Bradykinin
Role in Nociception
BK is known as a chemical mediator within the nociceptive pathway. Most stimulation of nociceptive nerve endings is, in fact, chemical although high levels of mechanical and thermal stimuli can also stimulate certain nociceptive endings. However, persistent pain, occurring after non-chemical and chemical stimuli, is largely due to an altered chemical state surrounding the nociceptive afferents and hence due to inflammation or ischaemic changes. [41]
The kinins, in particular BK and kallidin, are known to be potent pain producing chemicals – this is both direct and indirectly. The direct mechanism by which BK causes activation of nociceptive neurones is thought to be via direct opening of non-selective ion channels, which results in ion influxes and a resultant depolarisation of the membrane potential, which leads to the generation of an action potential within the nociceptive neurone. BK also acts indirectly, through a series of intracellular cascades, to produce both activation and sensitisation. These mechanisms are only fully known to be true for nociceptive neurones from the periphery, whose cell bodies are contained within the Dorsal Root Ganglia (DRG) of the spinal cord. The majority of experiments have been conducted in vivo in cultured or isolated DRG neurones, this is in order to remove the array of natural chemical stimulants present in vitro around the nerve endings and hence to further certify any results obtained with the application of specific chemicals. [41]
BK’s indirect actions occur through a variety of mechanisms, predominately via the production of prostaglandins and in particular PGE2 and PGI2, which are both potent vasodilators and PGE2 causes hyperalgesia. BK’s actions as a sensitiser and as a direct activator of nociceptor neurones follow two distinct mechanisms. Once the inflammation process has produced BK, for example, BK acts to stimulate the BK receptors, predominately BK2 due to BK1 not being consistently present in tissues. In the direct circumstance the G-Protein coupled mechanism opens a non-selective ion channel, causing activation, in the indirect circumstance the G-Protein coupled mechanism activates Phospholipase C. Phospholipase C then acts intracellularly to produce ionositol triphosphate, which in turn activates the release of intracellular calcium and also the production of DAG that produces Protein Kinase C (PKC). One of these pathways causes an ion channel to open, this may by the PKC mediated phosphorylation of the channel but the PKC may just cause direct sensitisation of the channel. The production of PKC is the primary factor in the development of sensitisation by BK. This sensitisation far outlasts the direct activation of a nociceptor by BK and so ids the primary long-term effect of BK. Other PKC activators can also mimic this sensitisation, this supports the evidence that PKC is the responsible agent and the findings are consistent both in vivo and in vitro; the sensitisation effect of PKC is well documented in the sensitisation of response to heat, causing the temperature threshold to be lowered and the response curve to be shifted towards hyperalgesia. [8, 29, 41]
Sensitisation is primarily achieved through the modulation of ion channels within the nociceptive neurone. The principal target ion channels are the sodium (Na+) and potassium (K+) channels. Na+ channels can be categorised according to their sensitivity to TTX. The majority of Na+ channels are TTX sensitive, meaning they are inactivated or inhibited by TTX. However, a number of TTX-Resistant channels have been identified in a small number of the DRG neurones. On isolation and mRNA cloning these channels have been identified and localised to nociceptive neurones only. These TTX-R channels are chiefly the Nav1.8 channels (the v refers to the channel being voltage sensitive). These channels also have a 65% homology with cardiac TTX-R channels and are termed collectively as Sensory Neurone Specific channels as these types are only present in nociceptive sensory neurones.
TTX-R and TTX-S channels co-exist within the nociceptive neurones and the differences are due to the differential operation and sensitivity. TTX-R channels are activated and inactivated much slower than TTX-S and they also have a more positive (higher) threshold of activation. However, the overall cellular threshold is dependent on the steady-state inactivation of the TTX-S channels. TTX-R can also be modulated by prostaglandins, adenosine and Serotonin. The prostaglandin PGE2 causes the amplitude of response to be doubled and the response to be shifted towards hyperpolarisation, hence causing increased excitability. This action is mimicked by dibutyryl cAMP and stimulation of adenylate cyclase and antagonised by Protein Kinase A (PKA) inhibitors. This suggests that the sensitising effects of PGE2 are via an increase in cAMP, which results in the production and activation of PKA. The active PKA is known to phosphorylate the site adjacent to the gating region of the TTX-R Na+ channel (the S4 Helix). The phosphorylation will alter the gating properties of the channel, causing increased sensitivity and lower threshold. Adenosine and Serotonin are likely to operate through similar intracellular mechanisms. PGE2 probably, due to the cAMP increases, operates through the EP2 (Prostaglandin) receptor and the adenosine through the A2 receptor. The PGE2 stimulated increase of excitability of non-selective cation channels results in the generation of spike trains and is a result of the direct action of cAMP on these channels. PGE2 may also be responsible for the suppression of sustained voltage activated K+ currents. These effects are exasperated in inflammation when BK receptors are upregulated. [5, 8, 32]
The majority of BK’s effects are known through the experimentation
in DRG neurones, the predominant neuronal targets of the periphery afferents.
The trigeminal nuclei are important in migraine and BK’s effects here
are far less understood. The question over whether BK acts comparably in the
trigeminal nuclei is still present and the answer may be crucial to the understanding
and treatment of migraine.
