Nerve growth factor and ATP excite different neck muscle nociceptors in anaesthetized mice

Neck muscle nociception probably plays a major role in the pathophysiology of tension-type headache. Recent studies have demonstrated sustained facilitation of brainstem nociception due to noxious neck muscle input evoked by nerve growth factor (NGF) or alpha,beta-methylene ATP (ATP) in mice. Hypothesized different afferent pathways in NGF and ATP models were addressed by local application of tetrodotoxin (TTX) in neck muscles. Brainstem nociception was monitored in 55 anaesthetized mice by the jaw-opening reflex elicited by electrical tongue stimulation. Sole administration of 100 nmol/l ATP or 0.8 micromol/l NGF evoked sustained reflex facilitation for at least 95 min. Preceding TTX administration prevented ATP-induced facilitation, but was without effect on NGF. Subsequent administration of 100 nmol/l TTX reversed ATP-evoked facilitation, but was ineffective on NGF. Divergent effects of TTX suggest preferential excitation of group III muscle afferents by ATP and group IV by NGF. Thus, both models address different pathways in pericranial pain.     

ATP induces sustained facilitation of craniofacial nociception through P2X receptors on neck muscle nociceptors in mice

Noxious input from neck muscles probably plays a key role in tension-type headache pathophysiology. ATP selectively excites group III and IV muscle afferents in vitro. Accordingly, ATP infusion into trapezius muscle induces strong pain and local tenderness in healthy man. The present study addresses the impact of ATP on neck muscle nociception in anaesthetized mice. Craniofacial nociceptive processing was tested by the jaw-opening reflex via noxious electrical tongue stimulation. Within 2 h after injection of 100 nmol/l or 1 micromol/l ATP into semispinal neck muscles, reflex integrals significantly increased by 114% or 328%, respectively. Preceding intramuscular administration of the P2X receptor antagonist PPADS (3-100 nmol/l) suppressed the ATP effect. Subsequent application of PPADS (100 nmol/l) caused a total recovery of facilitated reflex to baseline values. ATP induces sustained facilitation of craniofacial nociception by prolonged excitation of P2X receptors in neck muscles.     

Neuronal nitric oxide synthase is involved in the induction of nerve growth factor-induced neck muscle nociception

(Headache 2011;51:734‐743) Background.— Neck muscle nociception mediated by nitric oxide may play a role in the pathophysiology of tension‐type headache. Objective.— The present study addresses the involvement of neuronal nitric oxide synthase (nNOS) in the facilitation of neck muscle nociception after local application of nerve growth factor (NGF). Methods.— After administration of NGF into semispinal neck muscles, the impact of neck muscle noxious input on brainstem processing was monitored by the jaw‐opening reflex in anesthetized mice. The modulatory effect of preceding and subsequent administration of an inhibitor of neuronal nitric oxide synthase on central facilitation was addressed in a controlled study. Results.— With preceding i.p. application of saline or 0.096 mg/kg of the specific nNOS inhibitor Nω‐propyl‐L‐arginine (NPLA), NGF induced a sustained reflex facilitation within 60 minutes. Preceding injection of 0.96 mg/kg or 1.92 mg/kg NPLA completely prevented the potentially facilitatory effect of NGF. Subsequent administration of 0.96 mg/kg NPLA did not affect established NGF‐evoked reflex facilitation. Thus, NPLA prevents facilitation of brainstem processing by noxious myofascial input from neck muscles in a dose‐dependent manner. Conclusion.— These findings suggest that nNOS is involved in the induction but not the maintenance of NGF‐evoked facilitation of nociception in the brainstem. These results from an experimental animal model may support the idea of NOS and nNOS as potential targets for pharmacological treatment of tension‐type headache.     

Long-term potentiation of orofacial sensorimotor processing by noxious input from the semispinal neck muscle in mice

Tension-type headache is the most common type of primary headaches but no conclusive concept of pathophysiology exists. This may be due to a lack of an appropriate animal model. This study addressed the hypothesis that noxious neck muscle input induces central sensitization of orofacial sensorimotor processing. The effect of hypertonic saline injection into the semispinal neck muscle on the jaw-opening reflex (JOR) was investigated in anaesthetized mice (n = 11). Hypertonic saline injection into the neck muscle facilitated the JOR for at least one hour: integral (+94.5%) and duration (+18.7%) increased, latency decreased (-7.5%). The reflex threshold decreased to 61% after injection. Isotonic saline injection into the neck muscle (n = 11) or hypertonic saline injection into a hindpaw muscle (n = 10) did neither change the reflex integral nor the threshold. Long-term potentiation of the JOR by noxious neck muscle input may be an appropriate model to investigate tension-type headache pathophysiology.     

EMG analysis of the late exteroceptive suppression period of temporal muscle activity in episodic and chronic tension-type headaches

EMG analysis of the late exteroceptive suppression period of the temporal muscle activity is discussed as comparative methodology in the assessment of patients suffering from chronic tension-type headache and from migraineurs. After electrical perioral trigeminal nerve stimulation during maximum voluntary jaw occlusion, early (ES1) and late (ES2) exteroceptive suppression periods can be registered above the temples using surface EMG recordings. In patients suffering from chronic tension-type headache the duration of the late suppression period is shortened (p less than 0.001) compared to migraineurs or controls. However, patients suffering from episodic tension-type headache display late suppression periods of temporal muscle activity of differing lengths.     

Exteroceptive suppression of temporalis muscle activity: methodological and physiological aspects

In recent years studies of the suppression of EMG activity in temporalis muscle induced by stimulation in the trigeminal territory have opened new perspectives in headache research. The various methods that have been used in different laboratories are reviewed and some of the physiological modulations of temporalis exteroceptive suppression are described. Among different methods of recording, averaging 10 full-wave rectified EMG responses produces results with acceptable variability and discomfort. In order to obtain maximal responses the intensity of the stimulation should reach at least 20 mA. To avoid habituation of the second temporalis exteroceptive suppression period (ES2), the stimulation frequency has to be at O.1 Hz or below. The level of voluntary contraction is not a critical variable as long as it reaches 50% of maximum. Some physiological variations of temporalis suppression are well documented. In females, ES2 is shorter during menstruation than at mid-cycle and correlated with the estradiolprogesterone ratio in plasma. Conditioning temporalis ES2, by a preceding peripheral stimulus markedly reduces its duration, which is partly reversible by naloxone. Various pharmacological agents are able to modify temporalis ES2: its duration is increased by 5-HT₁ antagonists, but decreased by 5-HT uptake blockers; contradictory results have been obtained with acetylsalicylic acid. These results suggest that inhibitory brain-stem interneurons mediating temporalis ES2 are inhibited by serotonergic afferents, probably from the raphe magnus nucleus, and that the latter receives an excitatory input from the periaqueductal gray matter and other limbic structures, in part via opioid receptors.     

Forward head posture and neck mobility in chronic tension-type headache: a blinded, controlled study

Forward head posture (FHP) and neck mobility were objectively assessed in 25 patients with chronic tension-type headache (CTTH) and 25 healthy controls. Side-view pictures were taken in a sitting position to measure the cranio-vertebral angle. A cervical goniometer was employed to measure the range of all cervical motions. Patients with CTTH showed a smaller cranio-vertebral angle (45.3 degrees +/- 7.6 degrees) than controls (54.1 degrees +/- 6.3 degrees), thus presenting a greater FHP (P < 0.001). Patients also had lesser neck mobility for all cervical movements, except for right lateral flexion (P < 0.01). There was a positive correlation between the cranio-vertebral angle and neck mobility. Within the CTTH group, a negative correlation was found between the cranio-vertebral angle and headache frequency, but neck mobility did not correlate with headache parameters. Further research is needed to define a potential role of FHP and restricted neck mobility in the origin or maintenance of TTH.     

Stress-induced pain and muscle activity in patients with migraine and tension-type headache

We recorded deep pain and surface electromyographic (EMG) responses to stress in 22 migraineurs during headache-free periods, 18 patients with tension-type headache (TTH), and 44 healthy controls. Sixty minutes of cognitive stress was followed by 30 min relaxation. EMG and pain (visual analogue scale) in the trapezius, neck (splenius), temporalis and frontalis areas were recorded. TTH patients had higher pain responses in temporalis and frontalis (with similar trends for trapezius and splenius) and more potentiation of pain during the test than controls. Migraine patients developed more pain in the splenius and temporalis than controls. Muscle pain responses were more regional (more pain in the neck and trapezius compared with the temporalis and frontalis) in migraine than in TTH patients. TTH patients had delayed pain recovery in all muscle regions compared with controls, while migraine patients had delayed pain recovery in a more restricted area (trapezius and temporalis). EMG responses were not different from controls in headache patients, and EMG responses did not correlate with pain responses. TTH patients had delayed EMG recovery in the trapezius compared with controls and migraine patients. These results support the concept that (probably central) sensitization of pain pathways and the motor system is important in TTH. Less pronounced and more regional (either peripheral or central) trigeminocervical sensitization seems to be important in migraine. Surface-detectable muscular activation does not seem to be causal for pain during cognitive stress either in migraine or in TTH.     

Characteristics of headache in migraine without aura and episodic tension-type headache in the Turkish population according to the IHS classification

We evaluated the characteristics of headache in migraine without aura and episodic tension-type headache diagnosed according to the International Headache Society (IHS) Classification. Fifty migraine without aura and 50 tension-type headache patients were selected prospectively. Fifty-eight percent of migraineurs had pain of a pulsating quality; 88% had severe pain and 74% had unilateral pain; aggravation by routine physical activity was reported by 96%. Episodic tension-type headache was of a pressing quality in 52%, moderate in 40%, bilateral in 82% and aggravated by routine physical activity in 16%. Nausea and/or vomiting, photophobia and phonophobia were reported significantly more commonly in migraineurs than tension-type headache patients.     

Cross-correlation between stress, pain, physical activity, and temporalis muscle EMG in tension-type headache

Thirty-six tension-type headache subjects and 36 non-headache matched controls recorded their temporalis muscle electromyographic (EMG) activity and their pain intensity, stress and physical activity levels in a daily diary. Measurements were performed every 30 min for 6 days (EMG 3 days only). A time-lagged cross-correlational analysis between pain, stress, physical activity, and EMG shows that the highest correlation coefficient values occurred between pain and stress at the same ( r =0.33) and at the two preceding 0.5 h time points ( r =0.21 and r =0.26) in the headache group. Virtually no correlation was found between pain, stress, or physical activity with EMG for either group. These data show that temporalis muscle activity levels were not related to the rise and fall of the subjects' pain or stress levels. Conversely, elevated stress appeared to be highly related to pain; it occurs as both an antecedent and simultaneous event with elevated headache pain.     

Population-based validation of a German-language self-administered headache questionnaire

We validated a German-language self-administered headache questionnaire for migraine (M), tension-type headache (TTH) and trigeminal autonomic cephalalgia (TAC) in a general population sample of people with headache. Randomly selected subjects ( n  = 240) diagnosed by the questionnaire as M ( n  = 60), TTH ( n  = 60), a combination of M and TTH (M+TTH, n  = 60) and TAC ( n  = 60) were invited for examination by headache specialists. One hundred and ninety-three subjects (80%) were studied. Sensitivity and specificity for M were 0.85 and 0.85, for TTH 0.6 and 0.88, for M+TTH 0.82 and 0.87, respectively. Cohen's κ was 0.6 (95% confidence interval 0.50, 0.71). Of 45 patients with TAC according to the questionnaire, physicians diagnosed cluster headache in two patients only. We conclude: (i) the questionnaire can be used to diagnose M, TTH and M+TTH, but not TAC; (ii) screening questionnaires for epidemiological research should be validated in a general population sample but not in a tertiary headache clinic.     

Tension-type headache and sleep apnea in the general population

The main objective of this study is to investigate the relationship between tension-type headache and obstructive sleep apnea in the general population. The method involves a cross-sectional population-based study. A random age and gender stratified sample of 40,000 persons aged 20-80 years residing in Akershus, Hedmark or Oppland County, Norway were drawn by the National Population Register. A postal questionnaire containing the Berlin Questionnaire was used to classify respondents to be of either high or low risk of obstructive sleep apnea. Included in this study were 297 persons with high risk and 134 persons with low risk of sleep apnea, aged 30-65 years. They underwent an extensive clinical interview, a physical and a neurological examination by physicians, and in-hospital polysomnography. Those with apnea hypopnoea index (AHI) ≥5 were classified with obstructive sleep apnea. Tension-type headache was diagnosed according to the International Classification of Headache Disorders. Results showed the prevalence of frequent and chronic tension-type headache was 18.7 and 2.1% in the participants with obstructive sleep apnea. The logistic regression analyses showed no significant relationship between tension-type headache and obstructive sleep apnea, with adjusted odds ratios for frequent tension-type headache of 0.95 (0.55-1.62) and chronic tension-type headache of 1.91 (0.37-9.85). The results did not change when using cut-off of moderate (AHI ≥15) and severe (AHI ≥30) obstructive sleep apnea. Thus, we did not find any significant relationship between tension-type headache and the AHI. The presence and severity of sleep apneas seem not to influence presence and attack-frequency of tension-type headache in the general population.     

Behaviour during attacks and assessment of intensity in primary headaches of children and adolescents

Assessment of attack intensity in primary headaches of paediatric age has not received great attention in the literature to date and in the international classification the criteria to define pain intensity are also not specified. The purpose of this research was to evaluate whether behaviour during attacks, reported by the child or a parent, can be used as a measure of attack disability, and so as an indirect measure of attack intensity in primary headaches of children and adolescents. The subjects were 320 patients aged between 3 and 14 years (mean age 9.9 years, SD 2.6 years) affected by primary recurrent headaches and first seen at a headache clinic. Twelve variables taken from their history were considered and sequentially analysed with multiple correspondence analysis and cluster analysis. Five types of behaviour during attacks were identified: (i) the child (or the parent) is unable to answer the questions or the child has no limitation in activities; (ii) the child may have some activity limitation, but only in lively games; (iii) the child has limitations in daily life with regard also to quiet activities; (iv) at least during some attacks the child lies down with closed eyes or in the dark; (v) during each attack the child lies down with closed eyes or in the dark. The least important variables for the identification of the five behaviour types were studying at school and absence from school. There are some limitations in considering child's behaviour as a measure of attack intensity/disability; one of these is the fact that it was found to be related to the educational level of the mother. However, behaviour during attacks, reported by the child or the parent, provides useful information independently of child's age and, together with the score of pain, when this is given, it can be used as measure of attack intensity.     

Exteroceptive suppression of temporalis muscle activity: findings in headache

Exteroceptive suppression of temporalis muscle activity was proposed by Schoenen and co-workers in 1987 as a tool in headache diagnosis and research. Their finding of a decreased or abolished second silent period (ES2) in chronic tension-type headache sufferers has been confirmed by several independent laboratories during the last five years. Temporalis silent periods have also been studied in various other types of headaches. Their modulation by neuropsychological factors and pharmacological agents has also been investigated as well as their retest reliability. The pathophysiological concept of muscle contraction in tension-type headache has been challenged by studies using temporalis silent periods. The exterocepfive suppression of temporalis muscle activity points unequivocally towards a central pathogenetic mechanism, although it remains unclear whether the abnormalities of temporalis ES2 represent the primary dysfunction or a secondary phenomenon in chronic tension-type headache.     

Chronic daily headaches in children and adolescents: a study of clinical characteristics

The clinical characteristics of chronic daily headache were studied in 40 children and adolescents, as well as the associated factors responsible for maintenance of the continuous headache pattern. The study of the clinical headache characteristics, showed a female preponderance (75%), mean age of 11 years old at the first consultation, and onset of headache symptomatology at a mean age of 8.5 years old. The average time interval for the evolution of sporadic headache into chronic daily headache was 1.4 years, and psychosocial stressors were present, acutely or chronically, during the period of headache-frequency increase in 47% of the children. Headaches were classified as transformed migraine (65%), mixed pattern (17.5%) and chronic tension-type headache (17.5%). Sixty per cent of patients had mothers with migraine. Data regarding common analgesic use showed an average intake of 11.2 days/month.     

Headache-Free Controls? Evidence of Headaches in Individuals Who Deny Having Headaches During Diagnostic Screening

In the course of two studies investigating whether individuals with recurrent tension headache differ from headache-free controls in the frequency and appraisal of stressful life events, subjects were asked to complete a headache diary for I week. Subjects in the headache-free control group were screened twice and reported having infrequent headaches (two or less per month). However, 13 of 38 control subjects reported multiple headache days on their headache diaries. These subjects also reported a greater frequency of stressful events and a greater stress impact score. These results suggest that a careful screening of control subjects may be necessary in studies theft examine differences between subjects with recurrent headache and headache-free controls. There is also some evidence that the inclusion of these subjects in a control group may bias the sample, making it less likely to find between-group differences.     

Use and abuse of analgesics in tension-type headache

Eighty patients suffering from tension-type headache for an average of 21 years were asked to report on all drugs they had ever taken (type, dosage, duration of intake, efficacy) or were taking currently. The patients had consumed on average 6.3 different drugs. The cumulative doses of derivatives of para-aminophenol, pyrazolone, and salicylic acid in some cases reached a maximum of several kilograms. Most drugs were classified by the patients as "moderately effective". The rating "very effective" was assigned primarily to barbiturates; however, barbiturates are no longer used as components of compound analgesic drugs in Austria. At the time of investigation, patients consumed 2.5 (mean) different drugs, primarily as compound preparations. Seventeen patients (21%) showed signs of possible analgesics- or ergotamine-induced headache and were therefore advised to undergo withdrawal therapy. Our results show that patients with tension-type headache are at considerable risk of becoming drug-dependent and of acquiring analgesics-induced headache.     

Subjective Stress and Coping in Recurrent Tension-Type Headache

Subjects with tension-type headache and headache-free control subjects completed two mental stressor tasks, solving anagrams and mental arithmetic. During the experimental session, measures of heart rate, muscle tension, and subjective stress ratings were recorded. In addition, all subjects completed a week-long series of questionnaires which monitored headache activity in addition to frequency and intensity of stressful life events. Recurrent tension headache sufferers were found to have higher levels of depression and trait anxiety. Headache and control subjects were not found to respond differently to stressors presented in the laboratory based on measures of EMG, heart rate, or subjective stress ratings, nor were there differences in reports of coping. However, diary questionnaires revealed that headache subjects experienced stressful events more frequently than headache-free controls. Headache subjects also rated these events as causing more stress.