebrovascular circulation. Indeed, the manuscript provides evidence that two CGRP receptor antagonists (BIBN4096BS and CGRP8–37) inhibit neurons in the trigeminocervical complex following peripheral activation by stimulation of the superior sagittal sinus and activation by locally applied glutamate.

CGRP-receptor antagonists have demonstrated efficacy in migraine attacks: In a study1 randomized double-blind, placebo-controlled iv was effective application Olcegepant CGRP-antagonists. The CGRP antagonist telcagepant applied orally, in a randomized double-blind controlled doses of 300-600 mg HAD similar efficacy as rizatriptan 10 mg and more effective than placebo2. In a study3 controlled trial, 300 mg of telcagepant was just as effective as 5 mg of zolmitriptan and more effective than telcagepant 150 mg or placebo. In this study near 700 patients were treated with telcagepant.
Problems:
In another study on prophylaxis, in a small number of patients, were found elevated liver values every day taking this substance, which has delayed admission for telcagepant and that could have an overall effect on the substance.
Thus it is expected, after the approval of telcagepant and / or other CGRP antagonist a new treatment option for migraine, which probably will be used in patients with vascular disease. By a different mechanism of action, the GCRP-receptor antagonists may possibly be an alternative in patients unresponsive to triptans. Therefore, there are other provisions and possibilities in this respect (see Triptans).

Gli antagonisti CGRP-ricettori, sono una nuova classe di sostanze di cui si prevede in breve tempo la disponibilità per il trattamento acuto dell’emicrania. Il GCRP probabilmente può giocare un importante ruolo nella patofisiologia dell’emicrania. Si libera nei gangli trigeminali e ha la capacità di dilatare i vasi cerebrali e durali. Durante gli attacchi di emicrania e cefalea a grappolo, sono state misurate elevate livelli di GCRP nel sangue venoso iugulare e nella saliva. Gli antagonisti del GCRP-recettore sono stati sviluppati per la terapia dell’emicrania; essi non agiscono in modo vasocostrittivo e potrebbero pertanto rappresentare un’opzione di trattamento per pazienti con malattie vascolari comorbide.

CGRP-receptor antagonists have demonstrated efficacy in migraine attacks: In a study randomized double-blind, placebo-controlled iv was effective administration CGRP-antagonists Olcegepant. The CGRP antagonist telcagepant administered orally, in a randomized double-blind controlled doses of 300-600 mg had similar efficacy as rizatriptan 10 mg and is more effective than placebo2. In a study3 controlled trial, 300 mg of telcagepant was as effective as 5 mg of zolmitriptan and more effective than telcagepant 150 mg or placebo. In this study nerar 700 patients were treated with telcagepant.

Gli antagonisti CGRP-ricettori hanno dimostrato efficacia negli attacchi di emicrania: in uno studio1 randomizzato in doppio cieco e controllato con placebo, risultava efficace un’applicazione i.v. di CGRP-antagonisti Olcegepant. Il CGRP-antagonista Telcagepant applicato oralmente, in uno studio controllato randomizzato in doppio cieco con dosaggi di 300-600 mg si dimostrava che questi avevano un’efficacia simile al Rizatriptan 10 mg e maggiore del placebo. In uno studio3 controllato randomizzato, 300 mg di Telcagepant risultava altrettanto efficace quanto 5 mg di Zolmitriptan e più efficace di Telcagepant 150 mg o placebo. In questo studio sono stati trattati quasi 700 pazienti con Telcagepant.

In un altro studio sulla profilassi, in un piccolo numero di pazienti, sono stati trovati dei valori epatici elevati assumendo giornalmente tale sostanza, cosa che ha fatto ritardare l‘ammissione per il Telcagepant e che potrebbe avere un effetto deterrente sull’uso sulla sostanza.

Così é previsto, dopo l’approvazione di Telcagepant e/o di un altro CGRP antagonista , vi sia una nuova opzione di trattamento per l’emicrania, la quale probabilmente verrà usata anche in pazienti con malattie vascolari. Da un differente maccanismo di azione, gli GCRP-ricettori-antagonisti probabilmente potrebbe derivare un’alternativa in pazienti che non rispondono ai triptani. È quindi vi sono altre possibilità riguardo l’impiego di tali farmaci nei confronti di altri già in commercio (vedi Triptani).

Riferimenti selezionati:
1. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;350:1104-10.
2. Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70:1304-12.
3. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 2008;372:2115-23.

NGF e ANTAGONISTI NGF
DOLORI CRONICI
Targeting nerve growth factor in pain: what is the therapeutic potential?
Watson JJ, Allen SJ, Dawbarn D.
Source
University of Bristol, Bristol, UK.
Abstract
Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
« PreviousNext »PAIN
Volume 79, Issue 2 , Pages 265-274, 1 February 1999
Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve
• Long-Sun Ro
,
• Sien-Tsong Chen
,
• Lok-Ming Tang
,
• Jean M. Jacobs
Received 10 September 1997; received in revised form 12 August 1998; accepted 25 August 1998.
• Abstract
• Full Text
• PDF
• Images
• References
Abstract
The systemic administration of anti-nerve growth factor (NGF) antibodies can prevent local sensory hypersensitivity and block nociceptive fibers from sprouting into denervated adult rat skin. However, in the case of chronic constriction injury (CCI) in a rat, there is evidence that NGF reverses some effects of axotomy and alleviates thermal hyperalgesia. It is with this in mind that we investigated the influence of local anti-NGF and NGF on neuropathic pain and collateral sprouting caused by CCI. In our study, we looked at the effects to the ligated nerves after 30 consecutive days of local injections of anti-NGF and NGF. A high-dose of anti-NGF (1800 ng) was found to eradicate heat and cold hyperalgesia during postoperative days 16–28 and from days 8 to 34 after CCI, respectively. Our results show that a low-dose anti-NGF (18 ng) only mildly alleviates heat hyperalgesia but not cold hyperalgesia. There is evidence that a rebound phenomenon occurs for a short period of time after the anti-NGF injections cease. Results show that anti-NGF injections, whether in a high or low dose, significantly reduces the severity of autotomy or prevents the spread of collateral sprouting from the saphenous nerve into the sciatic innervation territory. In contrast, when a NGF (0.75 ng/g body weight) was applied to the ligated nerve immediately after the ligation, heat and cold hyperalgesia were eradicated during postoperative days 4–68 and from days 4 to 28, respectively. The results show that the effect of anti-NGF is delayed at the onset, is short in duration, and is dependent on the dosage. However, anti-NGF but not NGF blocked collateral sprouting and decreased the severity of autotomy, suggesting that anti-NGF may be a better potential alternative analgesic for the treatment of neuropathic pain in humans. The different initiation times to abolish thermal hyperalgesia by anti-NGF (delayed onset) and NGF (early onset) suggests that alterations in neurotrophic factors contribute to the development of behavioral hyperalgesia via a complex mechanism in CCI rats.

Il fattore di crescita dei nervi (NGF) gioca un ruolo cruciale nella generazione del dolore ed iperalgesia in molti stati dolorosi acuti e cronici. Antagonizzare l’NGF è uno dei nuovi approcci nello sviluppo di farmaci contro il dolore. Molti anticorpi specifici per NGF sono in studi di fase di sperimentazione, inclusi il tanezumab (Pfizer), SAR164877/REGN475 (Sanofi-Aventis/Regeneron) e JNJ-42160443/AMG403 (Johnson & Johnson/Amgen). Se approvato (forse nel 2012), tanezumab della Pfizer sarà verosimilmente il primo biologico per il trattamento del dolore cronico, e potrebbe diventare il primo farmaco della categoria ad essere approvato

The nerve growth factor (NGF) plays a crucial role in the generation of pain and hyperalgesia in several acute and chronic pain states. Antagonize the NGF is one of the new approaches in the development of drugs for pain. Many NGF-specific antibodies are in Phase II / III, including tanezumab (Pfizer), SAR164877/REGN475 (Sanofi-Aventis/Regeneron) and JNJ-42160443/AMG403 (Johnson & Johnson / Amgen). If approved (perhaps in 2012), tanezumab Pfizer will be the first biologic for the treatment of chronic pain

Targeting nerve growth factor in pain: what is the therapeutic potential?
Watson JJ, Allen SJ, Dawbarn D.
Source
University of Bristol, Bristol, UK.
Abstract
Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
Anticorpi anti NGF(Nerve Growth Factor) di sintesi contro il dolore son stati messi a punto e dimostrati quali proteine capaci di bloccare in modo selettivo l’azione della proteina NGF, il fattore di crescita
nervoso scoperto dal Premio Nobel Rita Levi Montalcini, interrompendo la serie
di reazioni cellulari che portano al dolore. ”I test sugli animali dell’Mnac13,
questo il nome dell’anticorpo monoclonale, hanno dato risultati veramente incoraggianti sia sul
dolore infiammatorio che su quello neuropatico senza manifestare effetti
collaterali nell’animale da laboratorio
Se i test clinici saranno altrettanto positivi entro qualche anno
potremmo avere gia’ i primi farmaci”. L’azione degli anticorpi monoclonali, cioe’
sintetizzati in laboratorio, e’ simile a quella degli anticorpi naturalmente presenti
nell’organismo, cioe’ il ‘sequestro’ di molecole, che per i secondi sono agenti
infettanti esterni. ”Nel nostro caso le molecole da sequestrare seguendo l’obiettivo dell’anticorpo e’
l’ NGF. Il nostro anticorpo lega il recettore, e gli impedisce di legarsi al fattore di crescita”. I test effettuati hanno dimostrato che l’anticorpo e’ in grado di indurre un innalzamento della soglia di
sensibilita’ al dolore in un modello di sofferenza legata alle infiammazioni, simile
al dolore postoperatorio, e un durevole effetto analgesico anche sul dolore
neuropatico, caratteristico di numerose neuropatie cliniche come la neuropatia posterpetica e altre che son protagoniste del dolore cronico

A ‘synthetic antibody’ against pain ‘was made
and studied, it has shown that the protein tuning blocks so
selective action of NGF (Nerve Growth Factor), the growth factor
nervous discovered by Nobel laureate Rita Levi Montalcini, interrupting the series
of cellular reactions that lead to pain. ” Animal testing Mnac13, the monoclonal antibody, have yielded excellent results on neuropathic pain without manifesting side effects. Next step will be clinical trials. If they are equally positive in a few years
we will have ‘the first drugs”. The action of monoclonal antibodies, ie ‘
synthesized in the laboratory, is ‘similar to that of naturally occurring antibodies
in the organism, ie, ‘the’ capture ‘of molecules, which are agents for the seconds
external infectious. ” In our case the target of the antibody is’
the NGF. Antibody binds receptor, and prevents it from binding to the growth factor.” Animal tests have demonstrated that the antibody is capable of inducing an increase in the threshold of
sensitivity ‘to pain in an animal model , and also a durable analgesic effect on pain neuropathic, characteristic of many clinical neuropathies such as postherpetic neuralgia

COX E NOS INIBIZIONE
DOLORI CRONICI
Capnellene, a natural marine compound derived from soft coral, attenuates chronic constriction injury-induced neuropathic pain in rats.
by Yen-Hsuan Jean, Wu-Fu Chen, Chun-Sung Sung, Chang-Yih Duh, Shi-Ying Huang, …show all authors
Biological Sciences › Miscellaneous Papers
• Overview
• References5
• Related research
British journal of pharmacology (2009)
Volume: 158, Issue: 3, Publisher: Blackwell Publishing Ltd, Pages: 713-725
• DOI: 10.1111/j.1476-5381.2009.00323.x
• PubMed: 19663884
Available from www.pubmedcentral.nih.gov
or
Abstract
BACKGROUND AND PURPOSE: Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopentapentalene-2,3a-diol (GB9) exhibited anti-inflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopentapentalen-2-yl ester (GB10). EXPERIMENTAL APPROACH: Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-gamma (IFN-gamma)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry. KEY RESULTS: In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-gamma. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury. CONCLUSION AND IMPLICATIONS: Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-gamma-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.

Da un corallo deriva il principio che reca sollievo contro il dolore cronico ovvero il dolore neuropatico che può destruire la qualità di vita. Un composto estratto dal corallo Capnella imbricata, il capnellene, ha dimostrato effetti contro il dolore molto specifici in modelli animali di dolore neuropatico, come spiegato sul British Journal of Pharmacology (vedi Abstract all’inizio del sottocapitolo).

Il dolore neuropatico è una forma di dolore cronico per cui si percepisce dolore, molto forte, anche in risposta a stimoli di per sé non dolorosi nell’individuo sano. In pratica, mentre di norma sentiamo dolore in seguito a stimoli dolorosi sul nostro corpo che sono trasferiti da nervi periferici al midollo spinale, quindi al cervello, in chi soffre di dolore cronico questa trasmissione risulta alterata, per cui ai centri neurali del dolore arriva informazione “Dolore Forte” anche per stimoli che di per sé non sono affatto dolorosi.

Per ora ci sono pochissimi veramente pochissimi farmaci contro il dolore cronico, e i semplici analgesici son specifici in senso generale per il dolore acuto, quello che si sente per esempio quando ci si ferisce, ma poi prestamente si guarisce. Il capnellene estratto da un corallo presente al largo della costa di Taiwan riesce a inibire le sensazioni dolorose improprie e potrebbe divenire una nuova possibilità farmacologica contro il dolore cronico.

PHE377, a TRPV1 antagonist under clinical development
TABLE 1 | Therapeutic targeting of TRPV1
From the following article:
Transient receptor potential channels as therapeutic targets
Magdalene M. Moran, Michael Allen McAlexander, Tamás Bíró & Arpad Szallasi
Nature Reviews Drug Discovery 10, 601-620 (August 2011)

Il dolore viene spesso considerato come un campanello di allarme per una particolare malattia, quindi molto spesso curato con dei farmaci appartenenti alla categoria dei analgesici. Il cosiddetto dolore neuropatico insorge quando vi è un danno irreversibile che colpisce il sistema di percezione del dolore. La presenza di questo tipo di dolore avviene in pazienti affetti da alcune malattie del sistema nervoso centrale, ad esempio distrofie muscolari, sclerosi multipla ma anche in soggetti sottoposti ad amputazioni ( il dolore post-herpetico o arto-fantasma). Le caratteristiche variano da paziente a paziente di solito con l’insorgenza di bruciore e scosse elettriche. Dato la tipicità del dolore e soprattutto la particolarità dell’insorgenza è molto difficile da curare: i semplici analgesici compresa la morfina non bastano, spesso si ricorre all’uso di terapie palliative e di antidepressivi. Alcuni ricercatori hanno studiato molecole di interesse per poter portare alla produzione di un farmaco specifico che possa ridurre il dolore neuropatico. La ditta PharmEst, ha avviato la sperimentazione clinica della molecola Phe377.

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