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OBJECTIVE: We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. BACKGROUND: Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. METHODS: This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial. RESULTS: For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3. CONCLUSIONS: This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials.
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Benzamidas/farmacología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Formularios como Asunto , Consentimiento Informado , Trastornos Migrañosos/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Piperidinas/farmacología , Piridinas/farmacología , Agonistas de Receptores de Serotonina/farmacología , Adulto , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/efectos adversos , TraducciónRESUMEN
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
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Benzamidas/farmacología , Trastornos Migrañosos/fisiopatología , Piperidinas/farmacología , Piridinas/farmacología , Receptores de Serotonina , Agonistas de Receptores de Serotonina/farmacología , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Humanos , Neuronas/metabolismo , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/fisiopatología , Triptaminas , Vasoconstricción/efectos de los fármacos , Receptor de Serotonina 5-HT1FRESUMEN
OBJECTIVE: The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene-related peptide (CGRP) within the context of the trigeminovascular system. BACKGROUND: Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system. DESIGN: This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points. RESULTS: The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second-order neurons. A shift in central sensitization from activity-dependent to activity-independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder. CONCLUSIONS: CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.
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Péptido Relacionado con Gen de Calcitonina/metabolismo , Trastornos Migrañosos/metabolismo , Ganglio del Trigémino/metabolismo , Nervio Trigémino/metabolismo , Animales , Humanos , Trastornos Migrañosos/fisiopatología , Neuroglía/metabolismo , Neuronas/metabolismo , Nocicepción/fisiología , Ganglio del Trigémino/fisiopatología , Nervio Trigémino/fisiopatologíaRESUMEN
WHAT IS KNOWN AND OBJECTIVE: The double-helical conformation of human DNA (hDNA) is so axiomatic that it is called the "canonical" form. Recently, though, intrastrand folds ("I-motifs" and "G-quadruplexes") have been identified in hDNA. These could be targets for novel drug discovery. COMMENT: Any interruption of the canonical form of hDNA fundamentally impacts the normal progression of transduction and translation. In particular, the synthesis of receptors and cognate protein ligands would be affected, as well as their affinity for-and signal transduction of-pharmacotherapeutic agents. Recent studies have identified normally occurring, folded structures superimposed on the usual double-helix motif of hDNA. WHAT IS NEW AND CONCLUSION: The newly identified "folded DNA" structures ("I-motifs" and "G-quadruplexes") could represent novel drug-discovery targets, most likely for cancer.
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Antineoplásicos/farmacología , ADN/química , Descubrimiento de Drogas/métodos , G-Cuádruplex , Humanos , Ligandos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Introduction Galcanezumab is a humanized monoclonal antibody binding calcitonin gene-related peptide, used for migraine prevention. Methods A global, double-blind, 6-month study of patients with episodic migraine was undertaken with 915 intent-to-treat patients randomized to monthly galcanezumab 120 mg (n = 231) or 240 mg (n = 223) or placebo (n = 461) subcutaneous injections. Primary endpoint was overall mean change from baseline in monthly migraine headache days. Key secondary endpoints were ≥50%, ≥ 75%, and 100% response rates; monthly migraine headache days with acute migraine medication use; Patient Global Impression of Severity rating; the Role Function-Restrictive score of the Migraine-Specific Quality of Life Questionnaire. Results Mean monthly migraine headache days were reduced by 4.3 and 4.2 days by galcanezumab 120 and 240 mg, respectively, and 2.3 days by placebo. The group differences (95% CIs) versus placebo were 2.0 (-2.6, -1.5) and 1.9 (-2.4, -1.4), respectively. Both doses were superior to placebo for all key secondary endpoints. Injection site pain was the most common treatment-emergent adverse event, reported at similar rates in all treatment groups. Both galcanezumab doses had significantly more injection site reactions and injection site pruritus, and the 240 mg group had significantly more injection site erythema versus placebo. Conclusions Galcanezumab 120 or 240 mg given once monthly was efficacious, safe, and well tolerated. Study identification EVOLVE-2; NCT02614196; https://clinicaltrials.gov/ct2/show/NCT02614196 . Trial Registration NCT02614196.
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Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Inyecciones Subcutáneas/efectos adversos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Péptido Relacionado con Gen de Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina/inmunología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/sangre , Trastornos Migrañosos/fisiopatología , Calidad de Vida , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.
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Trastornos Migrañosos , Antagonistas de Narcóticos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Naltrexona/análogos & derivados , Naltrexona/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.
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Analgésicos Opioides/metabolismo , Giro del Cíngulo/metabolismo , Morfina/administración & dosificación , Dimensión del Dolor/métodos , Dolor/metabolismo , Receptores Opioides/metabolismo , Animales , Giro del Cíngulo/efectos de los fármacos , Masculino , Microdiálisis/métodos , Microinyecciones/métodos , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Opioides/agonistasRESUMEN
Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward-valuation circuitry.
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Dolor/fisiopatología , Dolor/psicología , Refuerzo en Psicología , Recompensa , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Anestésicos Locales/administración & dosificación , Animales , Modelos Animales de Enfermedad , Antagonistas de Dopamina/administración & dosificación , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiopatología , Masculino , Modelos Neurológicos , Bloqueo Nervioso , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiopatología , Dolor/tratamiento farmacológico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/fisiopatología , Dolor Postoperatorio/psicología , Ratas , Ratas Sprague-Dawley , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiopatologíaRESUMEN
The myriad proteins may be involved in the mechanisms underlying the development and maintenance of neuropathic pain, an extremely disabling condition that originates from pathology of the nervous system. To address the mechanisms, we here analyzed proteins and cellular networks in the dorsal spinal cord mediating pain processing in a well-established rat model of neuropathic pain induced by spinal nerve ligation (SNL). Labeling-based proteomic methods together with high-resolution mass spectrometry for proteome analysis were applied. 38 proteins including synapsin 1 and microtubule-associated protein 2 were identified as differently expressed in the SNL group. Pathway analysis suggests that maladaptive changes in the levels of these proteins may contribute to abnormal synaptic transmission and neuronal intracellular signaling underlying the onset and development of neuropathic pain.
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Neuralgia/metabolismo , Proteoma/análisis , Proteómica/métodos , Médula Espinal/metabolismo , Nervios Espinales/lesiones , Animales , Hiperalgesia/metabolismo , Espectrometría de Masas , Análisis de Componente Principal , Mapas de Interacción de Proteínas , Proteoma/química , Proteoma/metabolismo , RatasRESUMEN
OBJECTIVE: Preclinical evaluation of headache by behavioral assessment of reward from pain relief. METHODS: Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. RESULTS: Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury. INTERPRETATION: Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.
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Conducta Animal/efectos de los fármacos , Cefalea/tratamiento farmacológico , Lidocaína/farmacología , Bloqueo Nervioso , Animales , Conducta Animal/fisiología , Giro del Cíngulo/efectos de los fármacos , Cefalea/inducido químicamente , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Lidocaína/administración & dosificación , Masculino , Microinyecciones , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
OBJECTIVE: The objective of this article is to evaluate electrically evoked thresholds for cortical spreading depression (CSD) and stress-induced activation of trigeminal afferents in a rat model of medication-overuse headache (MOH). METHODS: Sumatriptan or saline was delivered subcutaneously by osmotic minipump for six days to Sprague-Dawley rats. Two weeks after pump removal, animals were anesthetized and recording/stimulating electrodes implanted. The animals were pretreated with vehicle or topiramate followed by graded electrical stimulation within the visual cortex. CSD events were identified by decreased EEG amplitude and DC potential shift. Additional unanesthetized sumatriptan or saline-pretreated rats were exposed to bright light environmental stress and periorbital and hindpaw withdrawal thresholds were measured. Following CSD stimulation or environmental stress, immunohistochemical staining for Fos in the trigeminal nucleus caudalis (TNC) was performed. RESULTS: Sumatriptan pre-exposure significantly decreased electrical stimulation threshold to generate a CSD event. Topiramate normalized the decreased CSD threshold as well as stress-induced behavioral withdrawal thresholds in sumatriptan-treated rats compared to saline-treated animals. Moreover, CSD and environmental stress increased Fos expression in the TNC of sumatriptan-treated rats, and these effects were blocked by topiramate. Environmental stress did not elicit cutaneous allodynia or elevate TNC Fos expression in saline-treated rats. CONCLUSIONS: A previous period of sumatriptan exposure produced long-lasting increased susceptibility to evoked CSD and environmental stress-induced activation of the TNC that was prevented by topiramate. Lowered CSD threshold, and enhanced consequences of CSD events (increased activation of TNC), may represent an underlying biological mechanism of MOH related to triptans.
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Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Modelos Animales de Enfermedad , Cefaleas Secundarias/fisiopatología , Sumatriptán/toxicidad , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Humanos , Infusiones Subcutáneas , Masculino , Ratas Sprague-Dawley , Factores de Riesgo , Umbral Sensorial/efectos de los fármacos , Umbral Sensorial/fisiología , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatología , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/fisiopatologíaRESUMEN
A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the sensorimotor cortex produced contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms. We demonstrated that left- and right-sided hormonal signaling is differentially blocked by the δ-, κ- and µ-opioid antagonists. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord-signaling pathway since hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene-gene co-expression patterns identified the left- and right-side-specific gene co-expression networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.
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Transducción de Señal , Animales , Ratas , Sistemas Neurosecretores/metabolismo , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/fisiopatología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Masculino , Médula Espinal/metabolismo , Lateralidad Funcional/fisiología , Miembro Posterior/inervaciónRESUMEN
In this paper we describe a simple, fast, and inexpensive approach for quantitative analysis of proteins originated from small central nervous system (CNS) samples, i.e., rat spinal cord. The presented sample preparation protocol and quantification results from isotope dimethyl labeling were statistically evaluated and approved as a reliable and robust method for animal model studies of neurological disorders. Combined with the biopathway analysis tool IPA, the method was applied for comparative analysis of proteins in the dorsal and ventral segments of the rat spinal cord. The results are in agreement with the previously published protein patterns in these tissues. A majority (73%) of proteins identified as "related with CNS development and functions" were found to be overexpressed in the dorsal section compared to the ventral segment. The pathway related to neuropathic pain was overrepresented in the dorsal tissue samples. The developed novel approach may be applied for analyses of the spinal cord mediated neurological dysfunctions and pathological pain.
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Proteínas del Tejido Nervioso/metabolismo , Neuralgia/metabolismo , Médula Espinal/metabolismo , Animales , Masculino , Redes y Vías Metabólicas , Metilación , Proteínas del Tejido Nervioso/química , Percepción del Dolor , Proteolisis , Proteoma/química , Proteoma/metabolismo , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Transducción de Señal , Coloración y Etiquetado , Regulación hacia ArribaRESUMEN
Dorsal root injury results in substantial and often irreversible loss of sensory functions as a result of the limited regenerative capacity of sensory axons and the inhibitory barriers that prevent both axonal entry into and regeneration in the spinal cord. Here, we describe previously unknown effects of the growth factor artemin after crush injury of the dorsal spinal nerve roots in rats. Artemin not only promoted re-entry of multiple classes of sensory fibers into the spinal cord and re-establishment of synaptic function and simple behavior, but it also, surprisingly, promoted the recovery of complex behavior. These effects occurred after a 2-week schedule of intermittent, systemic administration of artemin and persisted for at least 6 months following treatment, suggesting a substantial translational advantage. Systemic artemin administration produced essentially complete and persistent restoration of nociceptive and sensorimotor functions, and could represent a promising therapy that may effectively promote sensory neuronal regeneration and functional recovery after injury.
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Síndromes de Compresión Nerviosa/prevención & control , Factores de Crecimiento Nervioso/fisiología , Proteínas del Tejido Nervioso/fisiología , Neuronas Aferentes/metabolismo , Recuperación de la Función/fisiología , Raíces Nerviosas Espinales/lesiones , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Estudios de Seguimiento , Masculino , Síndromes de Compresión Nerviosa/tratamiento farmacológico , Compresión Nerviosa , Factores de Crecimiento Nervioso/administración & dosificación , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Proteínas del Tejido Nervioso/administración & dosificación , Neuronas Aferentes/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Raíces Nerviosas Espinales/efectos de los fármacos , Raíces Nerviosas Espinales/metabolismo , Factores de TiempoRESUMEN
Migraine is a highly prevalent neurological disease of varying attack frequency. Headache attacks that are accompanied by a combination of impact on daily activities, photophobia and/or nausea are most commonly migraine. The headache phase of a migraine attack has attracted more research, assessment tools and treatment goals than any other feature, characteristic, or phase of migraine. However, the migraine attack may encompass up to 4 phases: the prodrome, aura, headache phase and postdrome. There is growing recognition that the burden of migraine, including symptoms associated with the headache phase of the attack, may persist between migraine attacks, sometimes referred to as the "interictal phase." These include allodynia, hypersensitivity, photophobia, phonophobia, osmophobia, visual/vestibular disturbances and motion sickness. Subtle interictal clinical manifestations and a patient's trepidation to make plans or commitments due to the unpredictability of migraine attacks may contribute to poorer quality of life. However, there are only a few tools available to assess the interictal burden. Herein, we examine the recent advances in the recognition, description, and assessment of the interictal burden of migraine. We also highlight the value in patients feeling comfortable discussing the symptoms and overall burden of migraine when discussing migraine treatment needs with their provider.
RESUMEN
PURPOSE OF REVIEW: An impediment to the investigation of mechanisms that drive headache is the inability of preclinical models to measure headache. Migraine attacks are associated with the development of cutaneous allodynia in some patients. Such cutaneous allodynia suggests a state of 'central sensitization' of pain transmission pathways and may additionally reflect the engagement of descending facilitation from pain modulatory circuits. For this reason, cutaneous allodynia has been measured in animal models as a surrogate of marker that may be relevant to headache. Overuse of antimigraine medications can promote an increase in the frequency and intensity of headache, a syndrome termed medication overuse headache (MOH). The mechanisms leading to MOH are not known, but may involve the processes of amplification including central sensitization and descending facilitation. This review explores potential mechanistic insights that have emerged from such studies and that could contribute to MOH. RECENT FINDINGS: Development of MOH has been recently associated with long-lasting adaptive changes that occur within the peripheral and central nervous systems. Preclinical studies have shown that repeated or continuous treatment with antimigraine drugs result in persistent upregulation of neurotransmitters within the orofacial division of the trigeminal ganglia and in development of cutaneous allodynia in response to migraine triggers, even weeks after discontinuation of the antimigraine drug. Additionally, descending facilitation is critical for the expression of cutaneous allodynia and may mask the expression of diffuse noxious inhibitory controls. SUMMARY: Medication-induced persistent pronociceptive adaptations might be responsible for lowering the threshold and amplifying the response to migraine triggers leading to increased frequency of headache attacks.
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Adaptación Fisiológica , Analgésicos Opioides , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Fenómenos Fisiológicos del Sistema Nervioso , Triptaminas , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Animales , Humanos , Dolor/fisiopatología , Triptaminas/efectos adversos , Triptaminas/uso terapéuticoRESUMEN
OBJECTIVE: Identification of the neural mechanisms underlying medication overuse headache resulting from triptans. METHODS: Triptans were administered systemically to rats by repeated intermittent injections or by continuous infusion over 6 days. Periorbital and hind paw sensory thresholds were measured to detect cutaneous allodynia. Immunofluorescent histochemistry was employed to detect changes in peptidic neurotransmitter expression in identified dural afferents. Enzyme-linked immunoabsorbent assay was used to measure calcitonin gene-related peptide (CGRP) levels in blood. RESULTS: Sustained or repeated administration of triptans to rats elicited time-dependent and reversible cutaneous tactile allodynia that was maintained throughout and transiently after drug delivery. Triptan administration increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure, when sensory thresholds returned to baseline levels, rats showed enhanced cutaneous allodynia and increased CGRP in the blood following challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent sensitization characterized by persistent pronociceptive neural adaptations in dural afferents and enhanced responses to an established trigger of migraine headache in humans. INTERPRETATION: Triptans represent the treatment of choice for moderate and severe migraine headaches. However, triptan overuse can lead to an increased frequency of migraine headache. Overuse of these medications could induce neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers. The latent sensitization could provide a mechanistic basis for the transformation of migraine to medication overuse headache.
Asunto(s)
Cefaleas Secundarias/fisiopatología , Trastornos Migrañosos/tratamiento farmacológico , Triptaminas/toxicidad , Animales , Péptido Relacionado con Gen de Calcitonina/análisis , Péptido Relacionado con Gen de Calcitonina/sangre , Esquema de Medicación , Duramadre/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Masculino , Donantes de Óxido Nítrico/farmacología , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiología , Factores de Tiempo , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/fisiopatología , Triptaminas/efectos adversosRESUMEN
INTRODUCTION: Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates. LITERATURE REVIEW: Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol. CONCLUSIONS: Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined.
Asunto(s)
Analgésicos Opioides/efectos adversos , Cefaleas Secundarias/etiología , Cefaleas Secundarias/fisiopatología , Triptaminas/efectos adversos , Humanos , Trastornos Migrañosos/tratamiento farmacológicoRESUMEN
OBJECTIVE: In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappaB, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. METHODS: Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappaB DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappaB subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were detected by immunohistochemistry. RESULTS: Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappaB/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. CONCLUSION: In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappaB activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Infecciosa/tratamiento farmacológico , Inhibidores de Cisteína Proteinasa/farmacología , Leupeptinas/farmacología , Infecciones por Mycobacterium/tratamiento farmacológico , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Infecciosa/metabolismo , Artritis Infecciosa/patología , Biomarcadores/metabolismo , Densidad Ósea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , ADN/metabolismo , Femenino , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Articulaciones/patología , Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Infecciones por Mycobacterium/patología , FN-kappa B/metabolismo , Dolor/prevención & control , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Sustancia P/metabolismoRESUMEN
The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.