Bradykinin Research
BK Mechanisms
BK is known to produce many of its peripheral effects through the production
of prostaglandins, in particular PGE2, in nociceptive neurones. BK is also
known to elicit PGE2 production in the trigeminal ganglia. As such, it is
important to investigate whether the effect of BK on trigeminal neurones that
has been observed so far is due to an indirect mechanism of producing PGE2
or whether BK acts directly to elicit its effects.
PGE2 is known to act on EP2 receptors to produce sensitisation. This is achieved
through Gs G-Proteins, which produce increased levels of adenylyl cyclase
and consequently cAMP. CAMP then acts in conjunction with Protein Kinase A
(PKA) to phosphorylate ion channels and thereby cause sensitisation. If this
mechanism is true in the trigeminal neurones, as it is thought to be, then
it is likely that this is the probable course of action for BK’s effects.
To test this the neurones were subjected to the administration of PGE2 alone. The responses were observed and measured in order to test whether PGE2 produces effects comparable to those elicited by BK administration.
Results
Bath application of 1mM PGE2 was undertaken on 14 of the neurones. The results did not show a mimic of the effects observed with BK administration. PGE2 had no noticeable effect on the neurones at all at this concentration. The graph shows the responses from the control (red) and after PGE2 administration (blue). Administration had no significant effect on the neurones responses to capsaicin either; depolarisation magnitude following 100nM capsaicin was 21±5 mV in PGE2 tests compared to 22±4 mV in control. It also did not affect the percentage of neurones that fired APs in response to capsaicin depolarisations (33% compared to 32% in control, p=0.3)
Discussion
It is clear that PGE2 does not produce comparable effects to the effects observed in response to BK administration. As such, it is highly unlikely that in trigeminal neurones BK produces sensitisation via the production of prostaglandins. This suggests that BK effects are more direct than the route tested here.
Effects of PGE2 (blue) on neuronal responses compared to control (red).
