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/PKCphosphrylation 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.