Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors

Abstract

Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception.

Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour

“…Consistently, CatS-overexpressing transgenic mice develop a skin disorder similar to chronic AD (Kim et al, 2012). Cleavage of PAR2 by proteases results in the sensitisation of TRP channels, including TRPV1 and TRPA1 (Amadesi, 2004, Amadesi et al, 2006, Chen et al, 2011, Dai, 2004, Dai et al, 2007, Mrozkova et al, 2016), which may be responsible for the transmission of itch signals in pruriceptors. CatS causes visceral hypersensitivity through PAR2-mediated mechanisms (Cattaruzza et al, 2011).…”

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

“…PAR2 has been highlighted as a target for multiple proteases and it can mediate pain in different conditions [7]. PAR2 in the peripheral nerve endings are implications of the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states [32]. The focus on the pathophysiology and therapeutic potential of purinergic signaling has been raised more recently [73].…”

“…The close relationship between PAR2 and TRPV1 is reflected by the co-expression of PAR2 and TRPV1 in nociceptive DRG neurons. Blocking PAR2 decreases expression of TRPV1, and the blockade of TRPV1 prevents the activation of PAR2-induced persistent thermal hyperalgesia [32,66]. PAR2 is also co-expressed with TRPA1 in small DRG neurons [74].…”

“…Transient Trpv1 gene silencing or selectively inhibition of TRPV1 produces antinociceptive action on relieving pain behavior [29,30]. Since the perception of painful thermal stimuli by sensory neurons is largely mediated by TRPV1 [31], the functional coupling of PAR2 and TRPV1 in DRG neurons may potentiate pain sensation signaling at different pathological conditions [32]. Interestingly, PAR2-triggered 'referred hyperalgesia' was inhibited by blocking TRPV1 suggesting a close relationship between PAR2 and TRPV1 in mediating pain or hyperalgesia [33].…”

Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling

“…IP3 acts on its receptor named inositol triphosphate receptor (IP3R) which leads to a prompt Ca 2+ mobilization from IP3R-dependent endoplasmic reticulum stores, and activation of protein kinases A, C and D (PKA, PKC and PKD) [ 41 , 42 , 43 , 44 ]. This leads to the sensitization of the transient receptor potential channels (TRP) including transient receptor potential vanilloid 1 (TRPV1) [ 42 , 45 , 46 ], transient receptor potential ankyrin 1 (TRPA1) [ 47 ] and transient receptor potential vanilloid 4 (TRPV4) [ 48 ] in sensory nerve fibers contributing to sensory disorders. On the other hand, full agonists signal through β-arrestin, which is associated with PAR2 internalization, and phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) [ 49 , 50 , 51 , 52 ].…”