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

Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.
Cephalalgia 2003 Oct
PMID:5-HT1F receptor agonists in acute migraine treatment: a hypothesis. 1451 Sep 23

Botulinum toxin type A (BoNT-A) produced by the bacterium Clostridium botulinum is a potent inhibitor of acetylcholine release in the neuromuscular junction and has been used to treat many disorders related to excessive muscle contraction. However, BoNT-A has recently been used in pain therapy to treat myofascial pain, low back pain and various types of headaches, including migraine. The purpose of this study is to investigate the antinociceptive effect of BoNT-A and its underlying mechanism in the rat formalin inflammatory pain model. BoNT-A (3.5, 7, 15 and 30 U/kg) or vehicle was administered to the plantar surface of the right hindpaw of male Sprague-Dawley rats. BoNT-A dose-dependently (P<0.05) inhibited formalin-induced nociceptive behavior during phase 2 but not during phase 1 when administered 5 h to 12 days before formalin challenge. The onset of the antinociceptive effect started at 5 h after pre-treatment and this effect lasted for at least 12 days. BoNT-A (7 U/kg) also reduced edema. Consistent with the lack of effect in the formalin phase 1, BoNT-A, at 15 U/kg, had no effect on acute thermal nociception; no local muscle weakness was observed at this dose. Pre-treatment of rats with BoNT-A (3.5, 7 or 15 U/kg) all significantly reduced formalin-evoked glutamate (Glu) release. These results demonstrate that local peripheral injection of BoNT-A significantly reduces formalin-induced nociceptive behaviors with the absence of obvious muscle weakness. Such an antinociceptive effect of BoNT-A is associated with the inhibition of formalin-induced release of Glu (and/or neuropeptides) from primary afferent terminals.
 ...
PMID:Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. 1471 98

Nitric oxide (NO) donors such as glyceryl trinitrate cause headache, which suggests involvement of NO in trigeminovascular sensory processing. Sensory transmission at first-order synapses is believed to involve glutamate and the question arises as to whether it is also involved in trigeminovascular sensation and whether it might interact with nitrergic mechanisms. We investigated these questions at the first central synapse in the trigeminovascular sensory system of the cat. Neuronal action potentials in the trigeminal nucleus were recorded while the superior sagittal sinus (SSS) or facial receptive field (RF) were stimulated electrically. Drugs, including the neuronal excitant glutamate, were applied to neurons via microiontophoresis. Results were obtained from 152 neurons activated with A-delta latencies by SSS stimulation and by glutamate. The NO donor S-nitrosoglutathione (SNOG, 50 nA) was applied iontophoretically to 41 neurons during SSS stimulation and 13 neurons during pulsatile glutamate ejection. Responses to both modes of stimulation were enhanced by SNOG; the proportion of neurons enhanced was 56% to SSS stimulation and 59% to glutamate. The inhibitor of nitric oxide synthase (NOS), N(omega)-propyl-L-arginine (p-ARG, 50 nA) was applied iontophoretically to 17 neurons during stimulation of SSS and to 10 neurons during pulsatile glutamate ejection. Responses to both stimuli were suppressed by p-ARG: The proportion of neurons suppressed were: to SSS stimulation 59% and to glutamate 80%. Microiontophoretic ejection of eletriptan (50 nA) reversibly suppressed responses of neurons to SSS stimulation, to RF electrical stimulation and to pulsatile iontophoretic application of glutamate. This suppression of responses was antagonised by the concurrent local iontophoretic application of the 5-HT1B/1D receptor antagonist GR127935 or by concurrent iontophoretic application of the selective 5-HT1D receptor antagonist BRL155732. These results suggest that glutamatergic mechanisms are important in sensory transmission in the trigeminovascular system and that they can be modulated by nitrergic and serotonergic mechanisms.
 ...
PMID:Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. 1516 37

Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists alpha-CGRP-(8-37) and BIBN4096BS. Cats were anaesthetised with alpha-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25-30 Hz by microiontophoresis of L-glutamate (n = 43 cells). Microiontophoresis of alpha-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by l-glutamate, demonstrating a non-presynaptic site of action for CGRP. alpha-CGRP-(8-37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 microg kg(-1)). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.
 ...
PMID:Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. 1523 96

Both preclinical and clinical data link glutamate to the migraine pathophisiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.
Cephalalgia 2004 Sep
PMID:Cerebrospinal fluid glutamate levels in chronic migraine. 1531 29

A young woman presented with multiple central hypersensitivity disorders, including fibromyalgia, headache, pelvic pain and several smooth muscle spasm disorders, including irritable bowel syndrome, irritable bladder and Raynaud's phenomenon. She also had significant fatigue and sleep problems. Her case illustrates the importance and surprising frequency of atypical bipolar mood disorders in people with multiple central hypersensitivity pain disorders, especially with depression and anxiety resistant to antidepressant treatment. Considering neurological mechanisms common to her overlapping disorders was very helpful in guiding treatment choices. This experience illustrates the value of serotonin receptor type 2 (5HT2) inhibition with atypical neuroleptics, of neural cation channel and glutamate inhibition with anticonvulsants, and the potential usefulness of antidepressants after establishing 5HT2 control to enhance downward inhibitory tracts. Medications with combined usefulness for both bipolar mood and pain disorders were highly effective for her multiple hypersensitivity problems.
 ...
PMID:Serotonin mechanisms in pain and functional syndromes: management implications in comorbid fibromyalgia, headache, and irritable bowl syndrome - case study and discussion. 1576 Aug 6

The pivotal role of nerve growth factor in inducing hyperalgesia and central sensitization has been emphasized in experimental pain models. Higher nerve growth factor levels have recently been found in the cerebrospinal fluid of patients with chronic daily headache. These levels were significantly correlated with the cerebrospinal fluid levels of substance P and calcitonin gene-related peptide, supporting the involvement of this neurotrophin in enhancing the production of the two sensory neuropeptides of the trigemino-vascular system in chronic daily headache. This may, in part, account for the long-lasting sensitization and activation of this system, which could contribute to headache chronicity. More recent research has shown a significant correlation between the higher cerebrospinal fluid levels of nerve growth factor and those of another neurotrophin, the brain-derived neurotrophic factor, as well as glutamate in chronic daily headache patients. These findings suggest the potential involvement of nerve growth factor-mediated upregulation of brain-derived neurotrophic factor in persistent head pain. Therefore, nerve growth factor appears to indirectly exert its effect through enhancing glutamatergic transmission involved in the processing of head pain via brain-derived neurotrophic factor. Based on these data, a potential application can be hypothesized for novel strategies targeting neurotrophins (nerve growth factor and brain-derived neurotrophic factor) and their receptors to chronic daily headache. To date, the majority of the molecules discovered in this regard have been scarcely or never proved in animal pain models and are far from clinical use in chronic pain, including chronic daily headache. If this approach is to be developed in the near future, research should be focused on identifying strategies with few central side effects and specific selective action on central sites involved in chronic head pain and more generally in chronic pain conditions. This will represent a very difficult challenge, taking into account the pleiotropic effect of nerve growth factor and the wide range of intracellular signalling pathways activated by this neurotrophin which are not limited to the nociceptive system.
 ...
PMID:Nerve growth factor and chronic daily headache: a potential implication for therapy. 1585 22

There is now evidence that melatonin may have a role in the biological regulation of circadian rhythms, sleep, mood, and ageing. Altered melatonin levels in cluster headache and migraine have been documented. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin. Treatment of headache disorders with melatonin and other chronobiotic agents is promising. A double-blind, placebo-controlled trial shows melatonin is effective in cluster headache prevention, other studies also show benefit in other disorders. Melatonin plays an important role in headache disorders, offering new avenues for studying their pathophysiology and treatment.
Cephalalgia 2005 Jun
PMID:Melatonin, the pineal gland and their implications for headache disorders. 1591 May 64

Clinical observations and genetic studies have suggested a role for high-threshold voltage-dependent calcium channels (VDCCs) in the pathogenesis of migraine. This study investigated the role of P/Q-, L- and N-type VDCCs in post-synaptic action potential generation in trigeminovascular nociceptive afferents in the trigeminocervical complex (TCC) of the cat in vivo. Trigeminovascular nociceptive afferents were identified in the TCC by electrical stimulation of the superior sagittal sinus. Forty-six cell bodies were identified by their response to microiontophoresis of l-glutamate and their bipolar action potential shape. Blockade of VDCCs was accomplished by microiontophoresis of omega-agatoxin IVa/TK (P/Q-), omega-conotoxin GVIa (N-) and calciseptine (L-type). Non-selective antagonism was studied using cadmium ions. Non-selective blockade of high threshold VDCC with cadmium resulted in a reduction in l-glutamate-evoked neuronal activity (P=0.01). Blockade of P/Q: TK- (P<0.001), IVA- (P=0.007), L- (P<0.001) and N-type (P<0.001) VDCCs resulted in significant reductions in post-synaptic action potential generation in response to l-glutamate. High threshold VDCCs, including P/Q-, L- and N-type VDCCs, can therefore modulate nociceptive transmission in the trigeminocervical complex in vivo. We discuss the evidence to suggest a role for VDCCs in the pathophysiology of primary headache disorders, and how abnormalities of function may contribute to their pathogenesis.
 ...
PMID:Calcium channels modulate nociceptive transmission in the trigeminal nucleus of the cat. 1608 58

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.
 ...
PMID:Potential therapeutic use of melatonin in migraine and other headache disorders. 1654 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>