Zhao, P.; Bland, K.; Khandeshi, S.; Huang, P.; Liu-Chen, L.-Y.

Purpose: We previously showed that mice expressing a phosphorylation-deficient kappa opioid receptor mutant (K4A) exhibited reduced U50,488H-induced anti-scratching tolerance in males and reduced conditioned place aversion in females, without changes in acute anti-scratching or hypo-locomotor effects. Here, we examined whether K4A mutations, which markedly diminish {beta}-arrestin-mediated signaling, alter U50,488H-induced increases in serum corticosterone and urine output. Methods: K4A and wildtype mice received U50,488H (5 mg/kg, s.c.) or saline. Serum corticosterone was measured by ELISA 1 h later. Urine was collected for 1 h beginning 10 min after injection. Results: U50,488H increased serum corticosterone to similar levels in wildtype and K4A mice of both sexes. Basal corticosterone levels were higher in females than males regardless of genotype. U50,488H also significantly increased urine output in both sexes, with no genotype differences. However, the increase in urine output was greater in males than females. Conclusions: KOR phosphorylation and associated {beta}-arrestin-mediated signaling are not required for U50,488H-induced increases in serum corticosterone or diuresis in either sex. These findings also demonstrate, for the first time, that KOR activation produces greater diuresis in male than female mice.