Investigation of gastrin-releasing peptide as a mediator for 5′-guanidinonaltrindole-induced compulsive scratching in mice

Gastrin-releasing peptide (GRP) has been implicated in the itch-scratch cycle. We investigated if this gut–brain–skin peptide plays a role in the compulsive, hindleg scratching of the neck of mice by 5′-guanidinonaltrindole (GNTI), the kappa opioid receptor antagonist, and in the antipruritic activity of nalfurafine, the kappa opioid agonist. Previously, we showed that GNTI (0.03–1 mg/kg, s.c.) elicits dose-related scratching and that nalfurafine (0.001–0.02 mg/kg, s.c.) inhibits this behavior in mice. Utilizing immunohistochemistry, GRP positive nerve fibers were detected in mouse skin and superficial layer of the dorsal horn of the spinal cord as well as GRP positive cells in the dorsal root ganglion. Pretreating mice with either a pseudopeptide GRP receptor antagonist, RC-3095 (10–30 mg/kg, s.c. at −15 min), or a peptide GRP receptor antagonist, [d-Phe6]bombesin(6-13) methyl ester (2–100 nmol, i.t. at −10 min), did not suppress GNTI-induced scratching. However, pretreating mice with either antagonist inhibited scratching precipitated by the GRP receptor agonist, GRP18–27 (2 nmol, i.t.). Pretreating mice with a muscarinic M1 receptor agonist, McN-A-343 (1.5–15 μg/5 μl, i.t. at −10 min) antagonized GNTI-induced scratching. Norbinaltorphimine (20 mg/kg, i.p. at −18 to −20 h), a kappa opioid antagonist, countered the antiscratch activity of nalfurafine. We conclude that (a) the GRP receptor system does not mediate GNTI-induced scratching and (b) the kappa opioid system is involved, at least in part, in the scratch suppressing activity of nalfurafine.

Research highlights▶ GRP immunoreactive nerve fibers were found in mouse skin. ▶ RC-3095, a GRPR antagonist, does not inhibit GNTI-induced scratching. ▶ [d-Phe6]bombesin(6-13) methyl ester, a GRPR antagonist, has no marked effect on GNTI-induced scratching. ▶ McN-A-343, a muscarinic M1 receptor antagonist, attenuates GNTI-induced scratching.