Implications
Discussion
The experiment results clearly indicate that bradykinin does affect trigeminal neurones, causing sensitisation and activation much like it affect neurones in the periphery. Experimental data has shown these effects to be generated through the activation of BK2 receptors, although activation of BK1 receptors in vitro cannot be ruled out due to the specialist nature of their development in response to prolonged inflammation. In vitro experiments under synthesised prolonged inflammation would allow the analysis of BK’s effects on the BK1 receptor in trigeminal neurones; this would be an important point to pursue for the full understanding of BK’s mechanism of action within the CNS.
It was also investigated as to how BK might produce its effects following the activation of the BK2 receptor. BK is known to stimulate the production of prostaglandins, particularly PGE2, which can also produce the sensitisation and activation seen. PGE2 mediated sensitisation is via activation of EP2 receptors by PGE2 and the subsequent G-protein coupling that elicits an increase in adenylyl cyclase and cAMP results in phosphorylation of the ion channels, which causes sensitisation. As such this possibility was investigated. The results showed categorically that this is not the case in the BK sensitisation of trigeminal neurones.
The remaining possibilities for BK’s mechanism of action are more direct. The most likely is the intracellular cascade initiated by BK2 activation that results in production of intracellular PKA, which causes ion channel phosphorylation and hence sensitisation. I.e. there is no secondary mode of action but a direct effect within the cell as a result of receptor stimulation by BK.
These findings are potentially an important step in understanding the aetiology of migraine. It is known that CGRP is abnormally released from the trigeminal neurones in the case of migraine but what causes this release has been previously not understood. The sensitisation and lowered threshold observed in trigeminal neurones in response to BK may hold the key; the increased excitability of the trigeminal neurones after BK activation may explain the unelicited release of CGRP, which is central to the pathophysiology of migraine. As such BK may have a key role in the pathogenesis of migraine.
The role of BK in migraine must be further researched in order to establish
how and why it is produced and when this may come into play in the development
of migraine. Understanding the aetiology and pathogenesis of migraine is vital
to the development of effective treatments. If BK is involved then the development
of appropriate BK antagonists may be crucial to the advance of migraine treatment.
In order to establish this then the next stage of experiments needs to be
in vivo in order to obtain indications of the full interactions with other
systems. We know that migraine has a number of contributing factors ranging
from different systems: vascular, noradrenergic and serotinergic. Understanding
what triggers these systems and how they interlink is important in developing
understanding and treatment of the condition. Investigating the effects of
BK antagonists in migraine may also contribute to our understanding of BK’s
involvement.
This website has investigated the background to migraine and bradykinin and investigated the possibility of a link between the two. The experimental evidence that BK directly acts on trigeminal neurones through BK2 receptors to cause sensitisation has established this link. However, whilst this research shows a link between BK and migraine, extensive further research is required in order to establish the extent and implications of this link.
