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Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany
Submitted 15 December 2003; accepted in final form 24 April 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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-nitro-L-arginine methyl ester (20 mg/kg), reduced the spontaneous activity in all neurons within 15 min. The results suggest that NO can induce delayed, slowly developing activation of central trigeminal neurons and that endogenous release of NO may contribute to the ongoing activity of these neurons. The delayed changes in neuronal activity may include gene expression of pro-nociceptive mediators. These mechanisms may be relevant for the pathogenesis of chronic headaches. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). Intravenous infusion of GTN can immediately induce headache both in healthy subjects and patients suffering from primary headaches (Dalsgaard-Nielsen 1955; Iversen et al. 1989; Olesen et al. 1993). This early headache has been described to be of mild to moderate intensity in healthy persons, whereas patients suffering from migraine and tension-type headaches respond with significantly higher pain scores (Olesen et al. 1993). Moreover, in migraine patients, this early headache is followed by a second headache phase that occurs several hours after the infusion of GTN and frequently fulfills the criteria of a genuine migraine attack (Thomsen et al. 1994). Similarly, in patients suffering from cluster headache, headaches resembling cluster attacks have been provoked within 1 h of sublingual administration of GTN (Ekbom 1968). Olesen and colleagues proposed therefore that NO derived from GTN is not only a key molecule in these experimental headaches but, as an endogenous signal substance, may play a causative role in migraine and other vascular headaches (Olesen et al. 1994). It was further proposed that inhibitors of NO synthesis or NO scavengers may be effective in the acute treatment of migraine because the infusion of a NO synthase inhibitor was able to relieve ongoing migraine attacks (Lassen et al. 1997, 1998) and to reduce the severity of chronic tension-type headaches (Ashina et al. 1999). Although NO concentrations cannot be directly measured due to the extremely short half-life of this molecule, there is clear evidence for an increase in NO production in different types of chronic headaches. Increased concentrations of nitrites and nitrates, products of the NO metabolism, have been found in blood samples taken from the internal jugular vein of migraineurs during their attacks (Sarchielli et al. 2000; Shimomura et al. 1999). Recent studies have also shown increased concentrations of nitrites in blood plasma of migraineurs with and without aura as well as cluster headache patients even between attacks (D'Amico et al. 2002). Similarly, the cerebrospinal fluid of patients suffering from chronic daily headache has recently been found to contain elevated concentrations of nitrites (Gallai et al. 2003). Thus it seems that increased NO concentrations are typical if not causative for the development of primary headaches.
The mechanisms underlying the induction of delayed headache after GTN infusion or endogenous increases in NO turnover are not yet sufficiently determined. Early experimental studies in animals indicated that gene expression in the trigeminal system may be involved. Systemic infusion of large doses of GTN have been shown to provoke c-fos expression, a marker for predominantly nociceptive input, in the caudal trigeminal nucleus of the rat (Pardutz et al. 2000; Tassorelli and Joseph 1995a,b). This response was reduced by pretreatment with the nonspecific NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (Tassorelli et al. 1997). Using an electrophysiological approach in the rat, infusion of GTN has been shown to reduce the activation threshold of trigeminal neurons and to potentiate responses to electrical stimulation of facial areas and the cranial dura mater (Jones et al. 2001). In the same study, GTN alone did not change c-fos expression but was able to augment c-fos expression provoked by intradermal injection of capsaicin in the periorbital area (Jones et al. 2001). Conversely, in a recent study in the rat, we have shown that infusion of the NO synthase inhibitor L-NAME is able to reduce the spontaneous activity of neurons in the caudal trigeminal nucleus that receive sensory input from the cranial dura mater (De Col et al. 2003).
In the present work, we examined the effects of both intravenous and local (intrathecal) application of the NO-donor sodium nitroprusside (SNP) on the spontaneous activity of neurons in the caudal trigeminal nucleus with afferent input from the cranial dura mater. To simulate ongoing nociceptive input from the meninges, repetitive electrical stimulation of the exposed cranial dura was performed in an additional group of experiments. In a third group, we extended our previous study looking at the effect of infusion of L-NAME.
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METHODS |
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The experiments were performed in accordance with the ethical guidelines of the International Association for the Study of Pain (Zimmermann 1983). The experimental protocol was reviewed by an ethics committee and approved by the local government. Male Wistar rats with body weights ranging from 270 to 440 g were used. Details of the surgical and recording procedures have been described elsewhere (Schepelmann et al. 1999). Briefly, rats were anesthetized with an initial intraperitoneal dose of 120–150 mg/kg thiopental. The femoral artery was cannulated to monitor mean arterial blood pressure, and the femoral vein was cannulated for the administration of drugs. The animals were tracheotomized, paralyzed with intravenous administration of gallamine triethiodide (40 mg/kg), and artificially ventilated with oxygen-enriched room air. Expiratory CO2 was monitored and maintained at 4.5–5%. Body temperature was maintained at 37–37.5°C with a feedback-controlled homoeothermic system (TKM 0902, FMI GmbH). The animals were kept under deep anesthesia throughout the experiment with supplemental doses of thiopental given as required to suppress nociceptive reflexes or blood pressure changes evoked by noxious pinch stimuli of the hindpaw and the earlobe. Vital parameters (blood pressure, heart rate, expiratory CO2 level, and body temperature) were continuously recorded throughout the experiment. To end an experiment, the rat was killed either with a lethal dose of intravenous thiopental or by perfusion of fixative after an additional dose of thiopental.
Head surgery and electrophysiological recordings
The animal was placed in a stereotaxic frame with the head held in a fixed position by ear bars. The skin overlying the skull was opened and the cranium exposed. Using a drill and fine forceps, a cranial window 
6 mm (rostrocaudal) and 4 mm (inferior-superior) was carefully cut into the left parietal bone to expose the dura mater. During surgery and throughout the experiment, the dura was protected from drying with isotonic saline. The neck muscles were divided along the animal's midline, and the medullary brain stem was exposed by cutting a window into the atlanto-occipital ligament and the underlying dura mater. Carbon fiber glass microelectrodes (impedance: 1–6 M
) were inserted into the ipsilateral medulla and advanced or retracted in 2.5-µm steps using a microstepper. Single shock stimuli (0.5-ms pulses, 10–12 V, 0.2 Hz) were delivered to the exposed dura through bipolar electrodes with their rounded tips touching the dural surface. Neurons in the subnucleus caudalis of the spinal trigeminal nucleus (STN) with input from meningeal afferents were identified by their regular discharge in response to electrical stimulation of the dura with a minimal latency that was fairly stable (but varied 
4 ms in neurons with high spontaneous activity) and by their responses to mechanical probing of the dura. The position and size of dural receptive fields were determined with von Frey filaments (5–10 mN), and facial receptive fields indicating convergent afferent input were located with a fine, blunt glass rod (Fig. 2, insets). The extracellular signals were band-passed, amplified, and digitized (sampling rate: 20 kHz) before being recorded to disk using SPIKE software (Forster and Handwerker 1990). The position of each recording site was determined by measuring the distance caudal and lateral to the obex of the electrode and by reading the depth of the microdrive. In some experiments, the recording site was marked by passing positive current through the microelectrode (50 µA for 30 s) to produce a detectable lesion (Fig. 1B). The animals in which such lesions were made were thoracotomized and perfused, through a catheter inserted into the left ventricle, with saline followed by 4% formaldehyde. Cryostat sections (20 µm) were cut from the medulla and Nissl stained to identify the lesion.
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Throughout the experiment, the number of impulses was counted at intervals of 1s. The spontaneous activity of all units was recorded for a control period of 
30 min before application of any substance. After the control period, SNP (50 µg/kg, Sigma) dissolved in 1 ml saline was intravenously infused over a period of 10 min. This dose was calculated to cause a blood plasma concentration of 5 µM (assuming a plasma volume of 3% of the body weight). In previous experiments, local concentrations of 1–10 µM SNP applied onto the cranial dura caused small increases in meningeal blood flow indicating a mild vascular effect, whereas higher concentrations caused significant and long-lasting effects. (Messlinger et al. 2000).
Using the same protocol, control experiments were made with SNP that had been photodegraded for 2 days at room temperature in a test tube (Ikeda et al. 1988). In five other control experiments, the effect of a systemic blood pressure decrease on the neuronal activity was examined. The nonspecific 
-receptor antagonist phentolamine (1 mg/kg iv) was injected over a few minutes at a rate that initially depressed the systemic pressure by 20 mmHg.
In another set of experiments, the cerebrospinal fluid covering the medullary brain stem was replaced by 50 µg/kg SNP, dissolved in 0.2 ml saline, and slowly applied onto the medulla over a period of3 min.
In eight experiments, the dura was repetitively stimulated with electrical pulses (0.5 ms, 5 Hz) at a stimulation strength of two to three times threshold (8–13 V). Beginning one minute after the intravenous administration of SNP, periods of 1-min stimulation were applied at 10-min intervals for the subsequent 2 h.
In a different set of experiments, after a control period of 30 min, a 0.5 ml saline solution containing L-NAME 20 mg/kg (Sigma) was slowly intravenously injected over a period of 60 s. In these experiments, neuronal activity was recorded for a period of 20 min before to 90 min after the L-NAME injection.
Data analysis
Action potential waveforms were analyzed off-line for each neuron using the SPIDI software package (Forster and Handwerker 1990). Spike frequency was normalized to the average rate of activity during the last 10 min of the control period before administration of substances. Averaged activity during each subsequent 10-min interval was statistically compared with the control interval before SNP administration using a t-test for dependent samples. In datasets containing the full observation period in all neurons, ANOVA with repeated measurements, extended by Fisher's least-square different (LSD) test, was used instead of the t-test. To evaluate changes in activity after application of substances in single neurons, 1-min intervals of activity were compared. If the discharge frequency exceeded the mean activity of the control period by >2 SDs, it was considered a short-term effect. Pairwise correlations between location coordinates, latency to electrical stimulation, spontaneous activity and relative changes of activity after treatment with SNP and L-NAME, were calculated. Data are given in mean ± SE if not designated otherwise. All statistical tests were performed using the STATISTICA 6.0 (StatSoft, Tulsa, OK) software package.
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RESULTS |
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A total of 54 units recorded in the left caudal subnucleus of the STN were included in this study. The recording sites were located 0.90/2.16/3.22 mm (min/mean/max) caudal to the obex and 0.50/1.40/2.50 mm lateral from the midline and at a depth of 0.06/0.95/1.55 mm from the dorsal surface of the medulla (Fig. 1A). The measured recording position was confirmed in four experiments by an electrolytic lesion visible in Nissl-stained serial sections (Fig. 1B). The electrical threshold, at which discharges could be evoked by electrical stimulation of the dura mater, was between 1.5 and 6 V. At threshold, the minimal response latency to dural electrical stimulation varied from 6 to 22 ms, indicating afferent input from C and A
fibers. In most units, only one response was elicited by electrical stimulation, even at stimulation intensities of two to three times the threshold intensity. There was a clear correlation between latencies and location of neurons (r = –0.57; P < 0.001). Neurons located more caudal to the obex had a shorter stimulus-response latency. Dural receptive fields were usually spot-like and located close to branches of the middle meningeal artery. Dural von Frey thresholds varied between different units from 4.5 to 56 mN. Most had low mechanical threshold facial receptive fields predominantly in the ophthalmic region as has been found in previous studies (Schepelmann et al. 1999; Yamamura et al. 1999). Two units could only be activated by strong pressure within a small facial area. The rate of mean spontaneous activity between units varied from less than 1 imp/min (minimum) to 3,270 imp/min (maximum), and the mean rate was 243.6 ± 94.4 imp/min. During the control period or within a longer observation time with topical or intravenous injection of saline the activity of units was fluctuating without preference.
Response to intravenous administration of SNP
After a control period of 30 min, intravenous injection of SNP (50 µg/kg) over 10 min produced either an increase or no change (Fig. 2A) in the ongoing activity of 14 neurons. For the whole sample, this increase in activity was significant when the activity was calculated in 10-min periods (repeated-measures ANOVA; Fig. 3A). After a latency of 50 min after SNP administration, the mean rate of spontaneous activity increased significantly (P = 0.05, repeated-measures ANOVA; Fig. 3A), and after 70 min this increase was nearly two times the rate of control activity (Figs. 2A and 3A). Eight single neurons were observed over a period of >2 h. Five of these units showed significant increases in spontaneous activity after SNP infusion (P < 0.05, t-test, 30 min before vs. 120 min after SNP) while no increase was seen in the other units. The relative change in activity was not correlated with the initial spontaneous activity nor was there any correlation of the response to SNP with other physiological properties of the units.
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-receptor antagonist phentolamine (1 mg/kg iv) was slowly injected in another series of five control experiments. Phentolamine caused an initial steep decrease in blood pressure that did not fully recover within two hours (Fig. 4B). Neither the large initial fall in pressure nor the persisting decrease by 5 mmHg on average caused significant changes in neuronal activity (Fig. 4B).
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In a separate sample of eight units, SNP infusion was combined with electrical stimulation applied at 5 Hz for periods of 1 min. The electrical stimuli were added to test whether the effect of delayed activation after SNP is influenced by repetitive peripheral stimulation mimicking an ongoing nociceptive input. An increase in spontaneous activity was registered during a period of 80–110 min after SNP infusion (P < 0.05, t-test with dependent samples; Fig. 3B). The time course of this response did not significantly differ from the pattern observed with SNP infusion alone (2-way ANOVA with repeated measures, comparing subsequent 10-min intervals in both samples).
Response to intrathecal administration of SNP
In a further 11 units, SNP was topically applied onto the medulla (intrathecally). During or within a period of 5 min after SNP application a short-term increase in activity was observed in five units (Fig. 2B). After a latency of 60 min after SNP administration, the mean rate of spontaneous activity increased significantly (10-min intervals, repeated-measure ANOVA), lasting until 100 min after the SNP administration (Fig. 3C). Separate analysis in single neurons revealed that this effect was due to six units with a significant increase in spontaneous activity (P < 0.05, t-test, 1-min intervals within the 30-min interval before vs. 90- to 120-min interval after SNP).
Response to administration of L-NAME
In a separate sample of 12 units, L-NAME (20 mg/kg iv) was injected over a period of 60 s. This treatment caused an elevation of the mean arterial blood pressure within five minutes from 107 ± 0.6 to 127 ± 5.0 mmHg (P < 0.001, n = 5, t-test using 10 1-min intervals; Fig. 5). An initial increase in activity, i.e., exceeding the mean plus two SDs, in the 2-min period immediately after L-NAME administration was seen in 8 of 12 units. This short-term effect was not significant when all neurons were averaged. Four minutes after L-NAME injection, the spontaneous activity decreased (n = 12, P < 0.05 for all minute periods, repeated-measure ANOVA; Fig. 5). This decrease in activity persisted in 12 units for the 17-min observation period after L-NAME injection (Fig. 5). In three units that were observed for 2 h after L-NAME administration, the decreased activity further persisted within this period. In five neurons of this sample, SNP was intravenously applied at different time points after L-NAME. This SNP injection caused a brief activation but did not reverse the (protracted) decrease in spontaneous activity (n = 5, data not statistically analyzed due to varying time points).
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DISCUSSION |
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1 h, both after intravenous and local application of SNP onto the medullary brain stem. The latency of the SNP induced increase in activity was not significantly altered with the addition of electrical stimulation of the dura. This observation suggests that either or both peripheral and central mechanisms are induced by NO that in turn produces delayed and long-lasting pro-nociceptive changes in neurons in the trigeminal nucleus. The majority but not all neurons showed delayed activation after SNP, and there was no correlation between the response to SNP and other physiological properties of the units. The reason for this differential SNP effect is not clear. The second important observation in this study is that the unspecific inhibitor of NO synthases, L-NAME, reduced the spontaneous activity in these neurons within some minutes, suggesting that the spontaneous activity is partly dependent on continuous NO production. An additional observation was that electrical stimulation of the dura mater simulating noxious input was not able to further increase or to prevent this increase in neuronal activity caused by infusion of the NO donor. General properties of neurons in the spinal trigeminal nucleus
All neurons included in this study were located in or near the caudal subnucleus of the spinal trigeminal nucleus. All neurons had convergent input from the parietal dura and from facial areas. Other properties such as recording depth, response latency to electrical stimuli, spontaneous activity, and activation threshold for dural mechanical stimulation were highly variable between the units as was the response to infusion of the NO donor. Therefore we looked for correlations between these general properties. The only correlation found was between the coordinates of the units' position and their response latency to electrical stimulation of the dura mater. There was a significant negative correlation of the latencies with the rostrocaudal coordinates of the units. This observation may indicate that intracranial trigeminal afferents project differentially to the STN, e.g., the most caudal part of the STN may receive more A fiber input, or more primary afferents may directly reach the caudal STN compared with the rostral parts.
There was also no correlation of these properties with the changes in neuronal activity after SNP infusion. In particular, the changes in activity induced by the NO donor and by the NOS inhibitor were not dependent on the initial activity of the neurons. This is important because initial high spontaneous activity could have been due to sensitization processes during the surgical procedures, which may also include NO-dependent mechanisms.
Downregulation of neuronal activity by L-NAME
In our previous study, L-NAME infusion decreased spontaneous activity in a sample of neurons in deep laminae of the caudal trigeminal nucleus, suggesting that NO is involved in the control of trigeminal neuronal activity (De Col et al. 2003). In the present study, we extended these experiments by including additional neurons located in more superficial laminae of the spinal trigeminal nucleus. The results of this study are in full accordance with our previous findings. There was no systematic variation in the response to L-NAME depending on the location of neurons. Although the preparation used in this study is not a complete model for migraine headache, our findings resemble clinical studies in which the severity of pain during spontaneous migraine attacks was significantly reduced by inhibition of NO synthase (Lassen et al. 1997, 1998; Olesen and Jansen-Olesen 2000; van der Kuy et al. 2002).
It is unclear so far which of the three isoforms of NO synthase, eNOS, iNOS, or nNOS (Moncada et al. 1991), is mainly responsible for the endogenous production of NO that obviously contributes to the maintenance of neuronal activity in the experimental situation. L-NAME is a nonspecific NOS inhibitor that blocks all three types of NOS and reduces NO production in many tissues including vascular endothelium leading to arterial vasoconstriction. The onset of blood pressure increase was associated with a transient increase in neuronal activity. Although the systemic pressure continued to be elevated after injection of L-NAME, the neuronal activity decreased and remained suppressed (see Fig. 5). Injections of SNP under this condition caused short-lasting increases in activity, similar to that observed in some experiments with initial SNP infusion, but the decrease in spontaneous activity caused by L-NAME was not reversed, indicating that NO derived from the applied SNP was not able to compensate for the blockade of endogenous NO production.
Acute effect of intravenous and intrathecal administration of SNP
Under the experimental conditions of slow intravenous SNP infusion, activation was observed in 7 of 14 neurons. Similarly, during or within the 5-min period after intrathecal SNP application, activation was seen in 5 of 11 units; however, across the whole sample, this effect failed to reach the level of significance. Fast nociceptive effects of NO donors in the trigeminal system have also been reported by other authors. Rat trigeminal nucleus neurons were sensitized to electrical stimulation of facial and dural areas during or immediately after the infusion of nitroglycerin, a NO donor that, unlike SNP, does not produce cyanide (Jones et al. 2001). In experiments on humans, intravenous nitroglycerin immediately provoked some form of mild headache in 9 of 10 healthy subjects (Iversen et al. 1989). The mechanism underlying this rapid onset of the NO effect is unclear. Mechanical activation of meningeal afferents by rapid vasodilatation is possible although not very likely because injection of phentolamine, which caused vasodilatation and a short-term decrease in blood pressure, was not accompanied by any significant changes in neuronal activity. Another possible mechanism is a direct effect of NO on trigeminal neurons or meningeal afferents. In this case, either the NO concentration produced by SNP infusion was too low to directly activate all neurons or not all neurons were sensitive to NO.
Delayed effect of intravenous and intrathecal administration of SNP
Application of the NO donor SNP was followed by an increase in spontaneous neuronal activity in most neurons with a delay of 1 h. These results are in good accordance with the clinical "migraine model" in which an infusion of the NO donor nitroglycerin provoked migraine attacks with a similar delay of one to several hours (Bank 2001; Iversen et al. 1989; Olesen et al. 1993; Peters 1953). Due to the short half-life of NO donors in the blood plasma, this effect cannot be explained by a direct activation of trigeminal neurons; rather the NO derived from SNP or nitroglycerin, respectively, is presumed to have triggered a long-term process. We can only speculate about the mechanisms underlying this process. NO, a vasoactive substance and a neuronal messenger (Garthwaite and Boulton 1995; Tassorelli et al. 1999), may act both on cerebral blood vessels leading to vasodilatation and on perivascular sensory endings to release neuropeptides and prostaglandins (Holzer et al. 1995; Strecker et al. 2002). As was hypothesized by some authors, COX and NOS pathways may interact and facilitate each other, and this mutual facilitation could contribute to the pain production in migraine (Sarchielli et al. 2000; Stirparo et al. 2000). It is known that most of the NO effects are mediated by activation of soluble guanylate-cyclase, which stimulates synthesis of cyclic guanosine monophosphate (Mayer 1994; Riedel 2000). NO is also able to stimulate neurotransmitter release (see reviews by Meller and Gebhart 1993; Wang and Robinson 1997) and to regulate neurotransmitter (glutamate, dopamine) reuptake (Pogun and Kuhar 1994; Riedel 2000). The contribution of these mechanisms to the effects observed in our experiments cannot be excluded, but none of these mechanisms work over a time course longer than a few minutes. Therefore other long-term effects must be assumed to underlie the delayed activation of trigeminal neurons, and therefore the most likely possibility is the involvement of gene expression.
It has been reported that treatment of cultured bovine pulmonary artery endothelial cells with NO-donors (S-nitroso-N-acetylpenicillamine, sodium nitroprusside, or spermine NONOate) stimulates endothelial NO synthase (eNOS) expression (Chen et al. 2001). Systemic injection of the NO-donor nitroglycerin has been shown to increase neuronal NO synthase (nNOS) levels in the caudal trigeminal nucleus in rats (Pardutz et al. 2000). Moreover, expression of inducible NO synthase (iNOS) has recently been found in the rat dura mater 4 h after intravenous GTN infusion, although this was due to the invasion of macrophages (Reuter et al. 2001). Thus it seems possible that gene expression of all three isoforms of NOS can be induced by NO. If NOS expression occurred in our experiments, subsequent endogenous NO production may have been the mechanism that led to the delayed increase in firing rate of caudal trigeminal nucleus neurons. Assuming that endogenous NO production is a source of delayed neuronal activation, the question is whether this may occur in the meninges or in the caudal trigeminal nucleus or both.
Peripheral versus central effects of the NO donor
To figure out whether the delayed activation of STN neurons is caused by a peripheral or central effect, we used two modes of SNP application—systemic (intravenous) and direct application onto the medulla (intrathecal). Although NO, generated by intravenous SNP injection, may interact with both central and peripheral neurons, intrathecal application should mainly affect brain stem structures. Because both modes of application produced the same result, we propose that the delayed changes in spinal trigeminal neuronal activity observed after SNP are mainly due to a central action. On the other hand, considering that the increase in neuronal activity was somewhat delayed and that the increase in activity was less pronounced after intrathecal compared with intravenous infusion of SNP, a contribution of peripheral effects of NO cannot be dismissed. In an in vitro preparation of the rat meninges, NO donators caused the release of calcitonin gene-related peptide and prostaglandin E2 (Strecker et al. 2002), supporting the idea of an additional peripheral effect of NO on meningeal primary afferents.
To further test the possibility that the increase in firing rate of spinal trigeminal neurons after SNP administration is a result of enhanced peripheral input from meningeal afferent fibers, we combined intravenous SNP administration with repetitive electrical stimulation of the dura mater. The effect of this combination was not significantly different from the experiments with intravenous SNP injection alone. This led us to conclude that regular stimuli that may activate trigeminal afferents, such as arterial pulsation, seem not to be involved in the delayed activation of trigeminal nucleus neurons by SNP. On the other hand, we cannot exclude the possibility that it was the 5-Hz stimulation frequency that caused depression rather than potentiation of activity in second-order neurons. In any case, we assume that it is mainly a central action by which systemic NO donors change the activity of trigeminal second-order neurons.
In conclusion, we suggest that systemic or central administration of NO donors may trigger a process that leads to a delayed and long-lasting activation of spinal trigeminal neurons resulting in an increase in ongoing impulse activity. This process is most likely central in origin and may include expression of NOS, possibly nNOS, in the STN. We speculate that similar mechanisms underlie the induction of experimental migraine and that these may play a role in the onset and maintenance of spontaneous migraine headache as has been previously proposed (Olesen et al. 1993–1995, Olesen and Jansen-Olesen 2000).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: Karl Messlinger, Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, Universitätstrasse 17, D-91054 Erlangen, Germany (E-mail: messlinger{at}physiologie1.uni-erlangen.de).
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Ashina M, Bendtsen L, Jensen R, Lassen LH, Sakai F, and Olesen J. Possible mechanisms of action of nitric oxide synthase inhibitors in chronic tension-type headache. Brain 122: 1629–1635, 1999.
Bank J. Migraine with aura after administration of sublingual nitroglycerin tablets. Headache 41: 84–87, 2001.[CrossRef][ISI][Medline]
Brunetti L. Nitric oxide: a gas as a modulator of neuroendocrine secretions. Clin Ter 144: 147–53, 1994.[Medline]
Bullitt E. Expression of C-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol 296: 517–530, 1990.[CrossRef][ISI][Medline]
Burstein R, Yamamura H, Malick A, and Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 79: 964–982, 1998.
Chen JX, Berry LC, Tanner M, Chang M, Myers RP, and Meyrick B. Nitric oxide donors regulate nitric oxide synthase in bovine pulmonary artery endothelium. J Cell Physiol 186: 116–123, 2001.[CrossRef][ISI][Medline]
Dalsgaard-Nielsen T. Migraine diagnostics with special reference to pharmacological tests. Int Arch Allerg 7: 312–322, 1955.[Medline]
D'Amico D, Ferraris A, Leone M, Catania A, Carlin A, Grazzi L, and Bussone G. Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine-NO pathway? Cephalalgia 22: 33–36, 2002.[CrossRef][ISI][Medline]
Davis KD, Meyer RA, and Campbell JN. Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J Neurophysiol 69: 1071–1081, 1993.
De Col R, Koulchitsky SV, and Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport 14: 229–232, 2003.[CrossRef][ISI][Medline]
Dohrn CS and Beitz AJ. NMDA receptor mRNA expression in NOS-containing neurons in the spinal trigeminal nucleus of the rat. Neurosci Lett 175: 28–32, 1994.[CrossRef][ISI][Medline]
Dragunow M and Faull R. The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 29: 261–265, 1989.[CrossRef][ISI][Medline]
Ekbom K. Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 19: 487–493, 1968.[ISI][Medline]
Feindel W, Penfield W, and McNaughton F. The tentorial nerves and localisation of intracranial pain in man. Neurology 10: 555–563, 1960.
Forster C and Handwerker HO. Automatic classification and analysis of microneurographic spike data using a PC/AT. J Neurosci Methods 31: 109–118, 1990.[CrossRef][ISI][Medline]
Gallai V, Alberti A, Gallai B, Coppola F, Floridi A, and Sarchielli P. Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid. Cephalalgia 23: 166–174, 2003.[CrossRef][ISI][Medline]
Garthwaite JG and Boulton CL. Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57: 683–706, 1995.[CrossRef][ISI][Medline]
Graham JR and Wolff HG. Mechanism of migraine headache and action of tartrate. Arch Neurol Psychiatry 38: 737–763, 1938.
Handwerker HO and Reeh PW. Pain and inflammation. In: Proceedings of the VIth World Congress on Pain, edited by Bond MR, Charlton JE, and Woolf CJ. Amsterdam: Elsevier, 1991, p. 59–70.
Holzer P, Jocic M, and Peskar BA. Mediation by prostaglandins of the nitric oxide-induced neurogenic vasodilatation in rat skin. Br J Pharmacol 116: 2365–2370, 1995.[ISI][Medline]
Honore P, Chapman V, Buritova J, and Besson J-M. Reduction of carrageenin oedema and the associated c-Fos expression in the rat lumbar spinal cord by nitric oxide synthase inhibitor. Br J Pharmacol 114: 77–84, 1995.[ISI][Medline]
Ikeda S, Frank PA, Schweiss JF, and Homan SM. In vitro cyanide release from sodium nitroprusside in various intravenous solutions. Anesth Analg 4: 360–362, 1988.
Iversen HK, Olesen J, and Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38: 17–24, 1989.[CrossRef][ISI][Medline]
Iwamoto ET and Marion L. Pharmacological evidence that nitric oxide mediates the antinociception produced by muscarinic agonists in the rostral ventral medulla of rats. J Pharmacol Exp Ther 269: 699–708, 1994.
Jansen I, Uddman R, Ekman R, Olesen J, Ottosson A, and Edvinsson L. Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides 13: 527–536, 1992.[CrossRef][ISI][Medline]
Jones MG, Lever I, Bingham S, Read S, McMahon SB, and Parsons A. Nitric oxide potentiates response of trigeminal neurones to dural or facial stimulation in the rat. Cephalalgia 21: 643–655, 2001.[CrossRef][ISI][Medline]
Kaube H, Keay KA, Hoskin KL, Bandler R, and Goadsby PJ. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res 629: 95–102, 1993.[CrossRef][ISI][Medline]
Kiechle FL and Malinski T. Nitric oxide biochemistry, pathophysiology and detection. Am J Clin Pathol 100: 567–573, 1993.[ISI][Medline]
Lassen LH, Ashina M, Christiansen I, Ulrich V, and Olesen J. Nitric oxide synthase inhibition in migraine. Lancet 349: 401–402, 1997.[CrossRef][ISI][Medline]
Lassen LH, Ashina M, Christiansen I, Ulrich V, Grover R, Donaldson J, and Olesen J. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 18: 27–32, 1998.[CrossRef][ISI][Medline]
Lee JH, Wilcox GL, and Beitz AJ. Nitric oxide mediates Fos expression of c-fos in the spinal cord induced by noxious stimulation. Neuroreport 3: 841–844, 1992.[ISI][Medline]
Leger L, Gay N, Burlet S, Charnay Y, and Cespuglio R. Localization of nitric oxide-synthesizing neurons sending projections to the dorsal raphe nucleus of the rat. Neurosci Lett 257: 147–150, 1998.[CrossRef][ISI][Medline]
Leong S, Liu H, and Yeo J. Nitric oxide synthase and glutamate receptor immunoreactivity in the rat spinal trigeminal neurons expressing Fos protein after formalin injection. Brain Res 855: 107–115, 2000.[CrossRef][ISI][Medline]
Malmberg AB and Yaksh TL. Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 54: 291–300, 1993.[CrossRef][ISI][Medline]
Mayberg R, Zervas NT, and Moskowitz MA. Trigeminal projections to supratentorial pial and dural blood vessels. J Comp Neurol 223: 45–56, 1984.
Mayer B. Regulation of nitric oxide synthase and soluble guanydil cyclase. Cell Biochem Funct 12: 167–177, 1994.[CrossRef][ISI][Medline]
Meller ST and Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 52: 127–136, 1993.[CrossRef][ISI][Medline]
Messlinger K, Suzuki A, Pawlak M, Zehnter A, and Schmidt RF. Involvement of nitric oxide in the modulation of dural arterial blood flow in the rat. Br J Pharmacol 129: 1397–1404, 2000.[CrossRef][ISI][Medline]
Mizumura K, Sato J, and Kumazawa T. Effects of prostaglandins and other putative chemical intermediators on the activity of canine testicular polymodal receptors studied in vitro. Pfluegers 408: 565–572, 1987.
Moncada S, Palmer RMJ, and Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43: 109–142, 1991.[ISI][Medline]
Moore PK, Babbedge RC, Wallace P, Gaffen ZA, and Hart SL. 7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol 108: 296–297, 1993.[ISI][Medline]
Morgan JI and Curran T. Stimulus-transcription coupling in the nervous system. Involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 14: 421–451, 1991.[CrossRef][ISI][Medline]
Moskowitz MA and Macfarlane R. Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 5: 159–177, 1993.[ISI][Medline]
Olesen J, Iversen HK, and Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 4: 1027–1030, 1993.[ISI][Medline]
Olesen J and Jansen-Olesen I. Nitric oxide mechanisms in migraine. Pathol Biol (Paris) 48: 648–657, 2000.[Medline]
Olesen J, Thomsen LL, and Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci 15: 149–153, 1994.[CrossRef][Medline]
Olesen J, Thomsen LL, Lassen LH, and Olesen IJ. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia 15: 94–100, 1995.[CrossRef][ISI][Medline]
Pardutz A, Krizbai I, Multon S, Vecsei L, and Schoenen J. Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport 11: 3071–3075, 2000.[ISI][Medline]
Peters GA. Migraine: diagnosis and treatment with emphasis on the migraine-tension headache, provocative tests and use of rectal suppositories. Proc Staff Meet Mayo Clin 28: 673–686, 1953.[Medline]
Pogun S and Kuhar MJ. Regulation of neurotransmitter reuptake by nitric oxide. Ann NY Acad Sci 738: 305–315, 1994.[CrossRef][ISI][Medline]
Ray BS and Wolff HG. Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. Arch Surg 41: 813–856, 1940.
Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, and Moskowitz MA. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124: 2490–2502, 2001.
Riedel W. Role of nitric oxide in the control of the hypothalamic-pituitary-adrenocortical axis. Z Rheumatol 59, Suppl 2: 36–42, 2000.
Saito K, Greenberg S, and Moskowitz MA. Trigeminal origin of beta-preprotachykinin products in feline pial blood vessels. Neurosci Lett 76: 69–73, 1987.[CrossRef][ISI][Medline]
Sarchielli P, Alberti A, Codini M, Floridi A, and Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20: 907–918, 2000.[CrossRef][ISI][Medline]
Schepelmann K, Ebersberger A, Pawlak M, Oppmann M, and Messlinger K. Response properties of trigeminal brain stem neurons with input from dura mater encephali in the rat. Neuroscience 90: 543–554, 1999.[CrossRef][ISI][Medline]
Shimomura T, Murakami F, Kotani K, Ikawa S, and Kono S. Platelet nitric oxide metabolites in migraine. Cephalalgia 19: 218–222, 1999.[CrossRef][ISI][Medline]
Steen KH, Reeh PW, Anton F, and Handwerker HO. Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro. J Neurosci 12: 86–95, 1992.[Abstract]
Steen KH, Steen AE, and Reeh PW. A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin in vitro. J Neurosci 15: 3982–3989, 1995.[Abstract]
Stirparo G, Zicari A, Favilla M, Lipari M, and Martelletti P. Linked activation of nitric oxide synthase and cyclooxygenase in peripheral monocytes of asymptomatic migraine without aura patients. Cephalalgia 20: 100–106, 2000.[CrossRef][ISI][Medline]
Strassman AM, Mason P, Moskowitz MA, and Maciewicz R. Response of brain stem trigeminal neurones to electrical stimulation of the dura. Brain Res 379: 242–250, 1986.[CrossRef][ISI][Medline]
Strassman AM and Vos BP. Somatotopic and laminar organisation of fos-like immunoreactivity in the medullary and upper cervical dorsal horn induced by noxious facial stimulation in the rat. J Comp Neurol 331: 495–516, 1993.[CrossRef][ISI][Medline]
Strassman AM, Raymond SA, and Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384: 560–564, 1996.[CrossRef][Medline]
Strecker T, Dux M, and Messlinger K. Increase in meningeal blood flow by nitric oxide—interaction with calcitonin gene-related peptide receptor and prostaglandin synthesis inhibition. Cephalalgia 22: 233–241, 2002.[CrossRef][ISI][Medline]
Tassorelli C and Joseph SA. Systemic nitroglycerin induces fos immunoreactivity in brain stem and forebrain structures of the rat. Brain Res 682: 67–78, 1995a.
Tassorelli C and Joseph SA. NADPH-diaphorase activity and fos expression in brain nuclei following nitroglycerin administration. Brain Res 695: 37–44, 1995b.[CrossRef][ISI][Medline]
Tassorelli C, Joseph SA, and Nappi G. Neurochemical mechanisms of nitroglycerin-induced neuronal activation in rat brain: a pharmacological investigation. Neuropharmacology 36: 1417–1424, 1997.[CrossRef][ISI][Medline]
Tassorelli C, Joseph SA, Buzzi MG, and Nappi G. The effects on the central nervous system of nitroglycerin—putative mechanisms and mediators. Prog Neurobiol 57: 607–624, 1999.[CrossRef][ISI][Medline]
Thomsen LL, Kruuse C, Iversen HK, and Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1: 73–80, 1994.
Thomsen LL and Olesen J. Nitric oxide theory of migraine. Clin Neurosci 5: 28–33, 1998.[CrossRef][ISI][Medline]
Uddman R, Edvinsson L, Ekman R, Kingman T, and McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62: 131–136, 1985.[CrossRef][ISI][Medline]
Uddman R, Hara H, and Edvinsson L. Neuronal pathways to the rat middle meningeal artery revealed by retrograde tracing and immunocytochemistry. J Auton Nerv Syst 26: 69–75, 1989.[CrossRef][ISI][Medline]
van der Kuy PH, Merkus FW, Lohman JJ, ter Berg JW, and Hooymans PM. Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study. Cephalalgia 22: 513–519, 2002.[CrossRef][ISI][Medline]
Vetter G, Geisslinger G, and Tegeder I. Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 92: 213–218, 2001.[CrossRef][ISI][Medline]
Wang X and Robinson PJ. Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system. J Neurochem 68: 443–456, 1997.[ISI][Medline]
Wiertelak EP, Furness LE, Watkins LR, and Maier SF. Illness-induced hyperalgesia is mediated by a spinal NMDA-nitric oxide cascade. Brain Res 664: 9–16, 1994.[CrossRef][ISI][Medline]
Wolff HG. Headache and Other Head Pain (2nd ed.). New York: Oxford University, 1963.
Yamamura H, Malick A, Chamberlin NL, and Burstein R. Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine. J Neurophysiol 81: 479–493, 1999.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16: 109–110, 1983.[CrossRef][ISI][Medline]
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