Abstract
Protease-activated receptor (PAR)-2 and PAR-4 are implicated in
nonhistaminergic itch. We investigated dose dependence, tachyphylaxis, and
cross-tachyphylaxis of itch-associated scratching elicited by intradermal
injections of PAR-2 and PAR-4 agonists, serotonin (5-hydroxytryptamine, 5-HT),
and histamine in ICR mice, as well as μ-opioid modulation of PAR-2
agonist-evoked scratching. Each agent elicited dose-related increases in
scratch bouts. Scratching elicited by the PAR-4 agonist and histamine both
exhibited significant tachyphylaxis but no cross-tachyphylaxis with each
other. Scratching evoked by 5-HT did not exhibit significant tachyphylaxis but
did exhibit significant cross-tachyphylaxis to scratching evoked by the PAR-2
and PAR-4 agonists and histamine. Naltrexone and high-dose morphine (10 mg/kg)
attenuated PAR-2 agonist-evoked scratching, whereas lower dose morphine (1
mg/kg) had no effect. High-dose morphine also significantly increased circling
behavior, which may have interfered with scratching. The PAR-2 agonist and
5-HT produced overlapping distributions of Fos-like immunoreactivity in the
superficial dorsal horn. These results indicate that PAR-2 and PAR-4 agonists,
histamine, and 5-HT elicit itch-related scratching and activate superficial
dorsal horn neurons that may participate in scratch reflex and ascending itch
signaling pathways.
