1- Introduction
The transient receptor potential vanilloid receptor 1(TRPV1), is a
heat-sensitive non-selective cation channel which plays a fundamental
role in thermal nociception1,2.
TRPV1 has essential roles in inflammatory thermal hyperalgesia as
illustrated by the observation that TRPV1 knockout mice have reduced
thermal inflammation-induced hyperalgesia3. Under normal
physiological conditions, TRPV1 is widely expressed throughout the
central and peripheral nervous systems, including dorsal root ganglion
neurons (DRG) 4. TRPV1
can be activated by noxious heat
(>43˚C), low pH and by
pungent compounds, such as capsaicin5,6,
as well as non-pungent capsaicin-analogs such as arvanil and olvanil7-10.
Nociceptor sensitization is considered the primary peripheral mechanism
underlying primary hyperalgesia11. A core feature of
nociceptors is that inflammatory mediators, such as prostaglandins and
bradykinin, activate their cognate receptors resulting inactivation of
signal transduction pathways and enhanced pain sensation12.
Bradykinin is 9-amino acid peptide chain generated following tissue
injury and acts as inflammatory mediator13. Bradykinin produces
its biological action by activation of two G-protein coupled receptors
subtypes, bradykinin receptor type B1(B1) and bradykinin receptor type (B2)13-15. Under normal
conditions, the B2 receptors are expressed in most
tissues and the inflammatory actions of bradykinin are strongly mediated
through the B2 receptor subtype16. B1receptors are overexpressed in inflammation and also make a contribution
to nociception via separate pathways17-19. Bradykinin
stimulates the formation of prostaglandins in many cell types20-22 and activation of
B2 (not B1) receptors can induce the
synthesis of prostaglandins in pain sensing adult rat trigeminal ganglia
cultures and in isolated rat DRG neurons21,23.
In fact, stimulation of B2 receptors leads to PKC
activation and a phosphorylation dependent increase in the TRPV1 channel
current 24. Bradykinin
sensitizes the nociceptor (TRPV1) response to heat and so is able to
mediate thermal hyperalgesia and activate these neurons and produce pain24,25.
Bradykinin sensitizes nociceptors by modulating other ion channels, for
example by reducing the activity of potassium channels26. Although, several
studies demonstrate that bradykinin sensitizes TRPV1 by means of the B2
dependent PLC/PKCphosphrylation pathway,21,23,27,
we present here evidence that another pathway is involved.
Prostaglandins are generated by either cyclooxygenase 1 or 2 in response
to inflammatory insult by damaged cells, and act on a range of
prostaglandin receptors on, for example, nociceptor endings. This
results in the activation of PLA and PLC-mediated phosphorylation
pathways within these endings to elicit changes in nociceptor
sensitivity. It is important to note that prostaglandins may also act as
intracellular messengers mediating the effects of some ligands, e.g.
glutamate acting at metabotropic glutamate receptors, thereby adding to
the intricacy of their actions.21,23,27,28.
In this study we explored the sensitization of TRPV1 receptor by
bradykinin, and investigated the role of prostaglandin receptors in
mediating the sensitizing effect of bradykinin on TRPV1 receptor, a
pathway of potential novel therapeutic importance.