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Paul L Durham

Publications and source records attributed to Paul L Durham.

15 recordsLinked to original sources
PubMed2006

An otolaryngology, neurology, allergy, and primary care consensus on diagnosis and treatment of sinus headache.

While "sinus" headache is a widely accepted clinical diagnosis, many medical specialists consider it to be an uncommon cause of recurrent headaches. Unnecessary diagnostic studies, surgical interventions, and medical treatments are often the result of the inappropriate diagnosis of sinus headache. Both the International Headache Society and the American Academy of Otolaryngology-Head and Neck Surgery have attempted to characterize conditions leading to headaches of rhinogenic origin. However, they have done so from different perspectives and in isolation from the other specialty groups. An interdisciplinary ad hoc committee recently convened to discuss the role of sinus disease and the nose in the etiology of headache and to review recent epidemiologic studies suggesting that sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. Clinical trial data are presented which clearly indicate that the majority of sinus headaches can actually be classified as migraines. This committee reviewed scientific evidence available from multiple disciplines and concludes that considerable research and clinical study are needed to further understand and explain the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, there was a consensus from this group that greater diagnostic and therapeutic attention needs to be given to patients complaining of sinus headache that may indeed be due to the nose.

Diagnosis, Differential↗
PubMed2006

Duplicate publication.

Explore the source record for details and available documents.

Consensus Statements as Topic↗
PubMed2006

Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons.

Calcitonin gene-related peptide (CGRP) and nitric oxide are involved in the underlying pathophysiology of migraine and other diseases involving neurogenic inflammation. We have tested the hypothesis that nitric oxide might trigger signaling mechanisms within the trigeminal ganglia neurons that would coordinately stimulate CGRP synthesis and release. Treatment of primary trigeminal ganglia cultures with nitric oxide donors caused a greater than four-fold increase in CGRP release compared with unstimulated cultures. Similarly, CGRP promoter activity was also stimulated by nitric oxide donors and overexpression of inducible nitric oxide synthase (iNOS). Cotreatment with the antimigraine drug sumatriptan greatly repressed nitric oxide stimulation of CGRP promoter activity and secretion. Somewhat surprisingly, the mechanisms of nitric oxide stimulation of CGRP secretion did not require cGMP or PI3-kinase signaling pathways, but rather, nitric oxide action required extracellular calcium and likely involves T-type calcium channels. Furthermore, nitric oxide was shown to increase expression of the active forms of the mitogen-activated protein kinases Jun amino-terminal kinase and p38 but not extracellular signal-related kinase in trigeminal neurons. In summary, our results provide new insight into the cellular mechanisms by which nitric oxide induces CGRP synthesis and secretion from trigeminal neurons.

Animals↗
PubMed2006

Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients.

BACKGROUND: Secretion of calcitonin gene-related peptide (CGRP) from trigeminal nerves and vasoactive intestinal peptide (VIP) from parasympathetic nerves is involved in the pathophysiology of migraine and rhinosinusitis. Analysis of these neuropeptides in human saliva samples can be used as markers of trigeminal and parasympathetic nerve activity in patients between and during attacks as well as in response to specific treatments. OBJECTIVE: To compare the amount of trigeminal sensory and parasympathetic nerve activation by measuring CGRP and VIP levels in the saliva of subjects experiencing noninfectious allergic rhinosinusitis, migraine with sinus symptoms, and no symptoms. METHODS: Subjects were enrolled in three groups. Group A: subjects without a history of migraine, "sinus" headache, or allergic rhinosinusitis within the previous 6 months. Group B: subjects with chronic recurrent noninfectious rhinosinusitis and no history of migraine or "sinus" headache. Group C: subjects with self-described "sinus" headaches whose symptoms met International Headache Society diagnostic criteria (1.1 or 1.2) for migraine. The total amount of CGRP and VIP present in saliva collected under normal, pathological, and therapeutic conditions was determined by radioimmunoassay. Neuropeptide levels were normalized to total volume and amount of protein, and levels were correlated to onset and change in clinical symptoms. RESULTS: Total volume, total protein, and CGRP and VIP levels did not significantly change in saliva collected on consecutive days in the clinic and at the subject's home, respectively. No appreciable change in baseline salivary levels of CGRP and VIP was detected in control subjects. However, baseline salivary levels of CGRP and VIP were significantly elevated between attacks in allergic rhinosinusitis and migraine subjects compared to control values. For rhinosinusitis subjects, the amount of CGRP and VIP during attacks returned to baseline values following treatment with pseudoephedrine and relief of symptoms. Similarly, CGRP and VIP levels during a migraine headache were significantly reduced within 2 hours after sumatriptan treatment and reported symptom relief. CONCLUSION: Correlation of CGRP and VIP saliva levels observed in our study supports physiologically coordinated regulation of trigeminal and parasympathetic nerve activation in allergic rhinosinusitis and migraine patients between and during attacks as well as following treatment. Furthermore, our findings demonstrate that analysis of human saliva neuropeptides may provide a semiquantitative index of pathological and therapeutic states and, therefore, function as a clinical model for studying neuronal mechanisms involved in migraine and rhinosinusitis.

Adolescent↗
PubMed2006

Calcitonin gene-related peptide (CGRP) and migraine.

The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. While clinical findings are consistent with such a role, the specific pathogenic mechanisms of CGRP in migraine have remained speculative until recently. Through advances in molecular neuroscience, the pathogenic mechanisms of CGRP in migraine have begun to be elucidated. This paper discusses the hypothesized role of CGRP in migraine and reviews recent findings on the molecular mechanisms of this neuropeptide in migraine pathophysiology. Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan.

Animals↗
PubMed2006

Repression of stimulated calcitonin gene-related peptide secretion by topiramate.

OBJECTIVE: The goal of the proposed research was to determine the effect of topiramate on basal and stimulated release of calcitonin gene-related peptide (CGRP) from trigeminal ganglia neurons. BACKGROUND: CGRP is implicated in migraine headaches. Clinical evidence supports topiramate as an effective migraine prophylactic. In this study, the connection between topiramate and CGRP expression was investigated. METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine the effects of topiramate on CGRP release stimulated by a depolarizing stimulus (KCl), nitric oxide, and/or protons. The amount of CGRP secreted into the culture media was determined using a CGRP-specific radioimmunoassay. RESULTS: Treatment of trigeminal cultures with KCl, nitric oxide donor S-nitroso-N-acetylpenicillamine, or protons (pH 5.5 media) caused a marked increase (3 to 5 fold) in the amount of CGRP release. Topiramate treatment repressed KCl-stimulated CGRP release in a time- and concentration-dependent manner. However, topiramate did not alter the amount of unstimulated or basal CGRP released from trigeminal neurons. In addition, topiramate inhibited nitric oxide and proton mediated CGRP secretion. CONCLUSIONS: Findings from these studies demonstrate that topiramate can directly repress the stimulated release of CGRP from sensory trigeminal neurons. We propose that topiramate's ability to prevent migraine attacks may involve inhibition of CGRP secretion from trigeminal neurons.

Animals↗
PubMed2005

Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons.

Expression of the neuropeptide calcitonin gene-related peptide (CGRP) in trigeminal ganglion is implicated in neurovascular headaches and temporomandibular joint disorders. Elevation of cytokines contributes to the pathology of these diseases. However, a connection between cytokines and CGRP gene expression in trigeminal ganglion nerves has not been established. We have focused on the effects of the cytokine tumor necrosis factor-alpha (TNF-alpha). TNFR1 receptors were found on the majority of CGRP-containing rat trigeminal ganglion neurons. Treatment of cultures with TNF-alpha stimulated CGRP secretion. In addition, the intracellular signaling intermediate from the TNFR1 receptor, ceramide, caused a similar increase in CGRP release. TNF-alpha caused a coordinate increase in CGRP promoter activity. TNF-alpha treatment activated the transcription factor NF-kappaB, as well as the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways. The importance of TNF-alpha induction of MAP kinase pathways was demonstrated by inhibiting MAP kinases with pharmacological reagents and gene transfer with an adenoviral vector encoding MAP kinase phosphatase-1 (MKP-1). We propose that selective and regulated inhibition of MAP kinases in trigeminal neurons may be therapeutically beneficial for inflammatory disorders involving elevated CGRP levels.

Alzheimer Disease↗
PubMed2005

Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment.

Sinus headache is a widely accepted clinical diagnosis, although many medical specialists consider it an uncommon cause of recurrent headaches. The inappropriate diagnosis of sinus headache can lead to unnecessary diagnostic studies, surgical interventions, and medical treatments. Both the International Headache Society and the American Academy of Otolaryngology-Head and Neck Surgery have attempted to define conditions that lead to headaches of rhinogenic origin but have done so from different perspectives and in isolation of each other. An interdisciplinary ad hoc committee convened to discuss the role of sinus disease as a cause of headache and to review recent epidemiological studies that suggest sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. This committee reviewed available scientific evidence from multiple disciplines and concluded that considerable research and clinical study are required to further understand and delineate the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, this group agreed that greater diagnostic and therapeutic attention needs to be given to patients with sinus headaches.

Adult↗
PubMed2004

Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons.

We have examined the regulation of calcitonin gene-related peptide (CGRP) promoter activity in primary cultures of rat trigeminal ganglia neurons. A viral vector was used to circumvent the potential complication of examining only a small subpopulation of cells in the heterogeneous cultures. Infection with high titers of recombinant adenovirus containing 1.25 kb of the rat CGRP promoter linked to the beta-galactosidase reporter gene (AdCGRP-lacZ) yielded expression in about 50% of the CGRP-expressing neurons. The CGRP-lacZ reporter gene was preferentially expressed in neurons, with 91% co-expression with endogenous CGRP. In contrast, an adenoviral vector containing a CMV-lacZ reporter was predominantly expressed in non-neuronal cells, with only 29% co-expression with CGRP. We then asked whether the CGRP promoter in the viral vector could be regulated by serotonin receptor type 1 (5-HT(1)) agonists. Promoter activity was decreased two- to threefold by treatment with five 5-HT(1B/D) agonists, including the triptan drugs sumatriptan, eletriptan, and rizatriptan that are used for migraine treatment. As controls, CMV promoter activity was not affected, and 5-HT(1B/D) receptor antagonists blocked the repression caused by sumatriptan and eletriptan. Thus, adenoviral gene transfer can be used in trigeminal ganglia neurons for studying the mechanisms of triptan drug action on CGRP synthesis.

Adenoviridae↗
PubMed2004

Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy.

OBJECTIVES: To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. BACKGROUND: The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. RESULTS: A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. CONCLUSIONS: These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.

Animals↗
PubMed2004

CGRP receptor antagonists: a new choice for acute treatment of migraine?

The neuropeptide calcitonin gene-related peptide (CGRP) is believed to play a central role in the underlying pathology of migraine. Serum levels of CGRP, elevated during a migraine attack, return to normal as pain alleviates. Recently, a causative role for CGRP in migraine has been suggested. Based on these findings, it was proposed that blockade of postsynaptic CGRP receptors, and hence the physiological effects of CGRP, should effectively abort a migraine attack. This review will discuss the therapeutic potential of olcegepant, the first non-peptide CGRP receptor antagonist available for human studies, within the context of current neurovascular theories on migraine pathology.

Calcitonin Gene-Related Peptide↗
PubMed2003

Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons.

Calcitonin gene-related peptide (CGRP) is involved in the underlying pathophysiology of all vascular headaches, including migraines. Elevated levels of CGRP during migraine are restored to normal coincident with headache relief after treatment with the antimigraine drug sumatriptan. We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter. Using reporter genes in transient transfection assays, we demonstrate that an 18 bp enhancer containing a helix-loop-helix element is both necessary and sufficient for full promoter activity. NGF treatment and cotransfection with an upstream activator of the extracellular signal-regulated MAP kinases (MAPKs) activated the enhancer. Treatment with sumatriptan repressed NGF- and MAPK-stimulated CGRP promoter activity. Repression was also observed using a synthetic MAPK-responsive reporter gene. Sumatriptan regulation of CGRP gene expression did not couple to a G(i)/G(o) pathway, but rather caused a prolonged increase in intracellular calcium. The importance of the prolonged calcium signal in repression of MAPK activity was demonstrated by using the ionophore ionomycin to mimic sumatriptan action. We propose that activation of MAPK pathways may increase CGRP gene expression during migraine, and that sumatriptan can diametrically oppose that activation via a prolonged elevation of intracellular calcium.

Animals↗
PubMed2002

NCS-1 inhibits insulin-stimulated GLUT4 translocation in 3T3L1 adipocytes through a phosphatidylinositol 4-kinase-dependent pathway.

Expression of NCS-1 (neuronal calcium sensor-1, also termed frequenin) in 3T3L1 adipocytes strongly inhibited insulin-stimulated translocation of GLUT4 and insulin-responsive aminopeptidase. The effect of NCS-1 was specific for GLUT4 and the insulin-responsive aminopeptidase translocation as there was no effect on the trafficking of the cation-independent mannose 6-phosphate receptor or the GLUT1 glucose transporter isoform. Moreover, NCS-1 showed partial colocalization with GLUT4-EGFP in the perinuclear region. The inhibitory action of NCS-1 was independent of calcium sequestration since neither treatment with ionomycin nor endothelin-1, both of which elevated the intracellular calcium concentration, restored insulin-stimulated GLUT4 translocation. Furthermore, NCS-1 did not alter the insulin-stimulated protein kinase B (PKB/Akt) phosphorylation or the recruitment of Cbl to the plasma membrane. In contrast, expression of the NCS-1 effector phosphatidylinositol 4-kinase (PI 4-kinase) inhibited insulin-stimulated GLUT4 translocation, whereas co-transfection with an inactive PI 4-kinase mutant prevented the NCS-1-induced inhibition. These data demonstrate that PI 4-kinase functions to negatively regulate GLUT4 translocation through its interaction with NCS-1.

1-Phosphatidylinositol 4-Kinase↗
PubMedDate not supplied

New insights into the molecular actions of serotonergic antimigraine drugs.

Migraine is a painful and debilitating neurological disorder that affects approximately 10% of the adult population in Western countries. Sensitization and activation of the trigeminal ganglia nerves that innervate the meningeal blood vessels is believed to play an important role in the initiation and maintenance of migraine pain. In this capacity, release of the neuropeptide calcitonin gene-related peptide (CGRP) and the resultant neurogenic inflammation is thought to underlie the pathophysiology of migraine. Largely due to the success of the serotonin Type 1 migraine drugs such as sumatriptan, migraine pathology and therapy has become a focus of intensive clinical and physiological research during the past decade. The effectiveness of these drugs is thought to be due to their ability to block the stimulated secretion of neuropeptides from trigeminal nerves to break the vicious nociceptive cycle of migraine. A component of this nociceptive cycle involves activation of mitogen-activated protein kinase signaling pathways. Indeed, activation of mitogen-activated protein kinase pathways can increase CGRP neuropeptide synthesis and secretion. Recently, the serotonin Type 1 agonists have been shown to cause a prolonged increase in intracellular Ca(2+) in trigeminal ganglia neurons and an increased phosphatase activity that can repress stimulated CGRP secretion and transcription. Identification of molecular signaling events in migraine pathology and therapy has provided new insight into the pharmacology and signaling mechanisms of sumatriptan and related drugs, and may provide the foundation for development of novel treatments for migraine.

Calcitonin Gene-Related Peptide↗