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OBJECTIVES: Identify how the American Headache Society (AHS) membership manages status migrainosus (SM) among outpatients. BACKGROUND: SM is defined as a debilitating migraine attack lasting more than 72 h. There is no standard of care for SM, including whether a 72-h duration is required before the attack can be treated as SM. METHODS: The Refractory Headache Special Interest Group from AHS developed a four-question survey distributed to AHS members enquiring (1) whether they treat severe refractory migraine attacks the same as SM regardless of duration, (2) what their first step in SM management is, (3) what the top three medications they use for SM are, and (4) whether they are United Council for Neurologic Subspecialties (UCNS) certified. The survey was conducted in January 2022. Descriptive statistical analyses were performed. RESULTS: Responses were received from 196 of 1859 (10.5%) AHS members; 64.3% were UCNS certified in headache management. Respondents treated 69.4% (136/196) of patients with a severe refractory migraine attack as SM before the 72-h period had elapsed. Most (76.0%, 149/196) chose "treat remotely using outpatient medications at home" as the first step, 11.2% (22/196) preferred procedures, 6.1% (12/196) favored an infusion center, 6.1% (12/196) sent patients to the emergency department (ED) or urgent care, and 0.5% (1/196) preferred direct hospital admission. The top five preferred medications were as follows: (1) corticosteroids (71.4%, 140/196), (2) nonsteroidal anti-inflammatory drugs (NSAIDs) (50.1%, 99/196), (3) neuroleptics (46.9%, 92/196), (4) triptans (30.6%, 60/196), and (5) dihydroergotamine (DHE) (21.4%, 42/196). CONCLUSIONS: Healthcare professionals with expertise in headache medicine typically treated severe migraine attacks early and did not wait 72 h to fulfill the diagnostic criteria for SM. Outpatient management with one or more medications for home use was preferred by most respondents; few opted for ED referrals. Finally, corticosteroids, NSAIDs, neuroleptics, triptans, and DHE were the top five preferred treatments for home SM management.
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BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.
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Anticuerpos Monoclonales , Trastornos Migrañosos , Adulto , Humanos , Estudios Prospectivos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , CefaleaRESUMEN
BACKGROUND: Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. METHODS: Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6-11 years and weighing 17-45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. RESULTS: In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. CONCLUSIONS: Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg.Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.
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Anticuerpos Monoclonales/farmacocinética , Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Niño , Ensayos Clínicos Fase I como Asunto , Humanos , PediatríaRESUMEN
Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.
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Dolor Crónico/sangre , Dolor Crónico/diagnóstico por imagen , National Institutes of Health (U.S.)/tendencias , Manejo del Dolor/métodos , Manejo del Dolor/tendencias , Analgésicos Opioides/efectos adversos , Biomarcadores/sangre , Dolor Crónico/genética , Dolor Crónico/terapia , Educación/métodos , Educación/tendencias , Humanos , Neuroimagen/métodos , Epidemia de Opioides/prevención & control , Epidemia de Opioides/tendencias , Trastornos Relacionados con Opioides/sangre , Trastornos Relacionados con Opioides/diagnóstico por imagen , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/terapia , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. METHODS: The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. FINDINGS: Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterly fremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI -3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. INTERPRETATION: Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. FUNDING: Teva Pharmaceuticals.
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Anticuerpos Monoclonales/administración & dosificación , Trastornos Migrañosos/prevención & control , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Péptido Relacionado con Gen de Calcitonina/agonistas , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. METHODS: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. RESULTS: Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).
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Analgésicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Cefalalgia Histamínica/prevención & control , Adulto , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas/efectos adversos , Masculino , Persona de Mediana Edad , Placebos/uso terapéuticoRESUMEN
The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT1D receptor labeling was not found on large proprioceptive afferents or α-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways. NEW & NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT1D receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT1D receptor plasticity.
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Fibras Nerviosas Amielínicas/metabolismo , Receptor de Serotonina 5-HT1D/metabolismo , Reflejo de Estiramiento , Traumatismos de la Médula Espinal/metabolismo , Animales , Femenino , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/fisiología , Ratas , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
There are currently no accepted therapies for posttraumatic headache (PTH). In order to meet the urgent need for effective therapies for PTH, we must continue to address fundamental gaps in our understanding of the clinical course and impact of PTH. Here we examine the existing schema used to characterize the clinical characteristics of PTH, including the International Classification of Headache Disorders (ICHD). There remain unresolved questions about whether to classify patients based on the extent of brain injury or on clinical symptom profiles. There also remain problematic issues of definition such as continuous headache, and chronic daily headache with features of "embedded" migraine-type within these headaches, which will need to be studied further. We make the case that a symptom-based classification is needed to begin an examination of these unresolved questions, and to establish clinically relevant endpoints for research and clinical trials for effective therapies.
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Cefalea Postraumática/clasificación , Humanos , Cefalea Postraumática/terapiaRESUMEN
The detection of cool temperatures is thought to be mediated by primary afferent neurons that express the cool temperature sensing protein Transient Receptor Potential Cation Channel, Subfamily M, Member 8 (TRPM8). Using mice, this study tested the hypothesis that sex differences in sensitivity to cool temperatures were mediated by differences in neurons that express TRPM8. Ion currents from TRPM8 expressing trigeminal ganglion (TRG) neurons in females demonstrated larger hyperpolarization-activated cyclic nucleotide-gated currents (Ih) than male neurons at both 30° and 18°C. Additionally, female neurons' voltage gated potassium currents (Ik) were suppressed by cooling, whereas male Ik was not significantly affected. At the holding potential tested (-60mV) TRPM8 currents were not visibly activated in either sex by cooling. Modeling the effect of Ih and Ik on membrane potentials demonstrated that at 30° the membrane potential in both sexes is unstable. At 18°, female TRPM8 TRG neurons develop a large oscillating pattern in their membrane potential, whereas male neurons become highly stable. These findings suggest that the differences in Ih and Ik in the TRPM8 TRG neurons of male and female mice likely leads to greater sensitivity of female mice to the cool temperature. This hypothesis was confirmed in an operant reward/conflict assay. Female mice contacted an 18°C surface for approximately half the time that males contacted the cool surface. At 33° and 10°C male and female mice contacted the stimulus for similar amounts of time. These data suggest that sex differences in the functioning of Ih and Ik in TRPM8 expressing primary afferent neurons leads to differences in cool temperature sensitivity.
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Neuronas/metabolismo , Canales Catiónicos TRPM/metabolismo , Ganglio del Trigémino/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos , Canales Catiónicos TRPM/genética , Ganglio del Trigémino/citologíaRESUMEN
Several lines of evidence affirm a positive role for exercise in the management of migraine. This review highlights the latest research supporting this view, covering not only its epidemiologic aspects but also the pain modulatory systems that are likely to be engaged by exercise. Recent research provides broad and consistent evidence indicating that cardiovascular exercise can activate multiple pain modulatory mechanisms, if not the underlying mechanisms that initiate the attack. Specifically, a synthesis of independent lines of recent research would indicate that exercise activates endogenous neurotransmitter signals that could be effective in reducing the intensity of migraine pain, though it may not have a direct effect on its overall frequency or duration.
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Ejercicio Físico , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/prevención & control , Dolor/metabolismo , Receptores de Neurotransmisores/metabolismo , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/terapia , Dolor/fisiopatología , Medición de Riesgo , Autocuidado , Resultado del TratamientoRESUMEN
Photophobia refers to a sensory disturbance provoked by light. However, because it arises distinctly in a broad range of clinical conditions, its definition remains elusive. Many underscore the painful sensory aspects of photophobia, while others emphasize its unpleasant, affective qualities. To add further complexity, recent discoveries in photophobia research have raised disparate and potentially conflicting results. In this installment of an occasional series, we asked clinicians and scientists to give their interpretation of what these discoveries tell us about photophobia in the clinic, and vice versa.
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Cefalea/diagnóstico , Luz/efectos adversos , Fotofobia/diagnóstico , Cefalea/complicaciones , Cefalea/terapia , Humanos , Fotofobia/complicaciones , Fotofobia/terapiaRESUMEN
Pain sometimes has a throbbing, pulsating quality, particularly when it is severe and disabling. We recently challenged the presumption that this throbbing quality is a sensory experience of arterial pulsations, but were unable to offer an alternative explanation for its rhythmic character. Here we report a case study of a woman with a history of daily headache consistent with the diagnosis of chronic migraine, but whose throbbing quality persisted long after the resolution of the headache. This chronic, daily, and persistent throbbing sensation, in the absence of headache pain, prompted closer examination for its neurophysiological correlate. By simultaneously recording the subjective report of the throbbing rhythm, arterial pulse, and high-density electroencephalogram, we found that the subjective throbbing rate (48±1.7beats per minute) and heart rate (68±2beats per minute) were distinct, in accord with our previous observations that the 2 are unrelated. On spectral analysis of the electroencephalogram, we found that the overall amount of activity in the alpha range (8 to 12Hz), or alpha power, increased in association with greater throbbing intensity. In addition, we also found that the rhythmic oscillations of overall alpha power, the so-called modulations of alpha power, coincided with the timing of the throbbing rhythm, and that this synchrony, or coherence, was proportional to the subjective intensity of the throbbing quality. This index case will motivate further studies whose aim is to determine whether modulations of alpha power could more generally represent a neurophysiological correlate of the throbbing quality of pain.
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Relojes Biológicos , Encéfalo/fisiopatología , Electroencefalografía/métodos , Cefalea/diagnóstico , Cefalea/fisiopatología , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/fisiopatología , Diagnóstico Diferencial , Femenino , Cefalea/clasificación , Humanos , Persona de Mediana Edad , Trastornos Migrañosos/clasificaciónRESUMEN
"Attack" is often a word associated with migraine, and for good reason. If you suffer from migraine headaches or know someone who does, you are well aware of its crippling nature. This story focuses on new research that has uncovered an important link between migraine and sleep patterns. A better understanding of the relationships among the body's circadian rhythms, the brain's hypothalamus, and a mutated gene holds enormous promise of improved care for the more than 36 million Americans who experience migraine (three times more common in women) and the number of people suffering from familial advanced sleep phase syndrome (FASP).
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Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the only functional photoreceptive cells in the eye of newborn mice. Through postnatal day 9, in the absence of functional rods and cones, these ipRGCs mediate a robust avoidance behavior to a light source, termed negative phototaxis. To determine whether this behavior is associated with an aversive experience in neonatal mice, we characterized light-induced vocalizations and patterns of neuronal activation in regions of the brain involved in the processing of aversive and painful stimuli. Light evoked distinct melanopsin-dependent ultrasonic vocalizations identical to those emitted under stressful conditions, such as isolation from the litter. In contrast, light did not evoke the broad-spectrum calls elicited by acute mechanical pain. Using markers of neuronal activation, we found that light induced the immediate-early gene product Fos in the posterior thalamus, a brain region associated with the enhancement of responses to mechanical stimulation of the dura by light, and thought to be the basis for migrainous photophobia. Additionally, light induced the phosphorylation of extracellular-related kinase (pERK) in neurons of the central amygdala, an intracellular signal associated with the processing of the aversive aspects of pain. However, light did not activate Fos expression in the spinal trigeminal nucleus caudalis, the primary receptive field for painful stimulation to the head. We conclude that these light-evoked vocalizations and the distinct pattern of brain activation in neonatal mice are consistent with a melanopsin-dependent neural pathway involved in processing light as an aversive but not acutely painful stimulus.
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Luz , Células Ganglionares de la Retina/metabolismo , Opsinas de Bastones/metabolismo , Vocalización Animal/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ratones , Estimulación Luminosa , Proteínas Proto-Oncogénicas c-fos/metabolismo , Tálamo/metabolismo , Ganglio del Trigémino/metabolismo , Visión Ocular/fisiologíaRESUMEN
Pain can have a throbbing quality, especially when it is severe and disabling. It is widely held that this throbbing quality is a primary sensation of one's own arterial pulsations, arising directly from the activation of localized pain-sensory neurons by closely apposed blood vessels. We examined this presumption more closely by simultaneously recording the subjective report of the throbbing rhythm and the arterial pulse in human subjects of either sex with throbbing dental pain-a prevalent condition whose pulsatile quality is widely regarded a primary sensation. Contrary to the generally accepted view, which would predict a direct correspondence between the two, we found that the throbbing rate (44 bpm ± 3 SEM) was much slower than the arterial pulsation rate (73 bpm ± 2 SEM, p < 0.001), and that the two rhythms exhibited no underlying synchrony. Moreover, the beat-to-beat variation in arterial and throbbing events observed distinct fractal properties, indicating that the physiological mechanisms underlying these rhythmic events are distinct. Confirmation of the generality of this observation in other pain conditions would support an alternative hypothesis that the throbbing quality is not a primary sensation but rather an emergent property, or perception, whose "pacemaker" lies within the CNS. Future studies leading to an improved understanding of the neurobiological basis of clinically relevant pain qualities, such as throbbing, will also enhance our ability to measure and therapeutically target severe and disabling pain.
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Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Dolor/fisiopatología , Pulso Arterial , Adulto , Ritmo Circadiano , Análisis Factorial , Femenino , Humanos , Masculino , Percepción del Dolor/fisiología , Análisis Espectral , Enfermedades Estomatognáticas/fisiopatologíaRESUMEN
The selective 5-HT1 receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5-HT1 receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca²âº transients. Pre-application of the 5-HT1 antagonist GR 127935 or the selective 5-HT(1D) antagonist BRL 15572 prevented inhibition while the selective 5-HT(1B) antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT(1D) receptor subtype. Sumatriptan inhibition of the action potential evoked Ca²âº signaling was mediated selectively through N-type Ca²âº channels. Although the T-type Ca²âº channel accounted for a greater proportion of the Ca²âº signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca²âº channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT1 receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.
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Péptido Relacionado con Gen de Calcitonina/fisiología , Bloqueadores de los Canales de Calcio , Canales de Calcio Tipo N/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Fibras Nerviosas/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Sumatriptán/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Duramadre/efectos de los fármacos , Estimulación Eléctrica , Inmunohistoquímica , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Dolor/fisiopatología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
Virtually everyone can recall an experience, migraine or not, in which pain had a throbbing, pulsatile quality, particularly in association with intense pain. Its pulsatile character strongly reinforces the common presumption that it coincides with the heartbeat. For migraine, a cerebral vascular origin of the throbbing quality is a central tenet of the prevailing scientific view of migraine pain. However, recent data challenge this perspective, with implications for our understanding of throbbing pain not only for migraine but also for the pathophysiology of throbbing pain in other conditions as well.
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Trastornos Migrañosos/complicaciones , Neurobiología , Dolor/etiología , HumanosRESUMEN
Much research in migraine focuses on understanding its initiation. But as migraine is typically self-limited, its offset may be as important as its onset. We pose the question "how does migraine stop?" to three investigators with different backgrounds. The consensus is that the termination of a migraine attack, rather than being the passive loss of a trigger, must itself be an active biologic process.