The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.

• Klíčová slova
• PAR2, TRPV1, inflammatory pain, nociception, peripheral inflammation, spinal cord, superficial dorsal horn, synaptic transmission, thermal hyperalgesia,
• MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   fyziologie   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály MeSH
• hyperalgezie etiologie   metabolismus   patofyziologie   MeSH
• karagenan farmakologie   toxicita   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu Rattus MeSH
• miniaturní postsynaptické potenciály MeSH
• nocicepce MeSH
• potkani Wistar MeSH
• receptor PAR-2 metabolismus   MeSH
• staurosporin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• cinnamáty MeSH
• karagenan MeSH
• kationtové kanály TRPV MeSH
• N-(3-methoxyphenyl)-4-chlorocinnamanilide MeSH Prohlížeč
• receptor PAR-2 MeSH
• staurosporin MeSH
• Trpv1 protein, rat MeSH Prohlížeč

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.

• MeSH
• alergie metabolismus   patologie   MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   fyziologie   MeSH
• chování zvířat účinky léků   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• hyperalgezie etiologie   prevence a kontrola   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu Rattus MeSH
• metoda terčíkového zámku MeSH
• mícha metabolismus   MeSH
• nervový přenos fyziologie   MeSH
• oligopeptidy farmakologie   MeSH
• potkani Wistar MeSH
• receptor PAR-2 agonisté   metabolismus   MeSH
• staurosporin farmakologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• cinnamáty MeSH
• inhibitory proteinkinas MeSH
• kationtové kanály TRPV MeSH
• N-(3-methoxyphenyl)-4-chlorocinnamanilide MeSH Prohlížeč
• oligopeptidy MeSH
• receptor PAR-2 MeSH
• seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide MeSH Prohlížeč
• staurosporin MeSH
• TRPV1 receptor MeSH Prohlížeč