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)

In migraine and other primary headaches there is a strong vascular component. Besides the trigeminovascular components some of the associated symptoms point to the involvement of brain stem regions. The central limb of the trigeminal vascular pathway is its projection to the trigeminal nucleus caudalis (TNC) and to the C1-C2 levels of the spinal cord. The aim of the present study was to demonstrate the occurrence of some neurotransmitters in these regions in man. In both the TNC and in the Rexed's laminae I and II of the dorsal horns at the C1 and C2 levels there were numerous substance P immunoreactive fibres. Fibres containing calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) were moderately dense in number. Fibres containing vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) were not seen in the TNC or at the C1 and C2 levels of the spinal cord.
Cephalalgia 2002 Mar
PMID:Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. 1197 78

There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperitoneally), and prepared for physiological monitoring. The superior sagittal sinus (SSS) was stimulated electrically, and linked units were recorded in the trigeminocervical complex. Post-stimulus histograms were constructed to analyse the responses and the effect of drug administration. Blood was sampled from the external jugular vein to determine levels of calcitonin gene-related peptide (CGRP) release before and after drug administration. Intravenous administration of the highly selective adenosine A1 receptor agonist, GR79236 (3-100 microg/kg) had a dose-dependent inhibitory effect on SSS-evoked trigeminal activity. The maximal effect (80 +/- 6% reduction in probability of firing) was seen at 100 microg/kg. The neuronal inhibitory effect of GR79236 could be inhibited by the selective adenosine A1 receptor antagonist DPCPX (300 microg/kg; P < 0.05). SSS stimulation increased cranial CGRP levels from 33 +/- 2 pmol/l (n = 6) to 64 +/- 3 pmol/l, an effect substantially reduced by pre-treatment with GR79236 (30 microg/kg; P < 0.01). The selective low efficacy adenosine A1 receptor agonist, GR190178 (30-1000 microg/kg i.v.), also inhibited SSS-evoked neuronal activity in a dose-dependent fashion. In this model of trigeminovascular nociception, adenosine A1 receptor activation leads to neuronal inhibition without concomitant vasoconstriction, suggesting a novel avenue for the treatment of migraine and cluster headache.
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PMID:Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission. 1202 27

This study addresses possible interactions of the vasodilators nitric oxide (NO), calcitonin gene-related peptide (CGRP) and prostaglandins, which may be implicated in the generation of vascular headaches. Local application of the NO donator diethylamine-NONOate (NONOate) to the exposed dura mater encephali of the rat caused dose-dependent increases in meningeal blood flow recorded by laser Doppler flowmetry. Pre-application of the CGRP receptor antagonist CGRP8-37 significantly attenuated the evoked blood flow increases, while the cyclooxygenase inhibitors acetylsalicylic acid and metamizol were only marginally effective. Stimulation of rat dura mater with NONOate in vitro caused increases in CGRP release. NADPH-diaphorase activity indicating NO production was restricted to the endothelium of dural arterial vessels. We conclude that increases in meningeal blood flow caused by NO depend partly on the release and vasodilatory action of CGRP from dural afferents, while prostaglandins are not significantly involved.
Cephalalgia 2002 Apr
PMID:Increase in meningeal blood flow by nitric oxide--interaction with calcitonin gene-related peptide receptor and prostaglandin synthesis inhibition. 1204 64

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.
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PMID:Triptans reduce the inflammatory response in bacterial meningitis. 1217 84

1. The detailed pathophysiology of migraine is beginning to be understood and is likely to involve activation of trigeminovascular afferents. 2. Clinically effective anti-migraine compounds are believed to have actions that include peripheral inhibition of calcitonin gene-related peptide (CGRP) release from trigeminal neurones, or preventing dural vessel dilation, or both. CGRP antagonists can block both neurogenic and CGRP-induced dural vessel dilation. 3. Nitric oxide (NO) can induce headache in migraine patients and often triggers a delayed migraine. The initial headache is thought to be caused via a direct action of the NO-cGMP pathway that causes vasodilation by vascular smooth muscle relaxation, while the delayed headache is likely to be a result of triggering trigeminovascular activation. Nitric oxide synthase (NOS) inhibitors are effective in the treatment of acute migraine. 4. The present studies used intravital microscopy to examine the effects of specific NOS inhibitors on neurogenic dural vasodilation (NDV) and CGRP-induced dilation. 5. The non-specific and neuronal NOS (nNOS) inhibitors were able to partially inhibit NDV, while the non-specific and endothelial NOS (eNOS) inhibitors were able to partially inhibit the CGRP induced dilation. 6. There was no effect of the inducible NOS (iNOS) inhibitor. 7. The data suggest that the delayed headache response triggered by NO donors in humans may be due, in part, to increased nNOS activity in the trigeminal system that causes CGRP release and dural vessel dilation. 8. Further, eNOS activity in the endothelium causes NO production and smooth muscle relaxation by direct activation of the NO-cGMP pathway, and may be involved in the initial headache response.
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PMID:Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. 1218 31

Migraine is characteristically accompanied by a throbbing quality of head pain thought to involve trigeminovascular afferents. Administration of nitric oxide (NO) donors provides the most reliable model of migraine induction in humans. The present studies used intravital microscopy to monitor the effect of local meningeal nerve stimulation and NO on dural blood vessels and any modulation of that effect by anti-migraine compounds. NO caused an immediate and reproducible dilation of meningeal blood vessels that was partially blocked by sumatriptan and indomethacin, while flunarizine and histamine H(1) and H(2) receptor antagonists were unable to block the dilation. Indomethacin also inhibited the neurogenic dilation while flunarizine did not. The present studies demonstrate that NO is unlikely to interact with histamine to produce its dilatory response. Sumatriptan and indomethacin inhibit the NO response by inhibiting trigeminal activation and calcitonin gene-related peptide (CGRP) release. Flunarizine does not modify either the neurogenic vasodilator response or the NO meningeal dilator response at least acutely.
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PMID:The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels. 1235 73

The impressive pain relief experienced by sufferers of dystonia and spasticity from intramuscular injections of botulinum toxin suggested that patients with other chronic, musculoskeletal pain conditions also may benefit. However, there have been relatively few placebo-controlled studies of botulinum toxin in such non-neurologic conditions as myofascial pain syndrome, chronic neck and low back pain, and fibromyalgia; the results of these studies have not been impressive. One explanation for the lack of positive findings may be the lack of clinically evident muscle spasms (overactivity), despite the presence of muscle tenderness, tightness, or trigger points. Clinical observations of pain relief from injections of botulinum toxin for dystonia and spasticity and its apparent efficacy in treating migraine suggest an anti-nociceptive action independent of its neuromuscular junction-blocking action. Evidence from animal experiments supports this notion, and other data provide plausible physiologic mechanisms in the periphery and central nervous systems. These involve modulation of the activity of the neurotransmitters glutamate, substance P, calcitonin gene-related peptide, enkephalins, and others. However, even if botulinum toxin is firmly established as an analgesic, there is insufficient clinical evidence of its efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.
Curr Pain Headache Rep 2002 Dec
PMID:Botulinum toxin for the treatment of musculoskeletal pain and spasm. 1241 5

Sixteen patients, 12 with episodic and four with chronic cluster headache (CH) according to the International Headache Society criteria (1), participated in the study. They were randomly selected to start with one out of two different hyperbaric treatments in a double-blind, placebo-controlled, cross-over study design. Both gases were administered by mask inside a multiplace hyperbaric chamber for 70 min at 250 kPa (2.5 ATA) in two sessions 24 h apart. Active treatment was 100% oxygen (HBO treatment), while placebo treatment was 10% oxygen in nitrogen (hyperbaric normoxic placebo = sham treatment) corresponding to breathing air at sea level. All patients were decompressed on air. The patients documented the number of headache attacks and their degree of severity according to a modified VAS scale (level 0-4, where level 0 = no headache and level 4 = very severe headache). A headache index (HI = sum of (number of attacks times degree of severity)) was calculated for the run-in week prior to and the week after each separate treatment. A treatment was regarded as effective if it reduced the HI by>50%. Blood samples were taken from the external jugular vein before and during hyperbaric treatment (after 30 and 70 min), 1 day and 1 week after each treatment for analyses of calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) and in a few patients also endotheline and nitrate. No difference between HBO and sham treatment on the HI or the prophylactic effect was observed in our study. However, 83% of the episodic CH patients and 25% of the chronic ones responded to either of the two treatments with at least 50% reduction of HI or remission for shorter or longer periods. This response rate exceeds an expected high placebo response due to the study procedure. Two episodic CH patients still experienced remission on follow-up 1 year after sham treatment. Five patients reported mild or moderate CH attacks during the sham treatment, and none during the HBO treatment. Changes in neuropeptides, endotheline and nitrate levels did not differ systematically when comparing the two different hyperbaric treatments or with respect to responders and non-responders. We conclude that two HBO sessions were not more effective than two sham treatments in reducing the HI and interrupting the CH period when given in a well-established cluster period or in chronic CH. The hyperbaric condition itself seems effective in reducing the HI, at least in patients with episodic CH, although a powerful placebo response can not be ruled out.
Cephalalgia 2002 Nov
PMID:Hyperbaric oxygen treatment of active cluster headache: a double-blind placebo-controlled cross-over study. 1242 Nov 59

A central sensitization has been advocated to explain chronic daily headache (CDH) due to sustained peripheral sensitization of allogenic structures responsible for sustained trigeminovascular system activation. Several mechanisms have been suggested to underlie central sensitization, but have been poorly investigated in CDH. They involve N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production and supersensitivity and increased and maintained production of sensory neuropeptides. The present study supports the above pathogenic mechanisms demonstrating a significant increase in glutamate and nitrite levels in the CSF of CDH patients, without a significant difference between patients without and those with analgesic overuse headache (P < 0.0001 and P < 0.002). The increase in CSF nitrites was accompanied by a significant rise in the CSF values of cyclic guanosine monophosphate (cGMP) in patients in comparison with controls (P < 0.0001). A statistically significant correlation emerged between visual analogic scale (VAS) values and glutamate, nitrites and cGMP. Although substance P (SP) and calcitonin gene-related peptide (CGRP), and to a lesser extent neurokinin A, were significantly increased in CSF compared with control subjects, their values did not correlate with glutamate, nitrites and cGMP levels in CSF in the patient group. The present study confirms the involvement of glutamate-NO-cGMP-mediated events underlying chronic head pain that could be the target of a new therapeutic approach which should be investigated.
Cephalalgia 2003 Apr
PMID:Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid. 1266 82

Patients with cervical facet lesions and facet joint injury sometimes experience diffuse neck pain, headache, and arm and shoulder pain. However, the pathophysiology of the intensity and expansion of facet joint pain has not yet been investigated. Retrograde transport of fluoro-gold (F-G) and immunohistochemistry of calcitonin gene-related peptide (CGRP) was used in 20 rats (control group, n=10; injured group, n=10). For the injured group, the whole facet capsule was incised. Of the total F-G labelled dorsal root ganglion (DRG) neurons innervating the C5/6 facet joint, the number and the cross-sectional area of cell profiles of F-G labelled CGRP-ir neurons were evaluated in the bilateral DRGs of both groups. The numbers of CGRP-ir F-G labelled DRG neurons as a percentage of all F-G labelled DRG neurons at C3, C4, C5, C6, C7, C8, T1, T2, and T3 respectively were 30, 22, 43, 47, 21, 19, 25, 36 and 30% in the control group, and 13, 15, 23, 17, 15, 8, 16, 28 and 35% in the injured group, with the injured group showing a significantly lower percentage of CGRP-ir F-G labelled neurons than the control group at C5 and C6 (P<0.05). However, the mean cross-sectional area of F-G labelled CGRP-ir cells from C3 to C8 DRGs increased from 625+/-22 micro m(2) to 878+/-33 micro m(2) in the injured group (P<0.001). Associated with the injured facet joints, the phenotypic switch to large neurons may complicate the mechanism of injured facet pain.
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PMID:Calcitonin gene-related peptide immunoreactive DRG neurons innervating the cervical facet joints show phenotypic switch in cervical facet injury in rats. 1270 60


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