Biomedical subjects

Dan Levy

Publications and source records attributed to Dan Levy.

14 recordsLinked to original sources

PubMed2006

Mast cell involvement in the pathophysiology of migraine headache: A hypothesis.

Migraine attacks are triggered by a variety of conditions including endogenous and exogenous factors. Evidence suggests that activation and sensitization of primary afferent meningeal nociceptive neurons, the peripheral arm of the trigeminovascular system, constitutes one of the earliest events promoting the intracranial pain of migraine. However, the link between the varied triggering factors and activation of meningeal nociceptive neurons is not completely understood. Local inflammation with release of mediators from local immune/inflammatory cells is thought to play a critical role in such neuronal response. Meningeal mast cells may play such a role by virtue of their proximity both to meningeal blood vessels and nociceptive axons and their ability to release a host of proinflammatory/algesic mediators. This paper reviews data relevant to the hypothesis that mast cells, upon activation by migraine triggers, contribute to the genesis of migraine headache. Epidemiologic findings, clinical data, and observations on anatomical and physiological characteristics of mast cells converge to suggest an important role of these immune cells in the pathogenesis of migraine. Migraine triggers might directly or indirectly promote mediator secretion from meningeal mast cells, and thereby cause inflammation and activation of the trigeminovascular system. While consistent, the evidence supporting mast cell involvement in the genesis of migraine is largely circumstantial to date. Further studies are needed to test directly the nature of mast cell involvement in the pathogenesis of migraine headache.

Humans↗

PubMed2006

Response properties of dural nociceptors in relation to headache.

Single-unit electrophysiological recording studies have examined the activity of sensory neurons in the trigeminal ganglion that innervate the intracranial meninges to better understand their possible role in headache. A key question is whether the meningeal sensory neurons are similar to nociceptive neurons in other tissues or, alternatively, whether they have unique properties that might be of significance for headache pathogenesis and drug therapy. Such studies have indeed found that the intracranial dura is innervated by neurons that exhibit properties characteristic of nociceptors in other tissues, including chemosensitivity and sensitization. This sensitization, consisting of an enhanced responsiveness to mechanical stimuli, might be relevant to symptoms that are characteristic of certain headaches that indicate the presence of an exaggerated intracranial mechanosensitivity. Studies that examined whether the anti-migraine agent sumatriptan might inhibit this sensitization (in addition to its well-known inhibition of neurotransmitter release) found that it had no inhibitory effect but rather produced a calcium-dependent discharge, which might account for the initial worsening of headache that can follow sumatriptan administration. In studies that examined the effects of vasodilator agents, nitroprusside produced mixed effects on mechanosensitivity, whereas calciton gene-related peptide (CGRP) had no effect on either spontaneous or mechanically evoked discharge. These results call into question the role of vasodilation in headache and suggest that the role of CGRP in headache may be through its action as a central neurotransmitter rather than through vasodilation and activation of meningeal nociceptors. In general, studies of meningeal sensory neurons have not found evidence of unique properties that distinguish them from nociceptive neurons in other tissues. Ultimately the distinctive clinical characteristics of headache may prove to be related not so much to any differences in the intrinsic molecular or cellular properties of the meningeal sensory neurons but rather to the distinctive properties of the tissue that they innervate.

Animals↗

PubMed2005

Beyond pairwise distances: neighbor-joining with phylogenetic diversity estimates.

The "neighbor-joining algorithm" is a recursive procedure for reconstructing trees that is based on a transformation of pairwise distances between leaves. We present a generalization of the neighbor-joining transformation, which uses estimates of phylogenetic diversity rather than pairwise distances in the tree. This leads to an improved neighbor-joining algorithm whose total running time is still polynomial in the number of taxa. On simulated data, the method outperforms other distance-based methods. We have implemented neighbor-joining for subtree weights in a program called MJOIN which is freely available under the Gnu Public License at http://bio.math.berkeley.edu/mjoin/.

Algorithms↗

PubMed2005

Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine.

Migraine is among the most common types of pain, but its mechanisms are poorly understood. A growing body of evidence points to a critical role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine headache. During migraine, CGRP is thought to be released from peripheral endings of perivascular meningeal nociceptors primary and to promote vasodilatation. A current hypothesis suggests that peripheral CGRP and its related meningeal vasodilatation results in activation and sensitization, leading to the generation of migraine headache. However, direct evidence supporting this idea is lacking. Here, using electrophysiological, extracellular, single-unit recording combined with laser-Doppler flowmetry measurements of dural blood flow (DBF), we examined whether CGRP and meningeal vasodilatation promote activation or sensitization of meningeal nociceptors. Changes in (DBF), ongoing discharge, and responsiveness to mechanical stimulation of the dura were studied after either topical administration or intravenous infusion of rat alpha-CGRP in anesthetized rats. Both topical and systemic administration of CGRP caused a significant increase in dural blood flow; however, neither method of CGRP administration resulted in activation or sensitization of meningeal nociceptors. The results of this study suggest that CGRP effects in the meninges, including meningeal vasodilatation, are not sufficient to activate or sensitize meningeal nociceptors.

Action Potentials↗

PubMed2005

Anti-migraine action of triptans is preceded by transient aggravation of headache caused by activation of meningeal nociceptors.

Consistent with previous accounts, some of the patients visiting our pain clinic during the course of a migraine attack have indicated-without solicitation-that sumatriptan injection initially intensified their headache before they were able to appreciate any pain relief. In this study, those patients who came forward complaining about pain exacerbation were asked to rate their headache intensity every 5 min. Within 5-15 min of sumatriptan injection, 17 of the 31 patients studied (55%) reported that their migraine pain intensified for 10-15 min before they started to notice any pain relief. Similar pattern of pain exacerbation was also observed in migraine attacks treated with oral formulation of almotriptan, eletriptan, rizatriptan, and zolmitriptan. To investigate the possible mechanism underlying this transient exacerbation of pain, we examined whether intravenous administration of sumatriptan can alter the response properties of C- and Adelta-meningeal nociceptors in the rat. Five to twenty minutes after intravenous administration of 300 microg/kg sumatriptan, 8/10 C-units and 2/8 Adelta-units increased their firing rate, and 6/10 C-units and 7/8 Adelta-units developed mechanical hyper-responsiveness to dural indentation. The minimal effective dose for activation and sensitization of meningeal nociceptors by sumatriptan was 3 microg/kg, suggesting that relatively low levels of triptans entering the circulation shortly after their administration can alter the physiological properties of meningeal nociceptors and produce a transient exacerbation of headache.

Action Potentials↗

PubMed2004

The anti-migraine agent sumatriptan induces a calcium-dependent discharge in meningeal sensory neurons.

The anti-migraine agent sumatriptan constricts cerebral blood vessels, and also blocks neuropeptide release from meningeal sensory neurons. We investigated whether sumatriptan can also affect neuronal discharge, by recording the activity of dural primary afferent neurons during dural application of sumatriptan in anesthetized rats. Sumatriptan (0.24-24 microM) induced a concentration-dependent increase in ongoing discharge. The discharge occurred only in the presence of calcium. The suppressive effect of calcium removal was not a result of a general decrease in excitability, because calcium removal produced a pronounced increase in mechanically evoked discharge. The excitatory effect on dural afferent discharge might underlie the initial worsening of the headache that can occur following sumatriptan administration, prior to the subsequent onset of headache relief.

Animals↗

PubMed2004

Axon diameters and intradural trajectories of the dural innervation in the rat.

Neurophysiological studies have characterized the sensory responses of primary afferent nociceptors that innervate the intracranial dura. The present study used anatomical methods to examine in greater detail the axonal trajectories within the dura, as well as the axonal size distribution of the dural innervation. Immunostaining for CGRP in dural wholemounts revealed a network of fibers extending across the entire dura, with an especially dense plexus running along the borders of the transverse and superior sagittal sinuses. The plexus along the caudal border of the transverse sinus partially overlapped the dural area that shows the greatest density of mast cells. Visualization of axon bundles by DiI application in formalin-fixed tissue revealed two separate systems of fibers in the dura that could be distinguished by the orientation of their trajectories: one that runs parallel to the middle meningeal artery (MMA), and another with a more or less orthogonal orientation that runs rostromedially from the transverse sinus across the MMA. Axons traversed large distances across the dura, but the majority of the branching and arborization was usually concentrated in the distal part of the trajectory. In separate animals, measurement of myelinated axon diameters with electron microscopy showed that approximately one-third of the myelinated axons in the nerves supplying the dura (nervus spinosus and tentorial nerves) could be classified as A-beta, since they were comparable in size to the majority of axons in the trochlear nerve and the upper end of the size range in the trigeminal nerve (i.e., > 5 microm).

Animals↗

PubMed2004

Modulation of dural nociceptor mechanosensitivity by the nitric oxide-cyclic GMP signaling cascade.

The role of the nitric oxide (NO)-cGMP signaling cascade in modulation of peripheral nociception is controversial. Although behavioral studies have suggested both pro- and anti-nociceptive effects, little is known about the direct action of this signaling cascade on primary afferent nociceptive neurons that mediate these behaviors. Here, using single-unit recordings, we examined the direct effect of NO-cGMP signaling on spontaneous activity and mechanical responses of nociceptive afferents that innervate the dura mater. We found that the NO donor sodium nitroprusside (SNP), when applied topically to the neuronal receptive field, induced both sensitization and inhibition of the mechanical responses, albeit in different populations of neurons, which could be distinguished based on their baseline mechanical thresholds. SNP, however, did not change the level of spontaneous activity. Administration of the cGMP analogue 8-pCPT-cGMP mimicked only the inhibitory effect. When SNP was co-applied with either an inhibitor of guanylyl cyclase or a cGMP blocker, sensitization never occurred, and the inhibitory effect of SNP could also be blocked. Our findings suggest that NO can either increase or decrease the mechanical responsiveness of nociceptors and that its action might depend, in part, on the baseline level of neuronal excitability. Our results also implicate cGMP in mediating the inhibitory effect of NO.

Animals↗

PubMed2004

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists.

Triptans are 5HT(1B/1D) receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT(1B/1D) receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.

Animals↗

PubMed2004

Comparing DNA damage-processing pathways by computer analysis of chromosome painting data.

Chromosome aberrations are large-scale illegitimate rearrangements of the genome. They are indicative of DNA damage and informative about damage processing pathways. Despite extensive investigations over many years, the mechanisms underlying aberration formation remain controversial. New experimental assays such as multiplex fluorescent in situ hybridyzation (mFISH) allow combinatorial "painting" of chromosomes and are promising for elucidating aberration formation mechanisms. Recently observed mFISH aberration patterns are so complex that computer and graph-theoretical methods are needed for their full analysis. An important part of the analysis is decomposing a chromosome rearrangement process into "cycles." A cycle of order n, characterized formally by the cyclic graph with 2n vertices, indicates that n chromatin breaks take part in a single irreducible reaction. We here describe algorithms for computing cycle structures from experimentally observed or computer-simulated mFISH aberration patterns. We show that analyzing cycles quantitatively can distinguish between different aberration formation mechanisms. In particular, we show that homology-based mechanisms do not generate the large number of complex aberrations, involving higher-order cycles, observed in irradiated human lymphocytes.

Algorithms↗

PubMed2004

NO pain: potential roles of nitric oxide in neuropathic pain.

The disabling human syndrome of "neuropathic pain" is an intractable complication of peripheral nerve injury or degeneration. A complex interaction between injured peripheral axons, sensory neurons and central nervous system signaling is thought to account for it. In this brief review, we present evidence that the free radical signaling molecule, nitric oxide (NO) may act at several levels of the nervous system during the development of experimental neuropathic pain. For example, NO may directly influence injured axons in the periphery, may indirectly influence pain by its role in the process of Wallerian degeneration, and may signal in the dorsal horn of the spinal cord. While it is premature to argue for therapeutic approaches that alter NO actions, it may be an important player in the cascade of events that generate neuropathic pain.

Journal Article↗

PubMed2002

Mechanical response properties of A and C primary afferent neurons innervating the rat intracranial dura.

The intracranial dura receives a small-fiber sensory innervation from the trigeminal ganglion that is thought to be involved in some types of headaches, including migraine. Mechanical response properties of dural afferent neurons were examined to investigate variation across the population in the properties of threshold, slope, adaptation, and incidence of mechanosensitivity. Dural afferent neurons were recorded in the trigeminal ganglion of urethan-anesthetized rats and were identified by their constant-latency response to dural shock. Neurons were classified as fast A (>5 m/s), slow A (5 >or= conduction velocity (CV) >or= 1.5 m/s), or C (<1.5 m/s), based on response latency to dural shock. Mechanical receptive fields were identified by stroking or indenting the outer surface of the dura. Stimulus-response curves were obtained from responses to 2-s constant-force indenting stimuli of graded intensities delivered to the dural receptive field with a servo force-controlled mechanical stimulator. The slow A population had the highest percentage of mechanosensitive units (97%) as well as the highest slopes and the lowest thresholds. Thus by all three criteria, the slow As had the highest mechanosensitivity. Conversely, the fast A population had the lowest mechanosensitivity in that it had the lowest percentage of mechanosensitive units (66%), the lowest slopes, and the highest thresholds. The C population was intermediate with respect to all three properties but was much more similar to the slow As than to the fast As. All three fiber classes showed a negative correlation between slope and threshold. The majority of neurons showed a slowly adapting response to a maintained 2-s stimulus. Adapting neurons could be subdivided based on whether the fitted exponential curve decayed to zero or to a nonzero plateau; the latter group contained the most sensitive neurons in that they had the lowest thresholds and highest slopes. Nonadapting neurons generally had lower initial firing rates than adapting neurons. Fast A neurons exhibited greater and more rapid adaptation than slow A and C neurons. Neurons with the lowest slopes, regardless of CV, had relatively rapid adaptation. The more slowly conducting portion of the C population was distinguished from the other C neurons by a number of properties: more mechanically insensitive neurons, higher thresholds, and more nonadapting neurons. These differences in mechanical response properties may be related in part to differences in membrane currents involved in impulse generation that have been described in subpopulations of dorsal root ganglion cells.

Adaptation, Physiological↗

PubMed2000

Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain.

We examined the role of B1 and B2 bradykinin receptors in promoting neuropathic hypersensitivity following peripheral nerve injury. Forty eight-hours following chronic constriction injury to a rat sciatic nerve there was an increased expression of B2 receptor mRNA in the lumbar dorsal root ganglia ipsilateral to the site of nerve injury. At 14 days following surgery there was also an ipsilateral increase of B1 receptor mRNA as well as a contralateral increased expression of B2 receptor mRNA. Increased expression of both receptors also coincided with analgesic effects of their antagonists. While HOE-140, a potent B2 receptor antagonist was analgesic at both time points tested, the B1 receptor antagonist des-Arg(9), [Leu(8)]-BK had an analgesic effect only at 14 days. The results support the concept that peripheral nerve injury is associated with local inflammation and that bradykinin, acting on both of its receptors promotes pain hypersensitivity.

Animals↗

PubMedDate not supplied

Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors.

OBJECTIVE: To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in the rat. BACKGROUND: The majority of migraineurs seeking secondary or tertiary medical care develop cutaneous allodynia during the course of migraine, a sensory abnormality mediated by sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus. Triptan therapy can render allodynic migraineurs pain free within a narrow window of time (20 to 120 minutes) that opens with the onset of pain and closes with the establishment of central sensitization. Can drugs that tackle ongoing central sensitization render allodynic migraineurs pain free after the window for triptan therapy has expired? METHODS: Patients exhibiting migraine with allodynia were divided in two groups (n=14, each): group 1 received delayed sumatriptan injection (6 mg) 4 hours after onset of attack--which failed to render them pain free-and ketorolac infusion (two 15-mg boluses) 2 hours later; group 2 received delayed ketorolac monotherapy 4 hours after onset of attack. Pain intensity (visual analog scale) and skin sensitivity (quantitative sensory testing) were measured when the patients were migraine free (baseline); 4 hours after onset of migraine (just before treatment); 2 hours after sumatriptan; 1 hour after ketorolac. In the rat, we tested whether infusion of ketorolac (0.4 mg/kg) or indomethacin (1 mg/kg) will block ongoing sensitization in peripheral and central trigeminovascular neurons. The induction of sensitization (using topical application of inflammatory soup on the dura) and its suppression by COX1/COX2 inhibitors were assessed by monitoring changes in spontaneous activity and responses to mechanical and thermal stimuli. RESULTS: Patients had normal skin sensitivity in the absence of migraine, and presented cutaneous allodynia 4 hours after onset of migraine. In group 1, all patients continued to exhibit allodynia 2 hours after sumatriptan treatment, and none of them became pain free. However, 71% and 64% of the patients in groups 1 and 2, respectively, were rendered free of pain and allodynia within 60 minutes of ketorolac infusion. Nonresponders from both groups, in contrast to the responders, had had a history of opioid treatment. In the rat, infusion of COX1/COX2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons. This inhibitory action was reflected by normalization of neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin. CONCLUSIONS: The termination of migraine with ongoing allodynia using COX1/COX2 inhibitors is achieved through the suppression of central sensitization. Although parenteral administration of COX1/COX2 inhibitors is impractical as routine migraine therapy, it should be the rescue therapy of choice for patients seeking emergency care for migraine. These patients should never be treated with opioids, particularly if they had no prior opioid exposure.

Adolescent↗