Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

Abstract

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.

Electroacupuncture Relieves Visceral Hypersensitivity via Balancing PAR2 and PAR4 in the Descending Pain Modulatory System of Goats

“…An intracolonically administered PAR2 agonist (SLIGRL-NH 2 ) can elicit sustained VH with enhanced spinal cord c-Fos expression [ 13 ]. Sub-inflammatory dosages of PAR2-AP administered intraplantar to mice elicit heat hyperalgesia, and the activation of PAR2 stimulates the release of neuropeptides (SP and CGRP) in neurons to generate neuroinflammation [ 45 , 46 ]. Most neurons show elevated CGRP expression following central inflammation and mice lacking CGRP expression in the central nervous system are not affected by inflammation-induced hyperalgesia [ 47 ].…”

Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions

“…The modulation of nociceptive synaptic transmission in the spinal cord dorsal horn underlies pathological pain states ( Spicarova and Palecek, 2008 , 2009 ; Spicarova et al, 2011 ; Li et al, 2015 ; Adamek et al, 2019 ; Heles et al, 2021 ; Mrozkova et al, 2021 ). Among others, two receptors - the Ca 2+ permeable transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel and the cannabinoid receptor 1 (CB 1 ) have been implicated to play important modulatory roles in spinal nociceptive signaling ( Katona and Freund, 2008 ; Spicarova and Palecek, 2009 ; Spicarova et al, 2011 ).…”