Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine.
Mutations in alpha1A, the pore-forming subunit of P/Q-type calcium channels, are linked to several human diseases, including familial hemiplegic migraine (FHM). We introduced the four missense mutations linked to FHM into human alpha1A-2 subunits and investigated their functional consequences after expression in human embryonic kidney 293 cells. By combining single-channel and whole-cell patch-clamp recordings, we show that all four mutations affect both the biophysical properties and the density of functional channels. Mutation R192Q in the S4 segment of domain I increased the density of functional P/Q-type channels and their open probability. Mutation T666M in the pore loop of domain II decreased both the density of functional channels and their unitary conductance (from 20 to 11 pS). Mutations V714A and I1815L in the S6 segments of domains II and IV shifted the voltage range of activation toward more negative voltages, increased both the open probability and the rate of recovery from inactivation, and decreased the density of functional channels. Mutation V714A decreased the single-channel conductance to 16 pS. Strikingly, the reduction in single-channel conductance induced by mutations T666M and V714A was not observed in some patches or periods of activity, suggesting that the abnormal channel may switch on and off, perhaps depending on some unknown factor. Our data show that the FHM mutations can lead to both gain- and loss-of-function of human P/Q-type calcium channels. (+info)
The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation.
Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression. (+info)
Computerised axial tomography in patients with severe migraine: a preliminary report.
Patients suffering from severe migraine, usually for many years, have been examined by the EMI scanner between attacks. Judged by criteria validated originally by comparison with pneumoencephalography, about half of the patients showed evidence of cerebral atrophy. Perhaps of more significance than generalised atrophy was the frequency of areas of focal atrophy and of evidence of infarction. (+info)
Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine.
Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. One conclusion of these studies was that when low- and high-intensity stimuli induce responses of similar magnitude in nociceptive neurons, low-intensity stimuli must be as painful as the high-intensity stimuli. The present study investigates in anesthetized rats the significance of the changes in the responses of central trigeminal neurons (i.e., in nucleus caudalis) by correlating them with the occurrence and type of the simultaneously recorded cardiovascular responses. Before chemical stimulation of the dura, simultaneous increases in neuronal firing rates and blood pressure were induced by dural indentation with forces >/= 2.35 g and by noxious cutaneous stimuli such as pinching the skin and warming > 46 degrees C. After chemical stimulation, similar neuronal responses and blood pressure increases were evoked by much smaller forces for dural indentation and by innocuous cutaneous stimuli such as brushing the skin and warming it to >/= 43 degrees C. The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine. (+info)
Cost-effectiveness of sumatriptan in a managed care population.
We conducted an open-labeled study to determine whether sumatriptan is more cost-effective than other therapies used to treat migraine headache. We contacted by phone 220 sumatriptan users enrolled in QualMed, a health maintenance organization (HMO) in Spokane, Washington. Of these, 203 met the inclusion criteria and 164 (81%) completed our telephone survey. The main outcome measures were healthcare costs to the HMO and number of days free of migraine-related disability before and after sumatriptan treatment. Before sumatriptan treatment, 89% of patients reported severe migraine, compared with 63% after sumatriptan treatment. The number of monthly migraine disability days decreased from 6.5 days per month before sumatriptan to 3.9 days per month after sumatriptan. Healthcare utilization rates (ie, number of hospitalizations, emergency department visits) and costs were lower after the patients began taking sumatriptan. The number of different over-the-counter medicines and prescription medications (other than sumatriptan) taken for migraine disabilities decreased. Although total drug expenditures per month increased, the total migraine healthcare expenditure was 41% lower after sumatriptan was initiated. The cost-effectiveness ratio was 47% more favorable after patients started taking sumatriptan. Overall, patients reported fewer migraine-related disabilities, had lower migraine severity scores, and used fewer healthcare resources when taking sumatriptan. These changes resulted in a better cost-effectiveness ratio for migraine treatment. (+info)
Migraine: a problem for employers and managed care plans.
Headache is probably the most common symptom in the workforce and in the general population. Among the many types of headache, the one with perhaps the greatest impact on well-being and functional capacity is migraine. It disrupts work and leisure activities and engenders significant use of healthcare resources. Migraine cannot be cured, but it can usually be managed. Managed care organizations can facilitate the treatment of migraine through disease management programs. Unfortunately, however, many migraineurs receive substandard, ineffectual, and inappropriate care--or no care at all. This article reviews the diagnosis, epidemiology, and treatment of migraine, with an emphasis on the perspectives of employers and managed care plans, with the hope of encouraging them to become more proactive in dealing with individuals with migraine. (+info)
Cost of migraine management: a pharmacoeconomic overview.
Migraine is a chronic, sometimes debilitating, condition that tends to afflict young people who are otherwise healthy and productive. Because diagnostic criteria and effective treatment modalities have not been well taught to physicians, the condition is often undiagnosed, misdiagnosed, and mismanaged, causing unnecessary pain, hardship to the individual, disability, loss of productivity, and increased expense to the healthcare system. This paper discusses a rational approach to the behavioral and pharmacologic treatment of migraine, highlighting the relative costs of preventive and acute care therapies. Several cases are presented to illustrate how the costs of inefficiently managed migraine therapy can be decreased even by using medications that have a higher per-dose cost, as they decrease the pain and disability and actually lower the total cost of managing the patient with migraine. (+info)
The inhibition of nicotine-evoked relaxation of the guinea-pig isolated basilar artery by some analgesic drugs and progesterone.
1. The purpose of this study was to investigate the mechanism of nicotine-evoked relaxation of the guinea-pig isolated basilar artery and to study the effects of drugs associated with the aetiology or treatment of migraine on the nicotine response. 2. The guinea-pig isolated basilar artery, pre-contracted with prostaglandin F2alpha (PGF2alpha), in the presence of atropine (3 microM) and guanethidine (3 microM), relaxed on addition of nicotine (0.1 mM) in approximately 50% of preparations. The responses to nicotine were of short duration and blocked in preparations pre-treated for 10 min with capsaicin (1 microM) and are therefore probably a consequence of the stimulation of trigeminal C fibre terminals. 3. Responses to nicotine were reduced in the presence of 5-carboxamidotryptamine, 5-hydroxytryptamine and sumatriptan in that order of potency. This is consistent with a 5-HT1 receptor mechanism. These agonists evoked small additional contractions in vessels pre-contracted with PGF2alpha. 4. Indomethacin (0.3-10 microM), aspirin (10-30 microM), and nitro-L-arginine methyl ester (L-NAME, 0.1 mM) reduced nicotine-evoked relaxation of the basilar artery, suggesting the involvement of both nitric oxide and cyclo-oxygenase products in this response. 5. Progesterone (1 microM) markedly reduced the response to nicotine, a possible reflection of the ion channel blocking activity of high concentrations of this compound. 6. The guinea-pig basilar artery is a preparation in which the effects of drugs on responses to stimulation of trigeminal nerve terminals can be studied in vitro and may thus be of interest in assessing the actions of drugs used in treatment of headache. (+info)