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��Blackwell Science, LtdOxford, UKCHACephalalgia1468-2982Blackwell Science, 2003243161172Review ArticleNeurobiology of chronic tension-type headacheM Ashina REVIEW Neurobiology of chronic tension-type headache M Ashina Department of Neurology and Danish Headache Center, Glostrup Hospital, University of Copenhagen, Glostrup, Copenhagen, Denmark Ashina M. Neurobiology of chronic tension-type headache. Cephalalgia 2004; 24:161 172. London. ISSN 0333-1024 central sensitization, microdialysis, muscle tenderness, nitric oxide, tension-type headache Messoud Ashina MD, PhD, DrSci, Department of Neurology and Danish Headache Centre, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark. Tel. + 45 4323 2300, ext. 3068, fax + 45 4323 3926, e-mail ashina@dadlnet.dk Received 30 January 2003, accepted 16 June 2003 was to study the neurobiology of chronic tension- Introduction type headache. Specific aims were: (i) to investigate Chronic tension-type headache is one of the most NO mechanisms in chronic tension-type headache common and important types of primary headaches sufferers; (ii) to study plasma levels of CGRP, SP, (1) and represents a considerable health and socio- NPY and VIP in patients with chronic tension-type economic problem (2). Increased tenderness of headache; and (iii) to study in vivo skeletal muscle pericranial myofascial tissues to manual palpation blood flow during static exercise in patients with is the most prominent abnormal finding in patients chronic tension-type headache. with chronic tension-type headache (3 6). Painful impulses from these tissues may be referred to the Nitric oxide in chronic tension-type headache head and perceived as headache, and myofascial mechanisms may therefore play a major role in Biosynthesis of nitric oxide the pathophysiology of tension-type headache (7). Progress in molecular neurobiology of pain (8) and The free radical NO is a messenger molecule involved an increasing number of studies on tension-type in various biological functions (10 12). NO is synthe- headache (9) have increased our knowledge about sized by a complex family of nitric oxide synthase the mechanisms underlying chronic head pain. (NOS) enzymes (13). Because NO is highly reactive Thus, substantial experimental evidence indicates and unstable, much of the research on its functions that central sensitization, i.e. increased excitability of is based on characterization of NOS. Three distinct neurons in the central nervous system (CNS) gener- NOS enzymes [neuronal NOS (nNOS), endothelial ated by prolonged nociceptive input from the peric- NOS, inducible NOS) have been purified, cloned and ranial myofascial tissues, plays an important role in biochemically characterized (13). The precise mech- the pathophysiology of chronic pain (8) and chronic anism of NO formation is not fully understood. It is tension-type headache (9). Furthermore, discovery known that NO is synthesized from L-arginine and of neurotransmitters and neuromodulators such as that the reaction also yields citrulline (Fig. 1). nitric oxide (NO), calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide Y (NPY) NO and nociception in animal studies and vasoactive intestinal polypeptide (VIP) involved in the pain processing provides new insights to our NO or NOS immunoreactivity has been identified in understanding of the biology of chronic head pain. the peripheral and central nervous system. In the To explore the neurobiology of human chronic pain peripheral nervous system, nNOS immunoreactivity conditions, it is necessary to utilize advances made was demonstrated in dorsal root ganglia in both man in basic research. The purpose of the present thesis and rat (14) and in perivascular nerves of large cere- � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 161 162 M Ashina H + H2N NH+ H2N N OH H2 O NH2 NH NH NH 1 NADPH 1 NADPH + " N=O O2 O2 H3N+ COO H3N+ COO H3N+ COO L-arginine NG-hydroxy-L-arginine L-citrulline Figure 1 Nitric oxide synthase-catalysed oxidation of L-arginine. Nitric oxide is synthesized from L-arginine and the reaction also yields citrulline. (Reproduced from Nitric oxide in the nervous system . In: V. B. Mayer, editor. Biochemistry and molecular pharmacology of nitric oxide synthases, Chapter 2, 1995:21 38, with permission from Elsevier.) bral arteries of the rat (15) and human brain (16). In type headache. Thus, several studies have consis- the central nervous system, nNOS is present exclu- tently reported increased myofascial tenderness as sively in neurons and NOS neurons were demon- the most prominent abnormal finding in patients strated in the spinal trigeminal nucleus (17) and in with chronic tension-type headache (3 6). Further the dorsal horn of the spinal cord (14, 18). support for myofascial involvement is the finding of NO derived from neurons was first recognized increased muscle hardness (30) and a positive corre- when N-methyl-D-aspartate (NMDA) receptor acti- lation between muscle hardness and tenderness in vation in cerebellar cultures resulted in NO generation chronic tension-type headache (31). In addition to (19). Involvement of NO in neuronal signalling was findings in the periphery, chronic tension-type head- confirmed by demonstrating that NOS inhibitors ache sufferers also exhibit signs of increased sensi- blocked the stimulation of cyclic guanosine mono- tivity in the CNS. Thus, pressure pain detection and phosphate in brain that is associated with activation tolerance thresholds to mechanical stimuli have been of NMDA receptor (20, 21). Later, it was demonstrated found decreased in these patients (32, 33). Further- that sensitization of pain pathways in the spinal cord more, Bendtsen et al. (34) demonstrated that patients may be caused by or associated with activation of with chronic tension-type headache had a qualita- nNOS and the generation of NO (22 24). Moreover, tively altered pain perception. On the basis of these prolonged elevation of NO levels within the spinal findings and data from basic pain research (35), it dorsal horn is important in maintaining the central has been suggested that the central sensitization and sensitization (25). Finally, it has been shown that inhi- thereby the chronic pain state in patients with bition of NOS reduces central sensitization in pain chronic tension-type headache may be due to sensi- models (22, 26, 27) and that nociceptive responses in tization at the level of the spinal dorsal horn/trigem- these models are enhanced by NO donors (28, 29). inal nucleus induced by prolonged nociceptive input Taken together, these data suggest that NO is an from pericranial myofascial tissues (9, 36). important transmitter in pain pathways of the spinal cord and that NO contributes to development and Inhibition of NOS in chronic tension-type headache maintenance of central sensitization at the spinal level. In order to test the hypothesis that inhibition of NO and thereby central sensitization would reduce Central sensitization and chronic tension-type chronic headache, Ashina et al. (37) investigated the headache analgesic effect of the NOS inhibitor L-NG methyl Nociception from pericranial myofascial tissues may arginine hydrochloride (L-NMMA) in patients with play a major role in the pathophysiology of tension- chronic tension-type headache. In a double-blind, � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Neurobiology of chronic tension-type headache 163 placebo-controlled crossover study patients received temporal region were largely unchanged following L-NMMA or placebo on 2 days. L-NMMA reduced treatment with L-NMMA. Thus, these studies (37, headache intensity significantly more than placebo 38) demonstrated that the NOS inhibitor, L-NMMA, (Fig. 2). To explore the mechanisms of this analgesic reduces headache intensity and muscle hardness in effect Ashina et al. (38) also studied the relationship patients with chronic tension-type headache. between myofascial factors and NOS inhibition. This An important question is how L-NMMA modu- study showed that both muscle hardness and ten- lates myofascial factors in patients with chronic derness were significantly reduced following treat- tension-type headache and whether the effects of L- ment with L-NMMA, while there was no significant NMMA are due to an action in muscle, peripheral reduction at any time after treatment with placebo nerves or the CNS. It is well established that persis- (Figs 3 and 4). The muscle hardness was significantly tent activity in peripheral nociceptors may lead to reduced following treatment with L-NMMA com- sensitization of neurons in the spinal dorsal horn, pared with placebo. The reduction in tenderness partly via activation of NMDA receptors (8). Many following treatment with L-NMMA did not reach of the effects of NMDA receptor activation are medi- statistical significance compared with placebo. The ated via production of NO (23) and, as described pressure pain detection thresholds in the finger and earlier, animal models of persistent pain have shown that inhibitors of NOS decrease sensitization of the spinal dorsal horn induced by continuous painful 0 15 30 60 90 120 input from the periphery (22, 24, 26, 27). On the basis Min 0 of these findings Ashina et al. (37, 38) suggested that the anti-nociceptive effect of NOS inhibition in patients with chronic tension-type headache is prob- 10 ably due to reduction of central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. * One should, however, also consider other possible 20 * mechanisms of action. Thus, it is possible that L- * NMMA has direct anti-nociceptive effects in myofas- * * 30 cial tissues. It has been demonstrated that NOS inhibitors have anti-nociceptive effects after periph- Figure 2 Percent changes from baseline pain intensity on a eral administration, probably due to inhibition of 100-mm visual analogue scale (VAS) in 16 patients with endothelial NOS (eNOS) (22, 39, 40). However, the chronic tension-type headache. The pain intensity was exact role of NO in the periphery is still far from significantly more reduced following treatment with L- NMMA ( ) compared with placebo ( ) (P = 0.01). *P < 0.05 understood, and additional research is needed to compared with baseline (time = 0). The plots represent mean scores. (Modified from Ashina et al. 1999, by permission of the 060 120 Lancet.) Min 0 0 60 120 5 Min 0 10 1 15 2 20 ** 3 25 ** 4 30 * 5 * Figure 4 Percent changes in total tenderness score (TTS) in 16 6 patients with chronic tension-type headache. The TTS tended to be reduced following treatment with L-NMMA ( ) Figure 3 Percent changes in muscle hardness in 16 patients compared with placebo ( ) (P = 0.11). Within each treatment, with chronic tension-type headache. Muscle hardness was the TTS was significantly reduced at 60 and 120 min after start significantly more reduced following treatment with L- of the infusion of L-NMMA, while there was no significant NMMA ( ) than with placebo ( ) in patients with chronic change at any time after treatment with placebo. **P < 0.01 myofascial pain (P = 0.04). *P < 0.05 compared with baseline compared with baseline (time = 0). The plots represent mean (time = 0). The plots represent mean scores. (Reproduced from scores. (Reproduced from Ashina et al. 1999, by permission of Ashina et al. 1999, by permission of Oxford University Press.) Oxford University Press.) � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 VAS (%) Change in tenderness (%) Change in hardness (%) 164 M Ashina clarify whether NO may activate or sensitize nocice- 5 ptors in myofascial tissues. 4 The anti-nociceptive effect of L-NMMA might also be due to blocking of vascular input. Excessive 3 vascular nociception may contribute to a primary 2 myofascial nociception in patients with tension- 1 type headache (41). L-NMMA inhibits all three types of NOS, including eNOS. Thus, it is possible 0 that L-NMMA exerts its action by blocking eNOS 0 20 40 60 90 120 4 8 12 and thereby moderate vasodilatation of cephalic/ Infusion Minutes Hours extracephalic arteries in patients with chronic ten- sion-type headache. Because of convergence of Figure 5 Median headache intensity over time during (20 min) and after infusion of glyceryl trinitrate (GTN) ( , nociceptive input from facial tissues at the spinal/ patients; , controls) and placebo ( , patients; D, controls) in trigeminal level (42), blocking of vascular input 16 patients with chronic tension-type headache and in 16 might also lead to reduction of myofascial nocicep- healthy subjects. Headache was scored on a 10-point verbal tion from pericranial muscles (38). rating scale (VRS). The patients developed significantly Taken together, these data indicate that the NOS stronger headache than healthy controls both during the first hour (immediate headache) (P = 0.02) and during the inhibitor L-NMMA elicits its anti-nociceptive effect subsequent 11 h (delayed headache) (P = 0.008). (Modified in chronic tension-type headache by modulation of from Ashina et al. 2000, by permission of Oxford University nociceptive information from myofascial tissues. Press.) This anti-nociceptive effect may mainly be due to reduction of central sensitization at the level of the spinal dorsal horn or trigeminal nucleus, or both. vasodilatation and headache in humans (48, 49). However, this effect of GTN was not confirmed in isolated guinea pig basilar arteries (50). Further- NO induction in chronic tension-type headache more, Iversen and colleagues (51) reported that In 1989, Iversen and colleagues introduced a NO plasma levels of CGRP are unchanged in the cranial donor, glyceryl trinitrate (GTN), model of experi- circulation of healthy subjects after GTN infusion. To mental headache (43). Using this model, it has been study the role of CGRP in NO-induced immediate demonstrated that patients with migraine are hyper- headache, Ashina et al. (52) measured plasma levels sensitive to NO, i.e. migraineurs develop signifi- of CGRP during and after infusion of GTN in cantly stronger headache after GTN infusion than patients with chronic tension-type headache (52). No healthy subjects (44, 45). Furthermore, it has been significant changes in plasma CGRP after GTN infu- shown that GTN may induce strong immediate sion were found in either patients or controls. Inter- headache in patients with episodic tension-type estingly, the dosage of GTN used in that study is headache compared with healthy subjects (44). To known to liberate CGRP in cats (48) and vasodilata- explore further the role of NO in development of tion in humans (53). headache and modulation of myofascial pain input, The unchanged sensitivity of pericranial myofas- Ashina et al. (46) studied the effect of GTN in cial pain pathways seems also to rule out sensitiza- patients with chronic tension-type headache. GTN tion of myofascial peripheral and central pathways infusion in patients resulted in a biphasic response as a mechanism of the immediate headache (52). with an immediate and a delayed headache (46). Unchanged pressure-pain detection thresholds in Patients developed significantly stronger immediate the finger, i.e. outside of the pain area, may also and delayed headache on a GTN day than on a pla- indicate no alteration in sensitivity of third-order cebo day (Fig. 5). Furthermore, patients developed neurons (52). significantly stronger headache after GTN than con- NO evokes pain in humans when injected trols (Fig. 5). paravascularly or perfused through a vascularly iso- The mechanisms responsible for the GTN-induced lated hand vein segment (54). These findings suggest headache in patients with primary headaches are that NO may directly activate or sensitize nocicep- unknown. CGRP is an important neuromodulator of tors around blood vessels. Intravenous infusion of the sensory system (47). An experimental study has GTN induces dilatation of the middle cerebral artery shown that GTN dilates cerebral arteries in cats via in healthy subjects (53), and in migraineurs and liberation of CGRP, and it has been suggested that patients with episodic tension-type headache (49). In this mechanism may explain the occurrence of these studies the dilatation lasted at least until 1 h � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Headache intensity on VRS Neurobiology of chronic tension-type headache 165 after cessation of GTN infusion and 3 h in another NOS- and c-fos-immunoreactive neurons in the cer- study (55). Collectively, these studies suggest that vical part of trigeminal nucleus caudalis in rats after immediate headache after GTN infusion in patients 4 h. These data indicate that GTN infusion may with chronic tension-type headache may originate result in storage and subsequent liberation of NO or from NO-induced activation or sensitization of sen- it may trigger endogenous NO production in the sory nerves around cephalic arteries, or from NO- CNS, thereby enhancing sensitization of nociceptive induced arterial dilatation, or both (46). pathways in the CNS of patients with chronic ten- The most important finding in the study by Ash- sion-type headache. ina et al. (46) was that systemic administration of NO Alternatively, sustained NO-induced vascular donor in patients with chronic tension-type head- nociception may lead to central sensitization and ache resulted in biphasic response with an immedi- subsequent convergence of nociceptive input from ate and a delayed headache (8 h after start of blood vessels and myofascial tissue. Thus, NO may infusion) (Fig. 5). Interestingly, the time profile of the activate or sensitize nociceptors around blood ves- GTN-induced headache in patients with chronic ten- sels directly (54) or by dilatation (53). Dilatation of sion-type headache was strikingly similar to the time meningeal blood vessels in rats causes sensitization profile of GTN-induced headache in patients with of central trigeminal neurons and facilitation of con- migraine (45). Thus, patients with migraine without vergent sensory responses (62). It is therefore pos- aura developed an immediate headache during sible that excessive vascular nociception caused by GTN infusion and a delayed headache fulfilling GTN may gradually augment the sensitizing effect International Headache Society (IHS) (56) criteria for of preexisting myofascial input in chronic tension- migraine several hours after cessation of the infu- type headache sufferers (41). sion. The characteristics of the delayed headache in As mentioned earlier, patients with chronic ten- chronic tension-type headache were, however, dif- sion-type headache and patients with migraine ferent from those in patients with migraine. Eighty develop increased delayed headache with different percent of migraine patients developed migraine characteristics. The most likely explanation is that without aura after infusion of GTN (45), while 87% preexisting facilitation of distinct nociceptive central of patients with chronic tension-type headache pathways in chronic tension-type headache sufferers developed a tension-type headache (46). These data (myofascial pathways) and migraineurs (vascular suggest that patients with chronic tension-type pathways) may be enhanced by NO-induced central headache are supersensitive to NO, similar to sensitization. This may explain why the delayed patients with migraine, and that the majority of headache fulfilled tension-type headache criteria in patients in both groups develop their usual head- patients with chronic tension-type headache and ache several hours after the infusion of GTN. migraine criteria in migraineurs. This could also What are the mechanisms of the delayed headache explain why NO does not induce strong delayed and why do patients with chronic tension-type head- headache in healthy subjects when no preexisting ache and patients with migraine develop delayed sensitization is present. headache resembling their usual type of headache, and why do most healthy subjects develop no Summary delayed headache or only a minor one? Studies in rats and in humans have shown that after intrave- Studies of NO mechanisms in chronic tension-type nous administration of GTN very little drug remains headache suggest that NO plays an important role in the blood and that the majority of the GTN is in the pathophysiology of this disorder (37, 38, 46). distributed to tissues (57). In the anaesthetized cat, The anti-nociceptive effect of NOS inhibitor suggests intravenous infusion of GTN induces a prolonged that inhibition of NOS may become a novel principle (60 min) increase of NO in brain parenchyma (58), in treatment of chronic tension-type headache. It is and a prolonged increase of NO levels in the spinal probable that the anti-nociceptive effect is due to dorsal horn was demonstrated during central sensi- reduction of central sensitization at the level of the tization (59). Furthermore, Wu and colleagues (60) spinal dorsal horn or trigeminal nucleus, or both. demonstrated that during central sensitization both Studies with selective NOS inhibitors are needed to endogenous and exogenous nitric oxide induce c-fos determine which type of NOS is involved and its (an immediate early gene) which can further acti- exact site of action in chronic tension-type headache. vate the production of other substances in the CNS. Data from the GTN model of experimental headache In addition, Pardutz et al. (61) reported that subcu- indicate that NO-induced delayed headache in taneous GTN produced a significant increase of patients with chronic tension-type headache is due � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 166 M Ashina to augmentation of preexisting central sensitization. ache has been investigated in three studies (78, 81, Moreover, these data indicate that NO contributes to 82). Bach and colleagues (81) reported normal CGRP mechanisms of several types of primary headaches levels in the cerebrospinal fluid (CSF) in patients and that NO-related central sensitization may be an with chronic tension-type headache. It was not important common denominator in the pain mecha- reported whether patients were examined during nisms of primary headaches, although their basic headache or in headache-free period or whether pathophysiological mechanisms are different. there was any relationship between CGRP levels and headache quality. To explore a possible role of neu- ropeptides in chronic tension-type headache, Ashina Neuropeptides in chronic tension-type and colleagues measured plasma levels of CGRP (82) headache and SP, NPY and VIP (78) in the cranial and periph- eral circulation of patients and controls. These stud- CGRP, SP, NPY, VIP and nociception in animal ies showed that plasma levels of CGRP, SP, NPY and studies VIP are normal in both cranial and peripheral circu- Immunohistochemical studies have shown that lation of patients. Moreover, plasma levels of neu- CGRP, SP, NPY, VIP are present in the peripheral and ropeptides were largely unrelated to headache state central nervous system (47, 63 69). Experimental (78, 82). Findings of normal plasma CGRP are par- studies demonstrated that acute and chronic nocice- ticularly important because they are clearly different ption leads to altered release of CGRP, SP, NPY and from our previous study in migraine patients with VIP from sensory nerve endings and from central elevated levels of CGRP (75). However, exploratory terminals of sensory afferents into dorsal horn of the testing in relation to headache characteristics spinal cord (70 73). These data suggest that CGRP, showed that eight patients with a pulsating pain SP, NPY and VIP are important neurotransmitters or quality, although fulfilling the IHS criteria for ten- neuromodulators in the nervous system and that sion-type headache and not for migraine, had higher these neuropeptides may play a role in the process plasma CGRP in the headache-free period than con- of central sensitization. trols (82). Plasma levels of CGRP in patients with predominantly pressing headache in the past did not differ from plasma CGRP in controls. In addition, CGRP, SP, NPY, VIP in chronic tension-type there was no relationship between CGRP levels and headache muscular factors (82). In the last 10 years there has been increasing interest How can we explain increased plasma CGRP in in the role of neuropeptides in primary headaches. chronic tension-type headache patients with pulsat- Particularly, a role for CGRP has been implicated in ing headache quality? Since CGRP levels are the pathophysiology of migraine (74, 75) and cluster increased in migraineurs (75) and in patients with headache (76, 77). However, the role of CGRP in pulsating headache in the headache-free period (82), generating headache pain is still unclear (75). Studies ongoing nociception from cephalic or extracephalic of SP, NPY and VIP in patients with primary head- vasculature, or both, seems to be ruled out. Circulat- aches or other chronic pain conditions have not led ing CGRP may be involved in the regulation of to consistent results (78). This is probably due to blood flow and in the maintenance of vascular tone variations in methodology [different methods of (83). It is possible that increased interictal CGRP analysis and/or field of sampling (plasma, platelets, levels in patients with pulsating headache like CSF, saliva)] or patient populations. migraineurs may reflect altered vascular control due As mentioned above, nociception from the peric- to abnormal release of CGRP from sensory neurons ranial myofascial tissues may be of importance in the (75). Therefore, the most likely explanation is that pathophysiology of chronic tension-type headache. these patients, although fulfilling the IHS criteria for In rat muscle, CGRP sensory fibres are preferentially chronic tension-type headache and not having any located in the wall of arteries (79) and nerve fibres migraine history, are in fact pathophysiologically containing CGRP, SP, NPY and VIP accompany related to migraine. Although the finding of small blood vessels in human cranial muscles (80). increased plasma CGRP in patients with pulsating These findings indicate that ongoing activity in sen- headache quality is very interesting, one should be sory neurons in the cranial muscles may be reflected very cautious with interpretation of post hoc analysis, in changes of plasma levels of neuropeptides in particularly with small numbers of patients. There- patients with chronic tension-type headache. The fore, a prospective study with a large number of role of neuropeptides in chronic tension-type head- patients is required to confirm this observation. � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Neurobiology of chronic tension-type headache 167 133 chronic myofascial pain (88). Using xenon clear- Summary ance technique, Langemark and co-authors (89) Studies on the role of neuropeptides in chronic ten- found normal resting blood flow and relative flow sion-type headache indicate that plasma levels of increase during isometric work in temporal muscle CGRP, SP, NPY and VIP are normal in patients and in patients with chronic tension-type headache. largely unrelated to headache state (78, 82). Further- However, in that study muscle blood flow was mea- more, findings of normal plasma CGRP add to the sured from a large muscle area and not in a tender growing list of differences between migraine and point. Thus, firm evidence of peripheral muscle tension-type headache. It is possible that changes of pathology as a cause of muscle pain and chronic neuropeptide levels at the spinal/trigeminal level or headache is still lacking. More sensitive techniques in the myofascial tissue of these patients do not reach are needed to answer the question of whether ten- the cranial or peripheral circulation. It would have sion-type headache and other myofascial pain disor- been optimal to measure SP, NPY and VIP levels in ders are associated with peripheral pathology in the pericranial muscles and CSF or even at the neu- tender points. ronal level. However, this is difficult for both practi- cal and ethical reasons. Thus, the findings of normal Muscle blood flow in chronic tension-type headache levels of CGRP, SP, NPY and VIP in the cranial and peripheral circulation do not exclude that abnormal- Microdialysis is a unique technique for investigating ities of these neuropeptides at the neuronal or and monitoring local muscle blood flow and metab- peripheral (pericranial muscle) levels play a role for olism in vivo within a tissue volume of <1 cm3 (90). the pathophysiology of chronic tension-type head- Using the microdialysis technique, Ashina and col- ache. Investigation of neuropeptides in other com- laborators (91) estimated blood flow and interstitial partments with new sensitive methods of analysis is lactate concentrations in the trapezius muscle at rest necessary to clarify their role in chronic tension-type and in response to static exercise in patients with headache. Finally, future CGRP studies in chronic chronic tension-type headache. The major finding of tension-type headache sufferers with pulsating pain that study was a decreased blood flow in response quality and in migraine patients with pressing pain to static exercise in a tender point in patients. Thus, quality, but otherwise fulfilling the IHS migraine cri- the increase in muscle blood flow from baseline to teria, are required to clarify whether increased CGRP exercise and post-exercise periods was significantly levels are associated with pulsating pain quality. lower in patients than in controls (Fig. 6) (91). There was no difference in resting blood flow between patients and controls. Microdialysis and chronic tension-type headache 0.1 Muscle pathology in tension-type headache? 0.08 It is a common experience for individuals who have been exposed to static or repetitive work for a long 0.06 period to develop tender areas in the pericranial muscles and tension-type headache. It has been hypothesized that local muscle ischaemia, distur- 0.04 bances in metabolism, microcirculation and mito- chondria function in the tender areas may explain 0.02 myofascial pain in tension-type headache and in other myofascial pain disorders such as trapezius 0 myalgia (84). Various in vitro and in vivo methods, Rest Ex 1 Ex 2 Pex 1 Pex 2 such as muscle biopsy, single-fibre laser-Doppler and magnetic resonance spectroscopy, have been Figure 6 Mean nutritive muscle blood flow in 16 patients used to explore the mechanisms responsible for with chronic tension-type headache and in 17 healthy control subjects. The figure shows that the increase in muscle blood myofascial pain. The results of these studies have flow from baseline (Rest) to exercise (Ex 1 and Ex 2) and post- been conflicting. While open studies suggested exercise periods (Pex 1 and Pex 2) was significantly lower in abnormalities in microcirculation (85, 86), controlled patients ( ) than in controls ( ) (P = 0.03). The plots represent and blinded studies failed to find firm evidence mean � SEM scores. (Reproduced from Ashina et al. 2002, by of peripheral abnormalities (87) in patients with permission of Oxford University Press.) � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Out/inflow ratio 168 M Ashina blood flow in response to static exercise (91). This is 6 supported by studies in animals and humans show- 5 ing that static exercise produces a one-to-one syn- chronization of activation of the muscle nociceptors 4 (group IV) and muscle nerve sympathetic activity (92). Furthermore, it has been shown that in patients 3 with fibromyalgia a complete sympathetic blockade produced a marked reduction of the number of ten- 2 der points, suggesting an improvement in microcir- culation (93). Moreover, it has been proposed that 1 central sensitization may maintain increased efferent 0 sympathetic outflow that in turn maintains sensiti- Rest Ex 1 Ex 2 Pex 1 Pex 2 zation of sensory afferents (94). These data suggest that the sympathetic outflow may influence or main- Figure 7 Mean interstitial concentration of lactate in 16 tain afferent activity in nociceptors or altered blood patients with chronic tension-type headache and in 17 healthy flow regulation in tender points of patients with control subjects. There was no difference in change in chronic tension-type headache. interstitial concentration of lactate from baseline (Rest) to exercise (Ex 1 and Ex 2) and post-exercise (Pex 1 and Pex 2) periods between patients ( ) and controls ( ) (P = 0.38). Summary (Reproduced from Ashina et al. 2002, by permission of Oxford University Press.) A microdialysis study provides in vivo evidence of altered blood flow regulation in tender skeletal mus- The question is, how do we explain the reduced cle during static work in patients with chronic ten- blood flow response to exercise in the tender point? sion-type headache (91). The lack of any difference Difference in the static load between patients and in local increase of interstitial lactate between controls is unlikely because there was no difference patients and controls seems to rule out the presence between groups, in either absolute force or relative of ischaemia in the tender point of patients with to maximal voluntary force. It could be suggested chronic tension-type headache during static exercise. that patients develop a relative ischaemia in the It is possible that because of increased excitability of tender point during static exercise. If so, one would neurons in the CNS the central interpretation and expect that the increase of interstitial lactate concen- response to normal sensory input are altered in tration would be higher in patients than in controls. patients with chronic tension-type headache. This However, Ashina and colleagues (91) observed no may lead to enhanced sympathetically mediated difference in local increase of interstitial lactate vasoconstriction and thereby a decreased blood flow between patients and controls (Fig. 7). This seems to in response to static exercise. rule out the presence of ischaemia in the tender point of patients with chronic tension-type headache dur- Concluding remarks and future perspectives ing rest and static exercise. The altered blood flow might be secondary to Advances made in basic pain research have chronic muscle pain. As mentioned in previous sec- improved our knowledge of the neurobiology of tions, chronic tension-type headache may be caused chronic head pain. Particularly, understanding of by prolonged painful input from pericranial myofas- molecular mechanisms involved in the process cial tissues, e.g. tender points, resulting in central of central sensitization contributes to the develop- sensitization (36, 38). The pathophysiological basis ment of novel therapeutic approaches for chronic for the painful input from the periphery is still headache. Studies of NO mechanisms suggest that unknown. Once the central sensitization had been NO may play a key role in the pathophysiology of established, chronic tension-type headache might be this disorder and that the anti-nociceptive effect of an entirely central process without further or only NOS inhibitor, previously demonstrated only in ani- minimal input from the periphery (9). Because of mal models, may become a novel principle in future central sensitization the central interpretation and treatment of chronic headache. The anti-nociceptive response to normal sensory input are altered, possi- effect of NOS inhibition is probably due to reduction bly mainly when input is increased, as during exer- of central sensitization at the level of the spinal dor- cise. This may lead to enhanced sympathetically sal horn or trigeminal nucleus, or both. However, the mediated vasoconstriction and thereby a decreased exact site of action and type of NOS involved in � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Interstitial lactate (mmol/l) Neurobiology of chronic tension-type headache 169 chronic tension-type headache is far from fully wide range of myofascial pain conditions. Using this understood. Future studies with selective NOS technique, it would be interesting to measure in vivo inhibitors are needed to determine which type of concentrations of inflammatory substances or neu- NOS is involved and its exact site of action. Whether ropeptides in the tender muscles of patients with the anti-nociceptive effect observed in patients was chronic tension-type headache. clinically relevant is also debatable, but the impor- In summary, the present study contributes to our tance of the results lies in the proof of the concept understanding of the complex mechanisms leading and not in the magnitude of the effect. to chronic tension-type headache and provides data In the future, chronic dosing should be tested that will hopefully lead to new treatment modalities. when a safe inhibitor of NOS with a longer half-life becomes available. Other important questions are Acknowledgements whether inhibition of NOS would have analgesic effects in other chronic pain conditions, or whether The studies in this thesis were supported by grants from the the effect of inhibition of NOS in tension-type head- University of Copenhagen, the Danish Headache Society, the Danish Medical Association Research Fund, the Danish Hos- ache is due to interaction with specific headache pital Foundation for Medical Research, Region of Copen- mechanisms. These important issues should be hagen, the Faroe Islands and Greenland, the Foundation for addressed in the future studies in patients with Research in Neurology, the Novo Nordisk Foundation, the other, non-headache, types of chronic pain. Data Gerda and Aage Haensch s Foundation, the Mauritzen La from the GTN model of experimental headache in Fontane s Foundation, and the Foundation of Jacob Madsen chronic tension-type headache indicate that NO con- and his wife OIga Madsen. tributes to mechanisms of several types of primary headaches and that NO-related central sensitization References may be an important common denominator in the pain mechanisms of primary headaches. However, 1 Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiol- additional research is needed to prove the role of ogy of headache in a general population a prevalence central sensitization during NO-induced delayed study. J Clin Epidemiol 1991; 44:1147 57. 2 Rasmussen BK, Jensen R, Olesen J. Impact of headache on headache. It would be interesting to detect possible sickness absence and utilisation of medical services: a sensitization of second-order neurons during the Danish population study. J Epidemiol Community Health delayed headache by quantitative sensory testing 1992; 46:443 6. techniques. Studies of the role of neuropeptides in 3 Bendtsen L, Jensen R, Jensen NK, Olesen J. Pressure- chronic tension-type headache indicate that plasma controlled palpation: a new technique which increases the levels of CGRP, SP, NPY and VIP are normal in reliability of manual palpation. Cephalalgia 1995; 15:205 patients and largely unrelated to headache state. 10. 4 Jensen R, Rasmussen BK, Pedersen B, Olesen J. Muscle Investigation of neuropeptides in other compart- tenderness and pressure pain thresholds in headache. A ments, such as CSF or pericranial muscles, with new population study. Pain 1993; 52:193 9. sensitive methods of analysis is necessary to clarify 5 Langemark M, Olesen J. Pericranial tenderness in tension their role in chronic tension-type headache. Further- headache. A blind, controlled study. Cephalalgia 1987; more, CGRP studies in chronic tension-type head- 7:249 55. ache sufferers with pulsating pain quality and in 6 Lipchick GL, Holroyd KA, Talbot F, Greer M. Pericranial migraine patients with pressing pain quality are muscle tenderness and exteroceptive suppression of tem- poralis muscle activity: a blind study of chronic tension- required to determine whether increased CGRP lev- type headache. Headache 1997; 37:368 76. els are associated with pulsating pain quality. 7 Jensen R, Bendtsen L, Olesen J. Muscular factors are of The results of microdialysis study indicate that importance in tension-type headache. Headache 1998; central sensitization may lead to enhanced sympa- 38:10 7. thetically mediated vasoconstriction which may be 8 Woolf CJ, Salter MW. Neuronal plasticity: increasing the responsible for decreased blood flow in tender skel- gain in pain. Science 2000; 288:1765 9. etal muscle during static work in patients with 9 Bendtsen L. Central sensitization in tension-type head- ache possible pathophysiological mechanisms. Cephala- chronic tension-type headache. Thus, it is possible lgia 2000; 20:486 508. that the central neuroplastic changes may affect the 10 Carvalho AJ, McKee NH, Green HJ. Metabolic and con- regulation of peripheral mechanisms and thereby tractile responses of fast- and slow-twitch rat skeletal mus- lead to increased tenderness and chronic headache. cles to ischemia. Can J Physiol Pharmacol 1996; 74:1333 41. The study also shows that the microdialysis tech- 11 Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman nique offers unique possibilities to study mecha- AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular nisms responsible for not only head pain but also a smooth muscle relaxation by organic nitrates, nitrites, � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 170 M Ashina nitroprusside and nitric oxide: evidence for the involve- neurons and neuropathic pain in the rat. Pain 1997; 72:355 ment of S-nitrosothiols as active intermediates. J Pharma- 66. col Exp Ther 1981; 218:739 49. 28 Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide 12 Furchgott RF, Zawadzki JV. The obligatory role of endot- in spinally mediated hyperalgesia in the mouse. Neurosci helial cells in the relaxation of arterial smooth muscle by Lett 1992; 14:1 5. acetylcholine. Nature 1980; 288:373 6. 29 Coderre TJ, Yashpal K. Intracellular messengers contribut- 13 Knowles RG, Moncada S. Nitric oxide synthases in mam- ing to persistent nociception and hyperalgesia induced by mals. Biochem J 1994; 298:249 58. L-glutamate and substance P in the rat formalin pain 14 Terenghi G, Riveros-Moreno V, Hudson LD, Ibrahim NB, model. Eur J Neuroscience 1994; 1:1328 34. Polak JM. Immunohistochemistry of nitric oxide synthase 30 Sakai F, Ebihara S, Akiyama M, Horikawa M. Pericranial demonstrates immunoreactive neurons in spinal cord and muscle hardness in tension-type headache. A non-invasive dorsal root ganglia of man and rat. J Neurol Sci 1993; measurement method and its clinical application. Brain 118:34 7. 1995; 118:523 31. 15 Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, 31 Ashina M, Bendtsen L, Jensen R, Sakai F, Olesen J. Muscle a calmodulin-requiring enzyme. Proc Natl Acad Sci USA hardness in patients with chronic tension-type headache: 1990; 87:682 5. relation to actual headache state. Pain 1999; 79:201 5. 16 Nozaki K, Moskowitz MA, Maynard KI, Koketsu N, 32 Bendtsen L, Jensen R, Olesen J. Decreased pain detection Dawson TM, Bredt DS, Snyder SH. Possible origins and and tolerance thresholds in chronic tension-type head- distribution of immunoreactive nitric oxide synthase- ache. Arch Neurol 1996; 53:373 6. containing nerve fibers in cerebral arteries. J Cereb Blood 33 Schoenen J, Bottin D, Hardy F, Gerard P. Cephalic and Flow Metab 1993; 13:70 9. extracephalic pressure pain thresholds in chronic tension- 17 Vincent SR, Kimura H. Histochemical mapping of nitric type headache. Pain 1991; 47:145 9. oxide synthase in the rat brain. Neuroscience 1992; 46:755 34 Bendtsen L, Jensen R, Olesen J. Qualitatively altered 84. nociception in chronic myofascial pain. Pain 1996; 65: 18 Lukacova N, Cizkova D, Marsala M, Jalc P, Marsala J. 259 64. Segmental and laminar distributions of nicotinamide ade- 35 Woolf CJ, Doubell TP. The pathophysiology of chronic nine dinucleotide phosphate-diaphorase-expressing and pain increased sensitivity to low threshold A beta-fibre neuronal nitric oxide synthase-immunoreactive neurons inputs. Curr Opin Neurobiol 1994; 4:525 34. versus radioassay detection of catalytic nitric oxide syn- 36 Bendtsen L, Ashina M. Sensitization of myofascial pain thase activity in the rabbit spinal cord. Neuroscience 1999; pathways in tension-type headache. In: Olesen J, Tfelt- 94:229 37. Hansen P, Welch KMA, editors. The headaches, 2nd edn. 19 Garthwaite J, Charles SL, Chess WR. Endothelium- Philadelphia: Lippencott Williams & Wilkins, 2000: 573 7. derived relaxing factor release on activation of NMDA 37 Ashina M, Lassen LH, Bendtsen L, Jensen R, Olesen J. receptors suggests role as intercellular messenger in the Effect of inhibition of nitric oxide synthase on chronic ten- brain. Nature 1988; 24:385 8. sion-type headache: a randomised crossover trial. Lancet 20 Garthwaite J, Garthwaite G, Palmer RM, Moncada S. 1999; 353:287 9. NMDA receptor activation induces nitric oxide synthesis 38 Ashina M, Bendtsen L, Jensen R, Lassen LH, Sakai F, from arginine in rat brain slices. Eur J Pharmacol 1989; Olesen J. Possible mechanisms of action of nitric oxide 172:413 6. synthase inhibitors in chronic tension-type headache. 21 Bredt DS, Snyder SH. Nitric oxide mediates glutamate- Brain 1999; 122:1629 35. linked enhancement of cGMP levels in the cerebellum. 39 Kindgen MD, Arndt JO. Nitric oxide as a chemical link in Proc Natl Acad Sci USA 1989; 86:9030 3. the generation of pain from veins in humans. Pain 1996; 22 Haley JE, Dickenson AH, Schachter M. Electrophysiologi- 64:139 42. cal evidence for a role of nitric oxide in prolonged chemical 40 Nakamura A, Fujita M, Shiomi H. Involvement of endog- nociception in the rat. Neuropharmacology 1992; 31:251 8. enous nitric oxide in the mechanism of bradykinin- 23 Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive induced peripheral hyperalgesia. Br J Pharmacol 1996; processing in the spinal cord. Pain 1993; 52:127 36. 117:407 12. 24 Wu J, Lin Q, McAdoo DJ, Willis WD. Nitric oxide contrib- 41 Olesen J. Clinical and pathophysiological observations in utes to central sensitization following intradermal injec- migraine and tension-type headache explained by integra- tion of capsaicin. Neuroreport 1998; 9:589 92. tion of vascular, supraspinal and myofascial inputs. Pain 25 Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, Willis 1991; 46:125 32. WD. Nitric oxide mediates the central sensitization of pri- 42 Sessle BJ. Acute and chronic craniofacial pain: brainstem mate spinothalamic tract neurons. J Neurophysiol 1999; mechanisms of nociceptive transmission and neuroplastic- 81:1075 85. ity, and their clinical correlates. Crit Rev Oral Biol Med 26 Hao J, Xu X. Treatment of chronic allodynia-like 2000; 11:57 91. response in spinally injured rats: effects of systemically 43 Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitro- administered nitric oxide synthase inhibitors. Pain 1996; glycerin as an experimental model of vascular headache. 66:313 9. Basic characteristics. Pain 1989; 38:17 24. 27 Mao J, Price DD, Zhu J, Lu J, Mayer DJ. The inhibition of 44 Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersen- nitric oxide-activated poly(ADP-ribose) synthase attenu- sitivity: a possible molecular mechanism of migraine pain. ates transsynaptic alteration of spinal cord dorsal horn Neuroreport 1993; 4:1027 30. � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 Neurobiology of chronic tension-type headache 171 45 Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric 62 Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Har- oxide donor (nitroglycerin) triggers genuine migraine greaves RJ. Dural vasodilation causes a sensitization of rat attacks. Eur Neurol 1994; 1:73 80. caudal trigeminal neurones in vivo that is blocked by a 5- 46 Ashina M, Bendtsen L, Jensen R, Olesen J. Nitric oxide- HT1B/1D agonist. Br J Pharmacol 1999; 126:1478 86. induced headache in patients with chronic tension-type 63 Otsuka M, Yoshioka K. Neurotransmitter functions of headache. Brain 2000; 123:1830 7. mammalian tachykinins. Physiol Rev 1993; 73:229 308. 47 Ishida YA, Tohyama M. Calcitonin gene-related peptide in 64 Hokfelt T, Kellerth JO, Nilsson G, Pernow B. Substance P: the nervous tissue. Prog Neurobiol 1989; 33:335 86. localization in the central nervous system and some pri- 48 Wei EP, Moskowitz MA, Boccalini P, Kontos HA. Calcito- mary sensory neurons. Science 1975; 190:889 90. nin gene-related peptide mediates nitroglycerin and 65 Gibson SJ, Polak JM, Allen JM, Adrian TE, Kelly JS, Bloom sodium nitroprusside-induced vasodilation in feline cere- SR. The distribution and origin of a novel brain peptide, bral arterioles. Circ Res 1992; 70:1313 9. neuropeptide Y, in the spinal cord of several mammals. J 49 Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial Comp Neurol 1984; 227:78 91. supersensitivity to nitric oxide (nitroglycerin) in migraine 66 Zhang X, Meister B, Elde R, Verge VM, Hokfelt T. Large sufferers. Cephalalgia 1993; 13:395 9. calibre primary afferent neurons projecting to the gracile 50 Jansen-Olesen I, Iversen HK, Olesen J, Edvinsson L. The nucleus express neuropeptide Y after sciatic nerve lesions: effect of nitroglycerin on sensory neuropeptides in isolated an immunohistochemical and in situ hybridization study guinea pig basilar arteries. In: Moncada S, Feelish M, Busse in rats. Eur J Neurosci 1993; 5:1510 9. R, Higgs EA, editors. Biology of nitric oxide, Vol. 3, Phys- 67 Yaksh TL, Abay EO, Go VL. Studies on the location and iology and clinical aspects. London: Portland Press, release of cholecystokinin and vasoactive intestinal pep- 1994:368 72. tide in rat and cat spinal cord. Brain Res 1982; 242:279 90. 51 Iversen H, Jansen I, Edvinsson L, Olesen J. Calcitonin 68 Fuji K, Senba E, Ueda Y, Tohyama M. Vasoactive intestinal gene-related peptide levels during nitroglycerin-induced polypeptide (VIP)-containing neurons in the spinal cord of headache. Cephalalgia 1993; 13 (Suppl.):185 [Abstract]. the rat and their projections. Neurosci Lett 1983; 37:51 5. 52 Ashina M, Bendtsen L, Jensen R, Sakai F, Olesen J. Possible 69 Gibson SJ, Polak JM, Anand P, Blank MA, Morrison JF, mechanisms of glyceryl-trinitrate-induced immediate Kelly JS, Bloon SR. The distribution and origin of VIP in headache in patients with chronic tension-type headache. the spinal cord of six mammalian species. Peptides 1984; Cephalalgia 2000; 20:919 24. 5:201 7. 53 Iversen HK, Holm S, Friberg L. Intracranial hemodynam- 70 Garry MG, Hargreaves KM. Enhanced release of immu- ics during intravenous nitroglycerin infusion. Cephalalgia noreactive CGRP and substance P from spinal dorsal horn 1989; 9 (Suppl.):84 5 [Abstract]. slices occurs during carrageenan inflammation. Brain Res 54 Holthusen H, Arndt JO. Nitric oxide evokes pain at noci- 1992; 5:139 42. ceptors of the paravascular tissue and veins in humans. J 71 Shehab SA, Atkinson ME. Vasoactive intestinal polypep- Physiol (Lond) 1995; 15:253 8. tide (VIP) increases in the spinal cord after peripheral axo- 55 Lassen LH, Thomsen LL, Kruuse C, Iversen HK, Ole- tomy of the sciatic nerve originate from primary afferent sen J. Histamine-1 receptor blockade does not prevent neurons. Brain Res 1986; 30:37 44. nitroglycerin induced migraine. Support for the NO- 72 Sluka KA, Westlund KN. Spinal cord amino acid release hypothesis of migraine. Eur J Clin Pharmacol 1996; and content in an arthritis model: the effects of pretreat- 49:335 9. ment with non-NMDA, NMDA, and NK1 receptor antag- 56 Headache Classification Committee of the International onists. Brain Res 1993; 5:89 103. Headache Society. Classification and diagnostic criteria for 73 Weihe E, Sch�fer MK, Nohr D, Persson S. Expression of headache disorders, cranial neuralgias and facial pain. neuropeptides, neuropeptide receptors and neuropeptide Cephalalgia 1988; 8 (Suppl. 7):1 96. processing enzymes in spinal neurons and peripheral non- 57 Sorkin EM, Brogden RN, Romankiewicz JA. Intravenous neural cells and plasticity in models of inflammatory pain. glyceryl trinitrate (nitroglycerin). A review of its pharma- In: Hokfelt T, Schaible H-G, Schmidt RF, editors. Neu- cological properties and therapeutic efficacy. Drugs 1984; ropeptides, nociception and pain. London: Chapman & 27:45 80. Hall, 1994:43 69. 58 Read SJ, Smith MI, Hunter AJ, Parsons AA. Enhanced 74 Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide nitric oxide release during cortical spreading depression release in the extracerebral circulation of humans during following infusion of glyceryl trinitrate in the anaesthe- migraine headache. Ann Neurol 1990; 28:183 7. tized cat. Cephalalgia 1997; 17:159 65. 75 Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evi- 59 Wu J, Lin Q, Lu Y, Willis WD, Westlund KN. Changes in dence for increased plasma levels of calcitonin gene- nitric oxide synthase isoforms in the spinal cord of rat related peptide in migraine outside of attacks. Pain 2000; following induction of chronic arthritis. Exp Brain Res 86:133 8. 1998; 118:457 65. 76 Goadsby PJ, Edvinsson L. Human in vivo evidence for 60 Wu J, Fang L, Lin Q, Willis WD. Fos expression is induced trigeminovascular activation in cluster headache. Neu- by increased nitric oxide release in rat spinal cord dorsal ropeptide changes and effects of acute attacks therapies. horn. Neuroscience 2000; 96:351 7. Brain 1994; 117:427 34. 61 Pardutz A, Krizbai I, Multon S, Vecsei L, Schoenen J. Sys- 77 Fanciullacci M, Alessandri M, Sicuteri R, Marabini S. temic nitroglycerin increases nNOS levels in rat trigeminal Responsiveness of the trigeminovascular system to nitro- nucleus caudalis. Neuroreport 2000; 11:3071 5. glycerine in cluster headache patients. Brain 1997; 120:283 8. � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172 172 M Ashina 78 Ashina M, Bendtsen L, Jensen R, Olesen J. Plasma levels 85 Larsson R, Oberg PA, Larsson SE. Changes of trapezius of substance P, neuropeptide Y and vasoactive intestinal muscle blood flow and electromyography in chronic neck polypeptide in patients with chronic tension-type head- pain due to trapezius myalgia. Pain 1999; 79:45 50. ache. Pain 1999; 83:541 7. 86 Larsson SE, Bodegard L, Henriksson KG, Oberg PA. 79 Reinert A, Kaske A, Mense S. Inflammation-induced Chronic trapezius myalgia. Morphology and blood flow increase in the density of neuropeptide-immunoreactive studied in 17 patients. Acta Orthop Scand 1990; 61:394 8. nerve endings in rat skeletal muscle. Exp Brain Res 1998; 87 Simms RW. Fibromyalgia is not a muscle disorder. Am J 121:174 80. Med Sci 1998; 315:346 50. 80 Uddman R, Edvinsson L, Jansen I, Stiernholm P, Jensen K, 88 Yunus MB, Kalyan-Raman UP, Masi AT, Aldag JC. Elec- Olesen J, Sundler F. Peptide-containing nerve fibres in tron microscopic studies of muscle biopsy in primary human extracranial tissue: a morphological basis for neu- fibromyalgia syndrome: a controlled and blinded study. J ropeptide involvement in extracranial pain? Pain 1986; Rheumatol 1989; 16:97 101. 27:391 9. 89 Langemark M, Jensen K, Olesen J. Temporal muscle blood 81 Bach FW, Langemark M, Ekman R, Rehfeld JF, Schifter S, flow in chronic tension-type headache. Arch Neurol 1990; Olesen J. Effect of sulpiride or paroxetine on cerebrospi- 47:654 8. nal fluid neuropeptide concentrations in patients with 90 Hickner RC, Bone D, Ungerstedt U, Jorfeldt L, Henriksson chronic tension-type headache. Neuropeptides 1994; J. Muscle blood flow during intermittent exercise: compar- 27:129 36. ison of the microdialysis ethanol technique and 133Xe 82 Ashina M, Bendtsen L, Jensen R, Schifter S, Jansen-Olesen clearance. Clin Sci (Colch) 1994; 86:15 25. I, Olesen J. Plasma levels of calcitonin gene-related peptide 91 Ashina M, Stallknecht B, Bendtsen L, Pedersen JF, Galbo in chronic tension-type headache. Neurology 2000; H, Dalgaard P, Olesen J. In vivo evidence of altered skeletal 55:1335 40. muscle blood flow in chronic tension-type headache. Brain 83 Girgis SI, Macdonald DW, Stevenson JC, Bevis PJ, Lynch 2002; 125:320 6. C, Wimalawansa SJ et al. Calcitonin gene-related peptide: 92 Mitchell JH, Victor RG. Neural control of the cardiovascu- potent vasodilator and major product of calcitonin gene. lar system: insights from muscle sympathetic nerve Lancet 1985; 2:14 6. recordings in humans. Med Sci Sports Exerc 1996; 28:S60 84 Henriksson KG, Lindman R. Morphologic, physiologic, S69. and biochemical changes in tender and painful muscle. In: 93 Bengtsson A, Bengtsson M. Regional sympathetic block- Olesen J, Schoenen J, editors. Tension-type headache: clas- ade in primary fibromyalgia. Pain 1988; 33:161 7. sification, mechanisms and treatment, Vol. 3. New York: 94 Roberts WJ. A hypothesis on the physiological basis for Raven Press, 1993:97 107. causalgia and related pains. Pain 1986; 24:297 311. � Blackwell Publishing Ltd Cephalalgia, 2004, 24, 161 172

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