Finding a significantly decreased activation of ACC and SII in response to trigeminal nociceptive stimulation in the ASA condition compared to placebo (Figure
1), we could replicate a trend shown in previous studies indicating a possible central mechanism of ASA not only on mechanically induced hyperalgesia but also on acute pain [
21,
26]. The ACC as well as SII are structures frequently found during nociceptive stimulation and known to play a crucial role in the processing of pain [
32‐
36]. While the ACC has been attributed among others to reflect an emotional pain component [
37,
38], it is also crucially involved in antinociception and anticipatory anxiety [
39]. SII, also shown to be modulated by ASA, is related to pain intensity coding [
36] and seems to be responsible for the integration of salient (painful and nonpainful) somatosensory stimuli [
40]. However, we did not observe any behavioral effect of ASA on pain intensity perception of the volunteer. This lack of a behavioral effect combined with an obtained CNS effect of ASA on painful stimulation is in line with an earlier study using mechanical pain [
21] and painful carbon dioxide pulses delivered to the nasal muscosa [
17]. More evidence for a central effect of ASA on pain processing is coming from an imaging study investigating pain ratings as well as stimulus evoked responses to nociceptive stimulation using an electroencephalogram (EEG). In this case, oral administration of 1000 mg ASA reduced the overall pain ratings as well as all pain related cerebral potentials significantly [
13]. Of note, effects of ASA increased with time, meaning that ASA showed an attenuating effect compared to placebo on all relevant variables during the experiment. But this effect did not reach significance before 90 minutes post medication [
13]. Additionally, a study using electrical brain potentials could show an effect of ASA on late but not early waveforms of the evoked potentials in healthy man, which are suggested to reflect pain perception processing [
18]. Nonetheless, investigating a possible difference between later and earlier VAS scores of ammonia, we could not find a significant difference within the ASA condition. However, as these earlier studies did not specifically investigate the effect of ASA on migraine, the exact mechanism of action how ASA reduces head pain is still controversial. Knowing that the trigeminal innervation plays a pivotal role in migraine, several studies investigated the effect of ASA on trigeminovascular nociceptive input [
19,
24]. Especially the use of an electrophysiological animal model of superior sagittal sinus stimulation [
24] was promising to gain further insight in the mechanisms of actions through which ASA exerts its clinical effect in migraine, as it reflects migraine-like pain or neuropeptide release similar to that in an acute attack [
41]. An inhibitory effect on the activation of central brainstem nuclei [
19] as well as reduced peak-to-peak amplitudes for trigeminal somatosensory evoked potentials in the dorsolateral spinal cord [
24] could be observed after ASA administration. Interestingly, naloxone did not invert the inhibitory effect on the brain evoked potentials [
24]. Furthermore, this effect was not due to a peripheral blockade of inflammatory induced neuropeptides [
24], proposing a central inhibitory mechanism of action for ASA on the trigeminovascular system [
19,
24]. Nonetheless, in the present study we could not reveal a significant difference in BOLD signal changes in response to trigeminal-nociceptive stimulation in the trigeminal nuclei after ASA administration compared to the saline condition. We note, that ASA and triptans inhibit the nociceptive blink reflex in the acute migraine attack, but seem to have no effect on trigeminal pain in migraineurs in the interictal state or in healthy volunteers [
42], suggesting a modulatory effect on the trigeminal nociceptive system which occurs only in the migraine attack but not in the healthy system nor in the interictal phase [
42], for example by blocking sensitization.
In 1988 it was shown that administration of acetylsalicylate of lysine leads to an increase in 5-hydroxyindoleacetic acid in the hypothalamus and the brainstem [
43]. Investigating the effect of aspirin on the inhibitory antinociceptive brainstem reflex, another study obtained a significant effect of ASA especially on the latency of the early suppression period (ES1) within this exteroceptive suppression of electrical activity in the temporal muscle [
44]. While ES1 latency was decreased in patients suffering from a primary headache disease after administration of ASA, it was increased in healthy participants [
44]. Moreover, ASA caused a significant growth in ES2 (late suppression period) duration [
44], whereas placebo failed to show this increase. An effect of ASA on complex pain control mechanisms was suggested [
44]. We did not find any significant difference in BOLD signal changes in response to trigeminal-nociceptive stimulation in the hypothalamus of healthy volunteers after ASA administration compared to saline condition. However, the dosage of ASA used in the present study differs from earlier used dosages [
21]. Even though we chose to administer 500 mg ASA (i.v.) because there is strong evidence showing its clinical effectiveness in the acute migraine attack [
1], the divergence between dosages could at least partly explain the obtained differences in neuronal activation. Finally, ASA reveals its effect by inhibiting COX-1 and COX-2 enzymes that lead to the expression of prostaglandins which play a crucial role within the inflammatory process [
7,
8]. It is therefore to be expected that the effect of ASA is much more pronounced in the state of hyperalgesia compared to acute pain [
21,
26] and this could be another reason why we did not find a significantly behavioral and only small central modulatory effects of ASA on pain processing structures.