Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve injury increases the spinal cord expression and/or activity of voltage- and ligand-gated ion channels, peptide receptors, and neuroimmune factors, which then drive dorsal horn neuron hyperexcitability. The intensity and duration of this central sensitization is determined by the net activity of local excitatory and inhibitory neurotransmitter systems, together with ongoing/evoked primary afferent activity and descending supraspinal control. Spinal endogenous inhibitory systems serve as opposing compensatory influences and are gaining recognition for their powerful capacity to restrain allodynia and hyperalgesia. These include numerous G protein-coupled receptors (mu- and delta-opioid, alpha(2)-adrenergic, purinergic A1, neuropeptide Y1 and Y2, cannabinoid CB1 and CB2, muscarinic M2, gamma-amino-butyric acid type B, metabotropic glutamate type II-III, somatostatin) and perhaps nuclear receptors (peroxisome proliferator-activated receptor gamma). Excessive downregulation or defective compensatory upregulation of these systems may contribute to the maintenance of neuropathic pain. An increasing number of pharmacotherapeutic strategies for neuropathic pain are emerging that mimic and enhance inhibitory neurotransmission in the dorsal horn.
Curr Pain Headache Rep 2009 Jun
PMID:Spinal inhibitory neurotransmission in neuropathic pain. 1945 81

Migraine attacks are characterized by unilateral throbbing, pulsating headache associated with nausea, vomiting, photophobia, phonophobia and allodynia. Peripheral sensitization is an acute, chemical-induced form of functional plasticity, which converts high-threshold nociceptors into low-threshold sensory neurons. This form of sensitization occurs when the nerve terminals (meningeal nociceptors) of the neurons of the trigeminal ganglion are soaked with the "inflammatory" soup (prostaglandin E2, bradykinin, serotonin and cytokines) along the vasculature of the cerebral dura mater. Peripheral sensitization in migraine attacks is explained clinically by intracranial hypersensitivity (the headache worsens during coughing or physical activity) and by a throbbing element in the pain of migraine (sensitized nociceptors become hyperresponsive to the otherwise innocuous and unperceived rhythmic fluctuation in intracranial pressure produced by normal arterial pulsation). The essence of central sensitization is that the second-order neurons in the trigeminocervical complex become hyperexcitable. The altered behavior of the second-order neurons is based on the increased glutamate sensistivity of the NMDA receptors and the neuronal nitric oxide synthase activity stimulated by nitric oxide. This process is explained clinically by face and scalp ollodynia and by neck stiffness (extracranial tenderness).
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PMID:[The mechanism of peripheral and central sensitization in migraine. A literature review]. 1973 14

Sports concussion is a major problem that affects thousands of people in North America every year. Despite negative neuroimaging findings, many athletes display neurophysiological alterations and post-concussion symptoms such as headaches and sensitivity to light and noise. It is suspected that neurometabolic changes may underlie these changes. In this study we investigated the effects of sports concussion on brain metabolism using (1)H-MR spectroscopy by comparing a group of 12 non-concussed athletes with a group of 12 concussed athletes of the same age (mean 22.5 years) and education (mean 16 years). All athletes were scanned 1-6 days post-concussion in a 3T Siemens MRI, and were administered a symptom scale to evaluate post-concussion symptomatology. Participants also completed a neuropsychological test battery to assess verbal memory, visual memory, information processing speed, and reaction time, and no group differences were detected relative to controls. Concussed athletes showed a higher number of symptoms than non-concussed athletes, and they also showed a significant decrease in glutamate in the primary motor cortex (M1), as well as significant decreases in N-acetylaspartate in the prefrontal and primary motor cortices. No changes were observed in the hippocampus. Furthermore, the metabolic changes in M1 correlated with self-reported symptom severity despite equivalent neuropsychological performance. These results confirm cortical neurometabolic changes in the acute post-concussion phase, and demonstrate for the first time a correlation between subjective self-reported symptoms and objective physical changes that may be related to increased vulnerability of the concussed brain.
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PMID:Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. 1976 85

Migraine is a common, disabling, neurological problem whose acute management would benefit from the development of purely neurally acting therapies. The trigeminocervical complex is pivotal in nociceptive signaling in migraine, and is an accepted target for putative antimigraine agents. Whole-cell patch-clamp or extracellular recordings were made of trigeminal neurons identified in rat brainstem slices. Bath application of the large conductance calcium-activated potassium (BKCa) channel opener NS1619 caused a dramatic decrease of cell firing that could be reversed by the co-application of iberiotoxin. NS1619 hyperpolarized the resting membrane potential and reduced the frequency of spontaneous action potentials in these neurons. These data suggest the presence of BKCa channels in the trigeminocervical complex. In vivo in cat L-glutamate-evoked firing was facilitated in nociceptive neurons, also responding to stimulation of the superior sagittal sinus, in the trigeminal nucleus caudalis by the BKCa peptide antagonists, iberiotoxin and slotoxin. Of units tested, 70% responded to microiontophoretic application of the blockers, identifying a subpopulation of trigeminal neurons expressing toxin-sensitive BKCa channels. NS1619 inhibited 74% of cells tested, and this was reversed by slotoxin, suggesting that the action of NS1619 in these cells was mediated through BKCa channels. These data are consistent with the presence of BKCa channels in the trigeminal nucleus caudalis that are potential targets for the development of antimigraine treatments, and may also offer insights into receptor mechanisms involved in sensitization and thus allodynia, in migraine.
Cephalalgia 2009 Dec
PMID:Large conductance calcium-activated potassium channels (BKCa) modulate trigeminovascular nociceptive transmission. 1991 62

Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP), TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care.
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PMID:Migraine pathogenesis and state of pharmacological treatment options. 1991 94

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side-effects, mainly headaches, the summaries of product characteristics of nitrate-containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate-induced migraine. Two different types of nitrate-induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine-type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3-6 h after the intake of nitrates, with debilitating, long-lasting symptoms including nausea, vomiting, photo- and/or phono-phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene-related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S-nitrosylation. Migraines usually need anti-attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti-migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.
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PMID:Headache-type adverse effects of NO donors: vasodilation and beyond. 2033 8

Migraine is one of the most prevalent neurological disorders with some 30% of patients additionally suffering from focal neurological disturbances: the aura. The underlying mechanism behind the aura is generally considered to be a form of cortical spreading depression (CSD). We used mechanical stimulation to induce hyperaemia associated with CSD in cats and rats, and studied the effect of a glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor, antagonist, and gamma-aminobutyric acid (GABA)(A) and GABA(B) receptor agonists, to understand better the pharmacology of CSD. All three were able to inhibit CSD-associated cerebral blood flow changes in the rat and in a proportion of cats studied; non-responders showed altered speed of propagation and time to induction. The data suggest AMPA and GABA receptors may be targets of migraine therapy in inhibiting CSD and thus may alter the frequency of migraine aura.
Cephalalgia 2010 May
PMID:Cortical spreading depression-associated cerebral blood flow changes induced by mechanical stimulation are modulated by AMPA and GABA receptors. 2051 Dec

Several episodic neurological diseases, including familial hemiplegic migraine (FHM) and different types of epilepsy, are caused by mutations in ion channels, and hence classified as channelopathies. The classification of FHM as a channelopathy has introduced a new perspective in headache research and has strengthened the idea of migraine as a disorder of neural excitability. Here we review recent studies of the functional consequences of mutations in the CACNA1A and SCNA1A genes (encoding the pore-forming subunit of Ca(V)2.1 and Na(V)1.1 channels) and the ATPA1A2 gene (encoding the alpha(2) subunit of the Na(+)/K(+) pump), responsible for FHM1, FHM3, and FHM2, respectively. These studies show that: (1) FHM1 mutations produce gain-of-function of the Ca(V)2.1 channel and, as a consequence, increased glutamate release at cortical synapses and facilitation of induction and propagation of cortical spreading depression (CSD); (2) FHM2 mutations produce loss-of-function of the alpha(2) Na(+)/K(+)-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(V)1.5 channels. These findings are consistent with the hypothesis that FHM mutations share the ability to render the brain more susceptible to CSD, by causing excessive synaptic glutamate release (FHM1) or decreased removal of K(+) and glutamate from the synaptic cleft (FHM2) or excessive extracellular K(+) (FHM3).
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PMID:Biological science of headache channels. 2081 11

Botulinum neurotoxin (BoNT) has been in clinical use for the treatment of headaches for over 15 years. Recent double-blind placebo-controlled trials have confirmed the efficacy of BoNT type A (onabtoulinumtoxinA, Botox) in the treatment of chronic migraine. The efficacy of BoNT in the treatment of episodic migraine headaches, cluster headaches, and chronic tension-type headache (TTH) has not been examined in large controlled trials. Presumed mechanisms of action of BoNT in headache disorders are the reduction of afferent input induced by muscle relaxation and inhibition of the release of neurotransmitters, such as glutamate and calcitonin gene-related peptide, from peripheral sensory nerve terminals. Over 20 years of extensive clinical experience has established a remarkable safety for BoNT, particularly type A and specifically Botox or onabotulinumtoxinA, which has been used much longer and more widely than any other form or serotype of BoNT. Because BoNT is a biological product, the safety and efficacy of one BoNT formulation cannot be extrapolated to a different one, even of the same serotype.
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PMID:Botulinum neurotoxin in the treatment of headache disorders. 2081 23

Chronic migraine (CM) is a prevalent and disabling neurological disorder. Few prophylactic treatments for CM have been investigated. OnabotulinumtoxinA, which inhibits the release of nociceptive mediators, such as glutamate, substance P, and calcitonin gene-related peptide, has been evaluated in randomized, placebo-controlled studies for the preventive treatment of a variety of headache disorders, including CM. These studies have yielded insight into appropriate patient selection, injection sites, dosages, and technique. Initial approaches used a set of fixed sites for the pericranial injections. However, the treatment approach evolved to include other sites that corresponded to the location of pain and tenderness in the individual patient in addition to the fixed sites. The Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) injection paradigm uses both fixed and follow-the-pain sites, with additional specific follow-the-pain sites considered depending on individual symptoms. The PREEMPT paradigm for injecting onabotulinumtoxinA has been shown to be safe, well-tolerated, and effective in well-designed, controlled clinical trials and is the evidence-based approach recommended to optimize clinical outcomes for patients with CM.
Headache 2010 Oct
PMID:Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. 2095 94


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