The role of kinin B₁ and B₂ receptors in the scratching behaviour induced by proteinase‐activated receptor‐2 agonists in mice

Abstract

Background and purpose: Activation of the proteinase-activated receptor-2 (PAR-2) induces scratching behaviour in mice. Here, we have investigated the role of kinin B1 and B2 receptors in the pruritogenic response elicited by activators of PAR-2. Experimental approach: Scratching was induced by an intradermal (i.d.) injection of trypsin or the selective PAR-2 activating peptide SLIGRL-NH2 at the back of the mouse neck. The animals were observed for 40 min and their scratching response was quantified. Key results: I.d. injection of trypsin or SLIGRL-NH2 evoked a scratching behaviour, dependent on PAR-2 activation. Mice genetically deficient in kinin B1 or B2 receptors exhibited reduced scratching behaviour after i.d. injection of trypsin or SLIGRL-NH2. Treatment (i.p.) with the non-peptide B1 or B2 receptor antagonists SSR240612 and FR173657, respectively, prevented the scratching behaviour caused by trypsin or SLIGRL-NH2. Nonetheless, only treatment i.p. with the peptide B2 receptor antagonist, Hoe 140, but not the B1 receptor antagonist (DALBK), inhibited the pruritogenic response to trypsin. Hoe 140 was also effective against SLIGRL-NH2-induced scratching behaviour when injected by i.d. or intrathecal (i.t.) routes. Also, the response to SLIGRL-NH2 was inhibited by i.t. (but not by i.d.) treatment with DALBK. Conversely, neither Hoe 140 nor DALBK were able to inhibit SLIGRL-NH2-induced scratching behaviour when given intracerebroventricularly (i.c.v.). Conclusions and implications:The present results demonstrated that kinins acting on both B1 and B2 receptors played a crucial role in controlling the pruriceptive signalling triggered by PAR-2 activation in mice.

The multiple pathways for itch and their interactions with pain

“…Since PAR-3 does not evoke scratching in mice, only PAR-2 appears to mediate cutaneous itch directly, through a histamine-independent mechanism72. Activation of PAR-2 with tryptase or PAR-2-Activating Peptides (APs) elicits scratching in mice that is not blocked by antihistamines27,72–78. Interestingly, c-fos+ neurons observed in the superficial dorsal horn after a PAR-2-AP injection were located in an anatomically distinct region compared with c-fos+ neurons after histamine injection79.…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…The intradermal administration of deoxycholic acid to rats, for example, activates kallikreins to generate bradykinin and stimulate B 2 R signaling (Hayashi and Majima, 1999). The role of B 1 R and B 2 R activity in PAR 2 -dependent pruritus has also been investigated and suggests that kinin receptors function downstream of protease-induced pruritic responses (Costa et al, 2010). Although the bile acidbradykinin system has not been clearly defined, TRPV1 sensitization was recently demonstrated to contribute to liver disease-induced itch and is predicted to play a major role, potentially via receptors for bradykinin, histamine, serotonin, or PAR 2 (Belghiti et al, 2013).…”

Mediators of Pruritus in Lichen Planus

“…One study also reported that mice which overexpressed epidermal KLK7 displayed massive itchy behavior [20]. Another study demonstrated that trypsin-induced scratching behavior in mice was inhibited by a PAR-2 blocking peptide, suggesting the role of serine protease/PAR-2 signaling in pruritus [21, 22]. PAR-2 is reported to interact synergistically with transient receptor potential (TRP) vanilloid type 1 (TRPV1), which belongs to the superfamily of TRP channels, thereby amplifying itch sensation.…”