Spicarova D, Palecek J. The role of the TRPV1 endogenous agonist N-oleoyldopamine in modulation of nociceptive signaling at the spinal cord level. J Neurophysiol 102: 234 -243, 2009. First published April 15, 2009 doi:10.1152/jn.00024.2009. Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 M) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 M) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34°C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.

Protease-activated receptors (PARs) belong to the G-protein-coupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles according to the location of their expression. Increased evidence supports the importance of PARs activation during nociceptive signaling and in the development of chronic pain states. This short review focuses on the role of PAR2 receptors in nociceptive transmission with the emphasis on the modulation at the spinal cord level. PAR2 are cleaved and subsequently activated by endogenous proteases such as tryptase and trypsin. In vivo, peripheral and intrathecal administration of PAR2 agonists induces thermal and mechanical hypersensitivity that is thought to be mediated by PAR2-induced release of pronociceptive neuropeptides and modulation of different receptors. PAR2 activation leads also to sensitization of transient receptor potential channels (TRP) that are crucial for nociceptive signaling and modulation. PAR2 receptors may play an important modulatory role in the development and maintenance of different pathological pain states and could represent a potential target for new analgesic treatments.

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