The triggers of headache include psychological stress, menstruation in females, fasting, changes in weather conditions and temperature, sleep disturbance and physical activity (section 3.3). These triggers all activate the SNS and HPA pathways (DeRosa & Cryer, 2004; Kotchen, et al., 1971; Pike, et al., 1997; Segel, et al., 2002; van de Borne, et al., 1997; Zhong, et al., 2005). In the presence of neural sensitisation (section 4.4), these triggers may activate the HPA and SNS pathways and lead to action potentials in the pathways of nociception, leading to headache episodes (Figure 5.6). Figure 5.7 shows that the same triggers may not lead to an action potential in people without neural sensitisation as the EPSP fades away, as it is not amplified at the synapse. An upregulation of the stress pathways are likely to increase the chances of developing headache episodes from triggers.
The timing of migraine headache also correlates with sympathetic tone which is consistent with the Adrenaline Model of Headache Causation. The timing of migraine headaches was investigated by examining the 24 hour distribution of migraine in a prospective study of 89 females over 12 consecutive months with participants recording timing of migraine
(Alstadhaug, Salvesen, & Bekkelund, 2008). The study recorded 2,314 migraine episodes and found migraine peaked between the hours of 10am and 4 pm and was lowest in the
Adrenaline, Noradrenaline
Histamine Serotonin
Stimulates second messenger cascade
Metabotropic receptor
Sensitised synapse
(EPSP reaches threshold for action potential) Peripheral nociceptor
Dorsal horn Thalamus Sensory cortex
Action potential
SNS and HPA hyperactivity Psychological stress Physical activity Changes in temperature Alcohol Fasting Sleep disturbance Viral illness Stimulates release
Post synaptic membrane EPSP Menstrual cycle (PGE2) Nitrates (cGMP) Headache episode Stimulation of nociceptors E.g. Myofascial, Neck
Adrenaline Noradrenaline
Histamine Serotonin
Stimulates second messenger cascade
Metabotropic receptor
Synapse
(without sensitisation EPSP fades) Peripheral nociceptor
Dorsal horn Thalamus Sensory cortex
No Action Potential
SNS and HPA hyperactivity Psychological stress Physical activity Changes in temperature Alcohol Fasting Sleep disturbance Viral illness Stimulates release
Post synaptic membrane EPSP
Menstrual cycle (PGE2) Nitrates (cGMP) No Headache Stimulation of nociceptors E.g.Myofascial, Neck
with the variation of sympathetic tone in 24 hours, with an increased tone present during increased onset of migraine episodes and a reduced sympathetic tone present during periods of reduced onset of migraine episodes. The sympathetic tone measured in 20 healthy
individuals by heart rate variability monitoring, also peaked between the hours of
approximately 10am to 4 pm and was lowest in the early hours of the morning (Nakagawa, et al., 1998). The timing of migraine episodes during the hours of increased sympathetic tone is consistent with the Adrenaline Model of Headache Causation, which proposes an increase in sympathetic tone may lower threshold for action potential in the pathways of nociception.
5.3.10.1 Psychological stress
Stress is known to be a predisposing factor for the onset of CTTH, accelerates the progression of headache disorder into a chronic condition and precipitates individual headaches (Nash & Thebarge, 2006). Psychological stress stimulates the HPA and SNS pathways leading to the release of noradrenaline, adrenaline and other neurotransmitters and a subsequent activation of second messenger cascades (Larsson, Martinsson, Olsson, & Hjemdahl, 1989). Larsson and colleagues (1989) tested the rise in plasma adrenaline, heart rate, blood pressure and cAMP after adrenaline infusion, placebo infusion (normal saline) and mental stress. Both adrenaline infusion and mental stress evoked a rise in adrenaline and cAMP while placebo infusion did not. The rise in cAMP and generation of action potentials in the pathways of nociception may lead to central and peripheral sensitisation as well as trigger acute episodes of headache once central and peripheral sensitisation is established.
Cortisol release in the stress response may contribute to sensitisation of the pathways of nociception by increasing the production of adrenaline. Both adrenaline and noradrenaline can act at the different adrenergic receptors with differing affinities. Noradrenaline is generally classified as β1 selective and adrenaline as mixed β1 andβ2 receptor agonist (MacGregor, et al., 1996). Both adrenaline and noradrenaline via the α1 receptor can excite neural transmission and via α2 receptors inhibit neural transmission. The final action of
noradrenaline, the concentration of receptors at the effector sites and their affinities to the receptors. Noradrenaline released from the locus coeruleus can act on α2 receptors in low concentration and act on α1 receptors at higher concentrations, due to its lower relative affinity to α1 receptors (Ramos & Arnsten, 2007).
5.3.10.2 Menstruation
As noted in section 3.3 several studies revealed that menstruation was a significant trigger for headaches in females (Andress-Rothrock, et al., 2010; Kelman, 2007; Wober, et al., 2007). Prostaglandin E2 (PGE2) and Prostaglandin F (PGF) are known to increase at the luteal and menstrual phases of the menstrual cycle and are elevated in women suffering from dysmenorrhea compared to women not suffering from dysmenorrhea (Benedetto, 1989). These prostaglandins bind to EP2 and EP4 receptors and increase cAMP (Hata & Breyer, 2004) that may generate action potentials in the pathways of nociception explaining menstrual migraine and headache (Figure 5.6).
5.3.10.3 Food
Chocolate has been implicated as a food trigger for migraine headache. Cacao contains phenylethylamine that causes the release of vasoactive amines including adrenaline. Tyramine is an amine derived from tyrosine and is found in cheese, cured meats, smoked fish, fermented food and other foods. Tyramine’s primary effect is the release of
noradrenaline and adrenaline (Okaa, Ohuchia, Yoshida, & Imaizumia, 1966). The link was initially observed in people eating aged cheese while taking monoamine oxidase inhibitors, as they developed headache and hypertensive crises (Sun-Edelstein & Mauskop, 2009). Although this may explain a mechanism for food triggers, most studies (Kelman, 2007; Marcus, et al., 2007) investigating migraine triggers are retrospective studies, and further prospective studies or control experimental studies are required to confirm if food does actually trigger episodes of headache or migraine.
Headache and generalised myalgia is common with viral illnesses. The HPA and SNS are activated causing a rise in adrenaline and cAMP during a viral illness (Mason, et al., 1979). Mason et al. (1979) measured adrenaline and noradrenaline blood levels that showed a 60% rise in levels after the onset of an adenovirus respiratory infection. Histamine was also measured during an infection with influenza A viral infection and showed a rise during infection (Gentile, Doyle, Fireman, & Skoner, 2001). Adrenaline will result in production of cAMP while histamine will stimulate the production of cGMP. Both second messengers will potentiate action potentials in the pathways of nociception leading to headache pain and myalgia.
5.3.10.5 Alcohol
Delayed alcohol induced headache has been described as diffuse, bilateral and throbbing, and migraine sufferers are at increased risk of developing headache after alcohol
consumption (Kuster, Piraja da Silva, Aquino, Ziviani, & Domingues, 2006). Alcohol may also cause hypoglycaemia that may contribute to the development of a hangover headache (section 5.3.10.7). The “hangover” headache caused by heavy alcohol consumption can be explained by the Adrenaline Model of Headache Causation (Figure 5.3) due to stimulation of the increased SNS activity and HPA activation overnight leading to subsequent
production of second messengers and the generation of action potentials in the pathways of nociception.
Alcohol has been shown to increase sympathetic nerve activity by up to 239 +/- 22% of baseline values in 16 healthy male subjects (van de Borne, et al., 1997). The morning plasma cortisol has also been shown to be increased in alcoholics while drinking but reduced to normal on abstinence (Merry & Marks, 1972) demonstrating activation of the HPA pathways.
Body temperature is monitored by the hypothalamus with feedback from thermal receptors in the skin to maintain a constant core temperature. Changes in weather may cause changes in skin temperature, that may activate both the HPA and SNS pathways and this may explain why changes of temperature trigger headache.
5.3.10.7 Hypoglycaemia
Glucose levels are monitored by the hypothalamus and a drop in glucose is a threat to life and a significant physiological stress (Spat, 2007) to the human body that activates the stress response of the body (HPA and SNS pathways) (Segel, et al., 2002), and generation of action potentials as proposed in the Adrenaline Model of Headache Causation (Figure 5.3). Fasting is a significant trigger for headache occurrence (section 3.3).