Neurobiology of chronic tension-type headache.pdf

Oxford, UKCHA

1468-2982Blackwell Science, 2003

Review Article

Blackwell Science, Ltd

Cephalalgia

243161172

Neurobiology 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 3926, e-mail ashina@dadlnet.dk

Received 30 January 2003, accepted 16 June 2003

45 4323 2300, ext. 3068, fax

was to study the neurobiology of chronic tension-

type headache. Speciﬁc aims were: (i) to investigate

NO mechanisms in chronic tension-type headache

sufferers; (ii) to study plasma levels of CGRP, SP,

NPY and VIP in patients with chronic tension-type

headache; and (iii) to study

Introduction

Chronic tension-type headache is one of the most

common and important types of primary headaches

(1) and represents a considerable health and socio-

economic problem (2). Increased tenderness of

pericranial myofascial tissues to manual palpation

is the most prominent abnormal ﬁnding in patients

with chronic tension-type headache (3–6). Painful

impulses from these tissues may be referred to the

head and perceived as headache, and myofascial

mechanisms may therefore play a major role in

the pathophysiology of tension-type headache (7).

Progress in molecular neurobiology of pain (8) and

an increasing number of studies on tension-type

headache (9) have increased our knowledge about

the mechanisms underlying chronic head pain.

Thus, substantial experimental evidence indicates

that central sensitization, i.e. increased excitability of

neurons in the central nervous system (CNS) gener-

ated by prolonged nociceptive input from the peric-

ranial myofascial tissues, plays an important role in

the pathophysiology of chronic pain (8) and chronic

tension-type headache (9). Furthermore, discovery

of neurotransmitters and neuromodulators such as

nitric oxide (NO), calcitonin gene-related peptide

(CGRP), substance P (SP), neuropeptide Y (NPY)

and vasoactive intestinal polypeptide (VIP) involved

in the pain processing provides new insights to our

understanding of the biology of chronic head pain.

To explore the neurobiology of human chronic pain

conditions, it is necessary to utilize advances made

in basic research. The purpose of the present thesis

skeletal muscle

blood ﬂow during static exercise in patients with

chronic tension-type headache.

in vivo

Nitric oxide in chronic tension-type headache

Biosynthesis of nitric oxide

The free radical NO is a messenger molecule involved

in various biological functions (10–12). NO is synthe-

sized by a complex family of nitric oxide synthase

(NOS) enzymes (13). Because NO is highly reactive

and unstable, much of the research on its functions

is based on characterization of NOS. Three distinct

NOS enzymes [neuronal NOS (nNOS), endothelial

NOS, inducible NOS) have been puriﬁed, cloned and

biochemically characterized (13). The precise mech-

anism of NO formation is not fully understood. It is

known that NO is synthesized from L-arginine and

that the reaction also yields citrulline (Fig. 1).

NO and nociception in animal studies

NO or NOS immunoreactivity has been identiﬁed in

the peripheral and central nervous system. In the

peripheral nervous system, nNOS immunoreactivity

was demonstrated in dorsal root ganglia in both man

and rat (14) and in perivascular nerves of large cere-

Cephalalgia,

2004,

, 161 – 172

161

162

M Ashina

H +

+ N

H 2 N

NH 2

H 2 N

NH 2

1 NADPH

•

N=O

O 2

H 3 N +

COO –

H 3 N +

COO –

H 3 N +

COO –

N G -hydroxy-L-arginine

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

the central nervous system, nNOS is present exclu-

sively in neurons and NOS neurons were demon-

strated in the spinal trigeminal nucleus (17) and in

the dorsal horn of the spinal cord (14, 18).

NO derived from neurons was ﬁrst recognized

when N-methyl-D-aspartate (NMDA) receptor acti-

vation in cerebellar cultures resulted in NO generation

(19). Involvement of NO in neuronal signalling was

conﬁrmed by demonstrating that NOS inhibitors

blocked the stimulation of cyclic guanosine mono-

phosphate in brain that is associated with activation

of NMDA receptor (20, 21). Later, it was demonstrated

that sensitization of pain pathways in the spinal cord

may be caused by or associated with activation of

nNOS and the generation of NO (22–24). Moreover,

prolonged elevation of NO levels within the spinal

dorsal horn is important in maintaining the central

sensitization (25). Finally, it has been shown that inhi-

bition of NOS reduces central sensitization in pain

models (22, 26, 27) and that nociceptive responses in

these models are enhanced by NO donors (28, 29).

Taken together, these data suggest that NO is an

important transmitter in pain pathways of the spinal

cord and that NO contributes to development and

maintenance of central sensitization at the spinal level.

type headache. Thus, several studies have consis-

tently reported increased myofascial tenderness as

the most prominent abnormal ﬁnding in patients

with chronic tension-type headache (3–6). Further

support for myofascial involvement is the ﬁnding of

increased muscle hardness (30) and a positive corre-

lation between muscle hardness and tenderness in

chronic tension-type headache (31). In addition to

ﬁndings in the periphery, chronic tension-type head-

ache sufferers also exhibit signs of increased sensi-

tivity in the CNS. Thus, pressure pain detection and

tolerance thresholds to mechanical stimuli have been

found decreased in these patients (32, 33). Further-

more, Bendtsen et al. (34) demonstrated that patients

with chronic tension-type headache had a qualita-

tively altered pain perception. On the basis of these

ﬁndings and data from basic pain research (35), it

has been suggested that the central sensitization and

thereby the chronic pain state in patients with

chronic tension-type headache may be due to sensi-

tization at the level of the spinal dorsal horn/trigem-

inal nucleus induced by prolonged nociceptive input

from pericranial myofascial tissues (9, 36).

Inhibition of NOS in chronic tension-type headache

In order to test the hypothesis that inhibition of NO

and thereby central sensitization would reduce

chronic headache, Ashina et al. (37) investigated the

analgesic effect of the NOS inhibitor L-N

Central sensitization and chronic tension-type

headache

methyl

arginine hydrochloride (L-NMMA) in patients with

chronic tension-type headache. In a double-blind,

Nociception from pericranial myofascial tissues may

play a major role in the pathophysiology of tension-

Cephalalgia,

2004,

, 161 – 172

Neurobiology of chronic tension-type headache

163

placebo-controlled crossover study patients received

L-NMMA or placebo on 2 days. L-NMMA reduced

headache intensity signiﬁcantly more than placebo

(Fig. 2). To explore the mechanisms of this analgesic

effect Ashina et al. (38) also studied the relationship

between myofascial factors and NOS inhibition. This

study showed that both muscle hardness and ten-

derness were signiﬁcantly reduced following treat-

ment with L-NMMA, while there was no signiﬁcant

reduction at any time after treatment with placebo

(Figs 3 and 4). The muscle hardness was signiﬁcantly

reduced following treatment with L-NMMA com-

pared with placebo. The reduction in tenderness

following treatment with L-NMMA did not reach

statistical signiﬁcance compared with placebo. The

pressure pain detection thresholds in the ﬁnger and

temporal region were largely unchanged following

treatment with L-NMMA. Thus, these studies (37,

38) demonstrated that the NOS inhibitor, L-NMMA,

reduces headache intensity and muscle hardness in

patients with chronic tension-type headache.

An important question is how L-NMMA modu-

lates myofascial factors in patients with chronic

tension-type headache and whether the effects of L-

NMMA are due to an action in muscle, peripheral

nerves or the CNS. It is well established that persis-

tent activity in peripheral nociceptors may lead to

sensitization of neurons in the spinal dorsal horn,

partly via activation of NMDA receptors (8). Many

of the effects of NMDA receptor activation are medi-

ated via production of NO (23) and, as described

earlier, animal models of persistent pain have shown

that inhibitors of NOS decrease sensitization of the

spinal dorsal horn induced by continuous painful

input from the periphery (22, 24, 26, 27). On the basis

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-

ably due to reduction of central sensitization at the

level of the spinal dorsal horn/trigeminal nucleus.

One should, however, also consider other possible

mechanisms of action. Thus, it is possible that L-

NMMA has direct anti-nociceptive effects in myofas-

cial tissues. It has been demonstrated that NOS

inhibitors have anti-nociceptive effects after periph-

eral administration, probably due to inhibition of

endothelial NOS (eNOS) (22, 39, 40). However, the

exact role of NO in the periphery is still far from

understood, and additional research is needed to

120

Min

–10

–20

–30

Figure 2

Percent changes from baseline pain intensity on a

100-mm visual analogue scale (VAS) in 16 patients with

chronic tension-type headache. The pain intensity was

signiﬁcantly more reduced following treatment with L-

NMMA (

) compared with placebo (

) (

0.01). *

0.05

compared with baseline (time

0). The plots represent mean

scores. (Modiﬁed from Ashina

et al

. 1999, by permission of the

120

Lancet

Min

120

–5

Min

–10

–1

–15

–2

–20

–3

–25

–4

–30

–5

Figure 4

Percent changes in total tenderness score (TTS) in 16

patients with chronic tension-type headache. The TTS tended

to be reduced following treatment with L-NMMA (

–6

)

Figure 3

Percent changes in muscle hardness in 16 patients

with chronic tension-type headache. Muscle hardness was

signiﬁcantly more reduced following treatment with L-

NMMA (

compared with placebo (

0.11). Within each treatment,

the TTS was signiﬁcantly reduced at 60 and 120 min after start

of the infusion of L-NMMA, while there was no signiﬁcant

change at any time after treatment with placebo. **

) (

) than with placebo (

) in patients with chronic

0.01

myofascial pain (

0.04). *

0.05 compared with baseline

compared with baseline (time

0). The plots represent mean

scores. (Reproduced from Ashina

(time

0). The plots represent mean scores. (Reproduced from

Ashina

et al

. 1999, by permission of

et al

. 1999, by permission of Oxford University Press.)

Oxford University Press.)

Cephalalgia,

2004,

, 161 – 172

164

M Ashina

clarify whether NO may activate or sensitize nocice-

ptors in myofascial tissues.

The anti-nociceptive effect of L-NMMA might

also be due to blocking of vascular input. Excessive

vascular nociception may contribute to a primary

myofascial nociception in patients with tension-

type headache (41). L-NMMA inhibits all three

types of NOS, including eNOS. Thus, it is possible

that L-NMMA exerts its action by blocking eNOS

and thereby moderate vasodilatation of cephalic/

extracephalic arteries in patients with chronic ten-

sion-type headache. Because of convergence of

nociceptive input from facial tissues at the spinal/

trigeminal level (42), blocking of vascular input

might also lead to reduction of myofascial nocicep-

tion from pericranial muscles (38).

Taken together, these data indicate that the NOS

inhibitor L-NMMA elicits its anti-nociceptive effect

in chronic tension-type headache by modulation of

nociceptive information from myofascial tissues.

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.

120

Infusion

Minutes

Hours

Figure 5

Median headache intensity over time during

(20 min) and after infusion of glyceryl trinitrate (GTN) (

patients;

, controls) in

16 patients with chronic tension-type headache and in 16

healthy subjects. Headache was scored on a 10-point verbal

rating scale (VRS). The patients developed signiﬁcantly

stronger headache than healthy controls both during the ﬁrst

hour (immediate headache) (

, controls) and placebo (

, patients;

0.02) and during the

subsequent 11 h (delayed headache) (

0.008). (Modiﬁed

from Ashina et al. 2000, by permission of Oxford University

Press.)

vasodilatation and headache in humans (48, 49).

However, this effect of GTN was not conﬁrmed in

isolated guinea pig basilar arteries (50). Further-

more, Iversen and colleagues (51) reported that

plasma levels of CGRP are unchanged in the cranial

circulation of healthy subjects after GTN infusion. To

study the role of CGRP in NO-induced immediate

headache, Ashina et al. (52) measured plasma levels

of CGRP during and after infusion of GTN in

patients with chronic tension-type headache (52). No

signiﬁcant changes in plasma CGRP after GTN infu-

sion were found in either patients or controls. Inter-

estingly, the dosage of GTN used in that study is

known to liberate CGRP in cats (48) and vasodilata-

tion in humans (53).

The unchanged sensitivity of pericranial myofas-

cial pain pathways seems also to rule out sensitiza-

tion of myofascial peripheral and central pathways

as a mechanism of the immediate headache (52).

Unchanged pressure-pain detection thresholds in

the ﬁnger, i.e. outside of the pain area, may also

indicate no alteration in sensitivity of third-order

neurons (52).

NO evokes pain in humans when injected

paravascularly or perfused through a vascularly iso-

lated hand vein segment (54). These ﬁndings suggest

that NO may directly activate or sensitize nocicep-

tors around blood vessels. Intravenous infusion of

GTN induces dilatation of the middle cerebral artery

in healthy subjects (53), and in migraineurs and

patients with episodic tension-type headache (49). In

these studies the dilatation lasted at least until 1 h

NO induction in chronic tension-type headache

In 1989, Iversen and colleagues introduced a NO

donor, glyceryl trinitrate (GTN), model of experi-

mental headache (43). Using this model, it has been

demonstrated that patients with migraine are hyper-

sensitive to NO, i.e. migraineurs develop signiﬁ-

cantly stronger headache after GTN infusion than

healthy subjects (44, 45). Furthermore, it has been

shown that GTN may induce strong immediate

headache in patients with episodic tension-type

headache compared with healthy subjects (44). To

explore further the role of NO in development of

headache and modulation of myofascial pain input,

Ashina et al. (46) studied the effect of GTN in

patients with chronic tension-type headache. GTN

infusion in patients resulted in a biphasic response

with an immediate and a delayed headache (46).

Patients developed signiﬁcantly stronger immediate

and delayed headache on a GTN day than on a pla-

cebo day (Fig. 5). Furthermore, patients developed

signiﬁcantly stronger headache after GTN than con-

trols (Fig. 5).

The mechanisms responsible for the GTN-induced

headache in patients with primary headaches are

unknown. CGRP is an important neuromodulator of

the sensory system (47). An experimental study has

shown that GTN dilates cerebral arteries in cats via

liberation of CGRP, and it has been suggested that

this mechanism may explain the occurrence of

Cephalalgia,

2004,

, 161 – 172

Neurobiology of chronic tension-type headache

165

after cessation of GTN infusion and 3 h in another

study (55). Collectively, these studies suggest that

immediate headache after GTN infusion in patients

with chronic tension-type headache may originate

from NO-induced activation or sensitization of sen-

sory nerves around cephalic arteries, or from NO-

induced arterial dilatation, or both (46).

The most important ﬁnding in the study by Ash-

ina et al. (46) was that systemic administration of NO

donor in patients with chronic tension-type head-

ache resulted in biphasic response with an immedi-

ate and a delayed headache (8 h after start of

infusion) (Fig. 5). Interestingly, the time proﬁle of the

GTN-induced headache in patients with chronic ten-

sion-type headache was strikingly similar to the time

proﬁle of GTN-induced headache in patients with

migraine (45). Thus, patients with migraine without

aura developed an immediate headache during

GTN infusion and a delayed headache fulﬁlling

International Headache Society (IHS) (56) criteria for

migraine several hours after cessation of the infu-

sion. The characteristics of the delayed headache in

chronic tension-type headache were, however, dif-

ferent from those in patients with migraine. Eighty

percent of migraine patients developed migraine

without aura after infusion of GTN (45), while 87%

of patients with chronic tension-type headache

developed a tension-type headache (46). These data

suggest that patients with chronic tension-type

headache are supersensitive to NO, similar to

patients with migraine, and that the majority of

patients in both groups develop their usual head-

ache several hours after the infusion of GTN.

What are the mechanisms of the delayed headache

and why do patients with chronic tension-type head-

ache and patients with migraine develop delayed

headache resembling their usual type of headache,

and why do most healthy subjects develop no

delayed headache or only a minor one? Studies in

rats and in humans have shown that after intrave-

nous administration of GTN very little drug remains

in the blood and that the majority of the GTN is

distributed to tissues (57). In the anaesthetized cat,

intravenous infusion of GTN induces a prolonged

(60 min) increase of NO in brain parenchyma (58),

and a prolonged increase of NO levels in the spinal

dorsal horn was demonstrated during central sensi-

tization (59). Furthermore, Wu and colleagues (60)

demonstrated that during central sensitization both

endogenous and exogenous nitric oxide induce

NOS- and

-immunoreactive neurons in the cer-

vical part of trigeminal nucleus caudalis in rats after

4 h. These data indicate that GTN infusion may

result in storage and subsequent liberation of NO or

it may trigger endogenous NO production in the

CNS, thereby enhancing sensitization of nociceptive

pathways in the CNS of patients with chronic ten-

sion-type headache.

Alternatively, sustained NO-induced vascular

nociception may lead to central sensitization and

subsequent convergence of nociceptive input from

blood vessels and myofascial tissue. Thus, NO may

activate or sensitize nociceptors around blood ves-

sels directly (54) or by dilatation (53). Dilatation of

meningeal blood vessels in rats causes sensitization

of central trigeminal neurons and facilitation of con-

vergent sensory responses (62). It is therefore pos-

sible that excessive vascular nociception caused by

GTN may gradually augment the sensitizing effect

of preexisting myofascial input in chronic tension-

type headache sufferers (41).

As mentioned earlier, patients with chronic ten-

sion-type headache and patients with migraine

develop increased delayed headache with different

characteristics. The most likely explanation is that

preexisting facilitation of distinct nociceptive central

pathways in chronic tension-type headache sufferers

(myofascial pathways) and migraineurs (vascular

pathways) may be enhanced by NO-induced central

sensitization. This may explain why the delayed

headache fulﬁlled tension-type headache criteria in

patients with chronic tension-type headache and

migraine criteria in migraineurs. This could also

explain why NO does not induce strong delayed

headache in healthy subjects when no preexisting

sensitization is present.

c-fos

Summary

Studies of NO mechanisms in chronic tension-type

headache suggest that NO plays an important role

in the pathophysiology of this disorder (37, 38, 46).

The anti-nociceptive effect of NOS inhibitor suggests

that inhibition of NOS may become a novel principle

in treatment of chronic tension-type headache. It is

probable that the anti-nociceptive effect is due to

reduction of central sensitization at the level of the

spinal dorsal horn or trigeminal nucleus, or both.

Studies with selective NOS inhibitors are needed to

determine which type of NOS is involved and its

exact site of action in chronic tension-type headache.

Data from the GTN model of experimental headache

indicate that NO-induced delayed headache in

patients with chronic tension-type headache is due

c-fos

(an immediate–early gene) which can further acti-

vate the production of other substances in the CNS.

In addition, Pardutz et al. (61) reported that subcu-

taneous GTN produced a signiﬁcant increase of

Cephalalgia,

2004,

, 161 – 172

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