Effect of mechanical insufflation-exsufflation for ineffective cough on weaning duration in diseases of the peripheral or central nervous system (MEDINE): study protocol for a randomised controlled trial in a neurological weaning centre.

INTRODUCTION: Patients with neurological or neurosurgical disease can suffer from impaired cough, which may result in life-threatening retention of tracheobronchial secretions, atelectasis, pneumonia and finally death. Due to a lack of alternatives and pathophysiological plausibility, the application of mechanical insufflation-exsufflation (MI-E) has already become international standard care in neuromuscular disease and spinal cord injury although a lack of evidence for efficacy. High-quality studies to support the use of MI-E in neurological and neurosurgical patients during weaning from mechanical ventilation are missing. The goal of this exploratory study is to display the effect size of MI-E intervention on the duration of mechanical ventilation and additional outcomes. METHODS AND ANALYSIS: One hundred adult patients with a cough deficiency or retention of secretion admitted to a neurological intensive care unit (ICU) are planned to be recruited for this randomised controlled trial. Patients are randomised 1:1 to receive either MI-E or best standard care. Observation will take place until discharge from the hospital, death or end of the study period. The primary endpoint of this trial is the duration of mechanical ventilation from randomisation until successful weaning. The outcome will be analysed with Kaplan-Meier estimation and competing risks analyses. Secondary endpoint is the proportion of patients with successful weaning. Further outcomes will include the incidence of hospital-acquired pneumonia, mortality, decannulation rate, length of stay on the ICU and the total score of the Glasgow Coma Scale. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee of the University of Oldenburg. The findings of this study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00020981.

Central Bradypnea and Ataxic Breathing in Myotonic Dystrophy Type 1 - A Clinical Case Report.

BACKGROUND: The occurrence of obstructive and central sleep apnea syndromes, ventilator pump failure and reduced hypercapnic ventilatory drive in myotonic dystrophy type 1 (DM1) is well established, and there are indications for an impairment of the hypoxic ventilator drive, too. Yet, it is still unknown, to which extent the respiratory rhythm is affected by DM1, thus if a central bradypnea, cluster breathing or ataxic ("Biot's") breathing can occur. Additionally, the causes of the impairment of the central respiratory drive in DM1 are not known. CASE PRESENTATION: We present the case of a tracheotomized female patient with DM1 with central bradypnea and ataxic breathing. A 57-year-old woman with DM1 was admitted to our Neurointensive Care Unit (NICU) due to refractory tracheobronchial retention of secretions resulting from aspiration of saliva. Due to a combination of chronic hypercapnic respiratory failure, severe central bradypnea with a minimal breathing frequency of 3 per minute and ataxic breathing a pressure-controlled home ventilation was initiated. CONCLUSIONS: In our patient central bradypnea and ataxic breathing possibly were respiratory sequale of DM1, that may have been caused by pontine white matter lesions affecting the pontine respiratory nuclei. From a clinical viewpoint, polygraphy is a suitable tool to objectify disorders of the respiratory rhythm in DM1 even in tracheotomized patients. Clinical studies combining respiratory diagnostics as polygraphy, transcutaneous capnometry and blood gas analysis with brain magnetic resonance imaging (MRI) are required to better understand disorders of respiratory regulation in DM1, and to identify their anatomical correlates.

[The Respiratory Therapist in Neurology An Evolving Specialization in Germany]. / Der Atmungstherapeut in der Neurologie ­ Ein Blick auf das Berufsbild und ein Ausblick in die Zukunft.

In Germany, nurses, physiotherapists and speech and language therapists follow a qualifying training for about 1,5 years to become respiratory therapists (RTs). With respect to neurological illness, RTs diagnose and treat disorders of respiration, cough and swallowing as well as a retention of tracheobronchial secretions. There is an increasing demand for RTs in neurology, in neurointensive care and in neurological and neurosurgical early rehabilitation. The certification of specialized centers for weaning in neurological and neurosurgical early rehabilitation was introduced by the German Society for Neurorehabilitation (DGNR) in 2021. As a certification criterion it includes the employment of a respiratory therapists. In neurological organizations treating critically and severely ill patients, RTs work at an important interdisciplinary intersection of physicians, nurses and therapists. RTs are qualified to train teams, patients and family caregivers and to establish care structures for critically and severely ill neurological patients. Due to the complexity of neurological illnesses RTs working in neurological institutions need specific qualification. Specific training for RTs in neurology and neurorehabilitation might improve care for critically and severely ill neurological patients. Further professionalization of RT in Germany requires standardizing curricula, a professional society for RTs and, finally, academization.

Levetiracetam in the prophylactic treatment of episodic migraine: A prospective open label study.

BACKGROUND: The prophylactic treatment of migraine includes anticonvulsant drugs such as valproic acid and topiramate. However, these substances are often poorly tolerated by migraine patients. So far levetiracetam has hardly been studied as an episodic migraine prophylactic agent in adults. OBJECTIVE: To perform a prospective pilot study for the evaluation of the efficacy and tolerability of levetiracetam in the prophylactic treatment of episodic migraine. METHODS: Fifty patients with episodic migraine were enrolled in this prospective, open label study. After a baseline period of four weeks, patients received 1,000 mg (starting dose 500 mg) bid levetiracetam for 12 weeks. Migraine frequency and accompanying symptoms were recorded in a headache diary. The primary endpoint was the comparison of attack frequency during the baseline with attack frequency during the last four weeks of treatment (treatment period 3). RESULTS: In the Intent-To-Treat analysis, 46% of the patients had a migraine reduction of more than 50% in the third period as compared to the baseline period. The mean number of migraine attacks decreased from 5.2 +/- 2.1 (baseline) to 3.4 +/- 2.7 (period 3). The most frequently reported side effects were somnolence, nausea, and weight gain; all were mild and transient. In a post-hoc comparison, responders to levetiracetam had significantly less migraine attacks at baseline and had significantly more often migraine with aura. CONCLUSION: The data suggest that levetiracetam has some potential in the prophylactic treatment of episodic migraine which seems, however, to be not superior to that of other anticonvulsant drugs. Levetiracetam was well tolerated and showed better efficacy in patients with migraine with aura and in less affected migraine patients. A larger placebo-controlled, double-blind study in adults seems justified on the basis of these data.

Psychophysiological Effects of Biographical Interventions in People With Unresponsive Wakefulness Syndrome and Minimally Conscious State.

Background: Various music interventions can evoke favorable behavioral responses or physiological reactions in people with disorders of consciousness (DOC), such as coma, unresponsive wakefulness syndrome (UWS), and minimally conscious state (MCS). However, it appears that no study thus far has investigated the effects of music on the endocrine system of people with DOC. Objective: This explorative study aimed to investigate the effects of biographical music and biographical language on the physiological and endocrine systems of people with UWS and MCS. Method: A cohort of 20 people with DOC (10 women, 10 men; age range 19-77) received 20 min of biographical music and biographical language. Before and afterward, they were exposed to silence. Physiological and hormonal measurements were conducted before, during, and after the interventions. Results: Paired t-tests showed a significant decrease of salivary cortisol in the condition with biographical language interventions. Conclusion: Biographical interventions can modulate reactions in the endocrine system in people with DOC. Further studies are needed to establish whether and how individuals living with DOC show psychoneuroendocrine responses to music and other arts-based interventions.

Disordered breathing in severe cerebral illness - Towards a conceptual framework.

Despite potentially life-threatening symptoms of disordered breathing in severe cerebral illness, there are no clear recommendations on diagnostic and therapeutic strategies for these patients. To identify types of breathing disorders observed in severely neurological comprised patients, to direct further research on classification, pathophysiology, diagnosis and treatment for disordered breathing in cerebral disease. Data including polygraphy, transcutaneous capnometry, blood gas analysis and radiological examinations of patients with severe cerebral illness and disordered breathing admitted to the neurological intensive care were analyzed. Patients (15) presented with acquired central hypoventilation syndrome (ACHS), central bradypnea, central tachypnea, obstructive, mixed and central apneas and hypopneas, Cheyne Stokes respiration, ataxic (Biot's) breathing, cluster breathing and respiration alternans. Severe cerebral illness may result in an ACHS and in a variety of disorders of the respiratory rhythm. Two of these, abrupt switches between breathing patterns and respiration alternans, suggest the existence of a rhythmogenic respiratory network. Polygraphy, transcutaneous capnometry, blood gas analysis and MRI are promising tools for diagnosis and research alike.

Neurostimulation Treatment in Chronic Cluster Headache-a Narrative Review.

PURPOSE OF REVIEW: In this narrative review, the current literature on neurostimulation methods in the treatment of chronic cluster headache is evaluated. These neurostimulation methods include deep brain stimulation, vagus nerve stimulation, greater occipital nerve stimulation, sphenopalatine ganglion stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, supraorbital nerve stimulation, and cervical spinal cord stimulation. RECENT FINDINGS: Altogether, only nVNS and SPG stimulation are supported by at least one positive sham-controlled clinical trial for preventive and acute attack (only SPG stimulation) treatment. Other clinical trials either did not control at all or controlled by differences in the stimulation technique itself but not by a sham-control. Case series report higher responder rates. The evidence for these neurostimulation methods in the treatment of chronic cluster headache is poor and in part contradictive. However, except deep brain stimulation, tolerability and safety of these methods are good so that in refractory situations application might be justified in individual cases.

CGRP release in an experimental human trigeminal pain model.

BACKGROUND: Migraine and trigemino-autonomic cephalalgia attacks are associated with an increase of α-calcitonin-gene related peptide levels in the ipsilateral jugular vein. It is however unknown whether trigeminal pain stimulation in healthy subjects without headache disorders also induces increase of calcitonin-gene related peptide levels. FINDINGS: We measured α-calcitonin-gene related peptide levels in eight healthy subjects after subcutaneous injection of capsaicin in the forehead and in the mandibular region and after injection of sodium chloride in the forehead. We observed a significant increase of α-calcitonin-gene related peptide level only after injection of capsaicin in the forehead (i.e. first trigeminal branch). We also observed trigemino-autonomic activation (lacrimation, rhinorrhea etc.) only after injection of capsaicin in the forehead. CONCLUSION: Increase of α-calcitonin-gene related peptide levels do not only occur in primary headache attacks but also after experimental trigeminal pain of the first branch. This finding suggests that α-calcitonin-gene related peptide elevation is, at least an additional, unspecific effect of first trigeminal branch stimulation following pain activation and not a specific mechanism of idiopathic headache disorders.

Differential actions of indomethacin: clinical relevance in headache.

ABSTRACT: Nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide (NO) signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of an NO donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen, and ibuprofen. Administration of indomethacin (5 mg·kg-1), ibuprofen (30 mg·kg-1), or naproxen (30 mg·kg-1) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. By contrast, only indomethacin was able to inhibit NO-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate NO-related signaling as a potential therapeutic approach to these disorders.

Very young age of onset in trigemino-autonomic cephalalgias - case report and review of the literature.

BACKGROUND: Trigemino-autonomic cephalalgias are very rare disorders and even rarer in children and adolescents. We report the onset of paroxysmal hemicrania in a very young girl and reviewed the scientific literature for similar cases. FINDINGS: We describe the case of a 1.6-year-old girl with left-sided headache attacks fulfilling the criteria of paroxysmal hemicrania including prompt responsiveness to indomethacin. In addition, we detected at least two children for every trigemino-autonomic cephalalgias subtype with an age of under 7 years at the onset of the trigemino-autonomic cephalalgias. Remarkable features were a vast majority of chronic course from onset on and left-sided attacks. CONCLUSION: Although very rare, trigemino-autonomic cephalalgias can occur even in very young children under the age of 6 years. This should be known in neuropaediatrics.

Primary headache and migraine in headache specialists - does personal history of doctors matter?

OBJECTIVE: Migraine is a common disorder affecting more than 10% of the population. The prevalence of migraine among physicians and, in particular, among headache specialists is widely unknown as is the impact of suffering from migraine on the attitudes towards migraine and on treatment recommendations of physicians. We designed a survey among headache specialists and neurologists and compared the results to general pain specialists and general practitioners. METHODS: A standardized interview in randomly selected samples of these four groups of physicians was performed. The interview included data on the prevalence of migraine and other primary headache disorders in the physician groups, self-report on their own treatment, attitudes towards migraine, and treatment recommendations for migraine. The prevalence rates were also compared to an age- and sex-matched German general population sample. RESULTS: The lifetime prevalence of migraine was higher in headache specialists (53.0%) than in general neurologists (43.0%), pain specialists (21.7%), general practitioners (19.3%), and in the general age- and sex-matched population (16.8%). Cluster headache prevalence was high in neurologists (1.9%) and in headache specialists (1.3%); episodic tension-type headache prevalence was significantly lower in general practitioners (19.5%). One reason, among others, was that being a migraine (or cluster headache) patient more often prompted the sufferers to become a specialist in neurology. Physicians with migraine rated the biopsychosocial concept of lower importance for migraine than did physicians without migraine. The self-treatment of migraine in physicians differs from the treatment recommendations to the patients. For example, only 36.4% of the headache specialists with migraine take triptans whereas 94.4% recommend triptans to their patients. CONCLUSIONS: We conclude that being a headache specialist or a neurologist is associated with an increased migraine or cluster headache prevalence. This personal history of migraine leads to a more somatic view of migraine as a disorder and to different treatment recommendations as compared to self-treatment.

[Mechanical ventilation in neurological organizational units in Germany]. / Beatmung in neurologischen Organisationseinheiten in Deutschland.

BACKGROUND: Mechanical ventilation is provided for neurological patients in the following settings: in neurointensive care units, in centers providing weaning and early rehabilitation and in home mechanical ventilation. In the last decade there has been a sharp rise in treatment and bed capacities for mechanically ventilated neurological patients in specialized centers in Germany in the areas of weaning and neurological neurosurgical early rehabilitation of ventilated patients. Neither the number of beds nor details about structures in these centers with respect to bed capacity, personnel and qualifications, equipment, treatment methods and concepts are known. OBJECTIVE: The aim of this survey was to generate detailed numbers regarding structural criteria of specialized centers for mechanically ventilated neurology patients, regarding hospital beds, technical infrastructure, personnel and qualifications as well as treatment methods and concepts. MATERIAL AND METHODS: An online survey with 48 questions on the type and size of the institution, structural criteria, equipment and personnel was developed and supported by the German Society for Neurology (DGN), the German Interdisciplinary Society of Out-of-Hospital Ventilation (DIGAB) and the German Society of Neurorehabilitation (DGNR). RESULTS: A total of 63 centers took part in the survey and reported a total of 687 beds for mechanically ventilated neurological patients. Furthermore, they reported complex structures regarding personnel and qualifications, medical devices, methods and concepts but neurophysiological electrophysiology was the only technical method provided in all centers. Of the institutions 49% (n = 27/55) provided the initiation of home mechanical ventilation, 18% (n = 18/55) provided inpatient control of home mechanical ventilation, 9% (n = 5/55) had an outpatient department for home mechanical ventilation and 18% (n = 10/55) extracted data from home ventilators. CONCLUSION: Mechanical ventilation in neurological units offers vast and complex treatment and bed capacities for severely ill patients in Germany. The structures are inhomogeneous and a consensus on specific criteria should be established. This is especially true for the treatment of patients needing out-of-hospital mechanical ventilation, also with respect to a possible weaning in the long-term duration of the disease.

Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine.

A single pulse of transcranial magnetic stimulation has been shown to be effective for the acute treatment of migraine with and without aura. Here we aimed to investigate the potential mechanisms of action of transcranial magnetic stimulation, using a transcortical approach, in preclinical migraine models. We tested the susceptibility of cortical spreading depression, the experimental correlate of migraine aura, and further evaluated the response of spontaneous and evoked trigeminovascular activity of second order trigemontothalamic and third order thalamocortical neurons in rats. Single pulse transcranial magnetic stimulation significantly inhibited both mechanical and chemically-induced cortical spreading depression when administered immediately post-induction in rats, but not when administered preinduction, and when controlled by a sham stimulation. Additionally transcranial magnetic stimulation significantly inhibited the spontaneous and evoked firing rate of third order thalamocortical projection neurons, but not second order neurons in the trigeminocervical complex, suggesting a potential modulatory effect that may underlie its utility in migraine. In gyrencephalic cat cortices, when administered post-cortical spreading depression, transcranial magnetic stimulation blocked the propagation of cortical spreading depression in two of eight animals. These results are the first to demonstrate that cortical spreading depression can be blocked in vivo using single pulse transcranial magnetic stimulation and further highlight a novel thalamocortical modulatory capacity that may explain the efficacy of magnetic stimulation in the treatment of migraine with and without aura.

Exploding head syndrome: six new cases and review of the literature.

BACKGROUND: Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake. METHODS: We present six new cases extending the clinical experience with the syndrome. We also reviewed all available cases from the scientific literature and evaluated the typical features of EHS. RESULTS: The female to male ratio is 1.5 to 1. The median age at onset is 54. In average, one attack per day to one attack per week occurs. Some patients suffer from several attacks per night. In about half of all patients, a chronic time course can be observed but episodic or sporadic occurrence is also common. The most frequent accompanying symptoms beside the noise are fear and flashes of light. Polysomnographic studies do not reveal any specific sleep pattern associated with EHS. Tricyclic antidepressants are helpful in some patients. However, most patients do not need treatment because of the benign nature of the syndrome. CONCLUSION: EHS is a well-defined disease entity with a benign nature.

Hypothalamic dopaminergic stimulation in cluster headache.

BACKGROUND: Cluster headache is associated with structural abnormalities of the hypothalamus. We were interested in the association of cluster headache with endocrinological functional abnormalities. Therefore, we applied the apomorphine challenge test, which is a specific test of hypothalamic dopaminergic activation. METHODS: We enrolled 13 patients with cluster headache outside the bout and without medication. They were stimulated with 0.005 mg/kg of body weight subcutaneous apomorphine hydrochloride. After 45 and 60 minutes, growth hormone (GH), prolactin and cortisol were measured. The test was also applied to 14 sex- and age-matched healthy control subjects. RESULTS: There were significantly higher GH levels in healthy subjects as compared to cluster headache patients 45 minutes after injection (10.8 ± 10.8 versus 4.4 ± 7.4 ng/ml; P = 0.038). Only in cluster headache, the GH level after 60 minutes was not significantly different from the baseline. The levels of prolactin and cortisol did not show any significant differences between cluster headache patients and in healthy subjects. DISCUSSION: Our data suggest that cluster headache is associated with an impaired dopaminergic stimulation. This finding supports the body of evidence that cluster headache is associated with a functional abnormality of the hypothalamus and that this association is a primary (i.e. idiopathic) and not a secondary phenomenon during the bout.

The impact of sexual activity on idiopathic headaches: an observational study.

BACKGROUND: Headache associated with sexual activity is a well-known primary headache disorder. In contrast, some case reports in the literature suggest that sexual activity during a migraine or cluster headache attack might relieve the pain in at least some patients. We performed an observational study among patients of a tertiary headache clinic. METHODS: A questionnaire was sent to 800 unselected migraine patients and 200 unselected cluster headache patients. We asked for experience with sexual activity during a headache attack and its impact on headache intensity. The survey was strictly and completely anonymous. RESULTS: In total, 38% of the migraine patients and 48% of the patients with cluster headache responded. In migraine, 34% of the patients had experience with sexual activity during an attack; out of these patients, 60% reported an improvement of their migraine attack (70% of them reported moderate to complete relief) and 33% reported worsening. In cluster headache, 31% of the patients had experience with sexual activity during an attack; out of these patients, 37% reported an improvement of their cluster headache attack (91% of them reported moderate to complete relief) and 50% reported worsening. Some patients, in particular male migraine patients, even used sexual activity as a therapeutic tool. CONCLUSIONS: The majority of patients with migraine or cluster headache do not have sexual activity during headache attacks. Our data suggest, however, that sexual activity can lead to partial or complete relief of headache in some migraine and a few cluster headache patients.

Mechanism of action of indomethacin in indomethacin-responsive headaches.

Indomethacin, as a member of the non-steroidal anti-inflammatory drug class, plays a special role in the treatment of headaches. By definition, it is completely efficacious in the treatment of the primary headache disorders paroxysmal hemicrania and hemicrania continua. Therefore, indomethacin is also used as a tool for differential diagnosis in headache clinics. Indomethacin has a clear action as a cyclooxygenase inhibitor. Additional mechanisms and interactions with cell signaling pathways and inflammatory pathways are considered in this article. However, it is not known what mechanism or interaction with pathophysiological mechanisms is the key to indomethacin's specific pharmacology in headache therapy. Focusing on headache therapy, we summarize the current knowledge of pharmacology, treatment options, and recommendations for the use of indomethacin in primary headaches. New findings from the field of headache research, as well as from Alzheimer's disease and cancer research on the pharmacological actions of indomethacin and their potential implications on the pathophysiology of indomethacin sensitive headaches, are discussed.

A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system.

The transient receptor potential vanilloid channel 1 (TRPV1) is a nociceptive transducer located on nociceptive neurons. TRPV1 channels located on peripheral neurons mainly transduce the sense of heat and are also activated by low pH or capsaicin. The role of centrally located TRPV1 channels is not fully understood. Likewise their importance in pain syndromes of central origin, such as migraine, is not known. Experimental data suggest a relationship to migraine. However, experimental studies with TRPV1 receptor antagonists indicate that the receptor may not be a useful target for new acute migraine treatments. Any potential role for the receptor in the chronification of migraine has not been investigated. The present study aimed at analyzing the use of the TRPV1 channel as a target to desensitize trigeminal neurons and thereby inhibit neuronal activity in the trigeminocervical complex. The TRPV1 receptor agonist olvanil was used for desensitization because, as compared with capsaicin, it is non-noxious and lacks capsaicin's pungency and CGRP release potential. We further investigated a possible effect of olvanil on cannabinoid (CB(1)) receptors, as an interaction between both receptor systems has been described previously. The results show that olvanil dose-dependently inhibited spontaneous and stimulus-induced activity within the trigeminocervical complex, whereas it had no effect on CSD susceptibility. We further demonstrated that the inhibiting effect of olvanil is mediated by vanilloid and cannabinoid receptor systems, thereby using the synergistic effects this dual mechanism offers. Curiously, TRPV1 receptor agonism may have anti-nociceptive properties through central mechanisms that would be of considerable interest to elucidate.

TRPV1 receptor blockade is ineffective in different in vivo models of migraine.

BACKGROUND: It has been proposed that TRPV1 receptors may play a role modulating trigeminal sensory processing. We used models of trigeminovascular nociceptive activation to study the involvement of TRPV1 receptors in the rat. Due to a possible role of TRPV1 receptors in cortical spreading depression (CSD), an experimental phenomenon sharing many features with migraine aura, we also utilized a model of mechanically induced CSD. METHODS: Male Sprague Dawley rats (N = 39) were anesthetized and cannulated for monitoring and drug administration to study the effects of the TRPV1 receptor antagonist A-993610 (8 mg kg(-1) IV). Wide-dynamic-range neurons, responding to electrical stimulation of the middle meningeal artery (MMA)/dura mater were identified and recorded using electrophysiological techniques. Intravital microscopy was used to study neurogenic dural vasodilation (NDV) of the MMA comparing capsaicin and electrical stimulation, and the effect of A-993610 on mechanically induced CSD was examined. RESULTS: Administration of A-993610 had no significant effect on trigeminal firing of A- or C-fibers elicited by electrical stimulation of the MMA. It also showed no effect on NDV whilst blocking vasodilation due to intravenous capsaicin injection. The mechanically induced CSD response could not be altered by A-993610 administration. CONCLUSIONS: Although there is evidence that TRPV1 receptors play an important role in sensory processing in general, the new data do not support a role in the treatment of acute migraine.