u-0126 and Pruritus

Pruritus is the most common complication of intrathecal morphine; however, its exact molecular mechanism is unclear, and treatment is challenging. The analgesic effect of N-methyl-D-aspartate (NMDA) receptor antagonists and the morphine-associated increase in NMDA receptor activation suggest potential role of NMDA receptor in the spinal itch sensation. Male C57BL/6 mice were given intrathecal morphine to induce scratching behavior. The effects of NMDA, ketamine, ifenprodil and U0126 on morphine-induced pruritus and analgesia were evaluated also. The number of scratching responses was counted for 30 min post-injection to evaluate pruritus. A warm-water tail immersion assay was conducted before and until 120 min post-injection at 30-min intervals. Percent of maximal possible effect (%MPE) and area under curve (AUC) were calculated based on tail-flick latency to evaluate analgesic efficacy. Compared with control treatment, intrathecal morphine elicited an obvious scratching response and analgesic effect in a dose dependent manner. Ketamine (1 μg), ifenprodil (0.1 μg) and U0126 (0.1 μg and 1.0 μg) all significantly attenuated morphine induced scratches. Ifenprodil (0.1 μg) injection significantly prolonged the analgesic effect of intrathecal morphine. The ERK1/2 phosphorylation induced by intrathecal morphine was inhibited by ketamine, ifenprodil and U0126 as well. U0126 inhibited morphine-induced pruritus with no effect on its analgesia. Therefore, intrathecal coadministration of morphine with NMDA receptor antagonists ketamine and ifenprodil alleviated morphine-induced scratching. Intrathecal morphine increased ERK phosphorylation in the lumbar spinal dorsal horn, which may be related with morphine-induced pruritus, and was counteracted by NMDA receptor antagonists.

Topics: Analgesia; Animals; Butadienes; Extracellular Signal-Regulated MAP Kinases; Injections, Spinal; Ketamine; Male; Mice, Inbred C57BL; Morphine; Nitriles; Phosphorylation; Piperidines; Pruritus; Receptors, N-Methyl-D-Aspartate

Itch, chronic itch in particular, can have a significant negative impact on an individual's quality of life. However, the molecular mechanisms underlying itch processing in the central nervous system remain largely unknown.. We report here that activation of ERK signaling in the spinal cord is required for itch sensation. ERK activation, as revealed by anti-phosphorylated ERK1/2 immunostaining, is observed in the spinal dorsal horn of mice treated with intradermal injections of histamine and compound 48/80 but not chloroquine or SLIGRL-NH2, indicating that ERK activation only occurs in histamine-dependent acute itch. In addition, ERK activation is also observed in 2, 4-dinitrofluorobenzene (DNFB)-induced itch. Consistently, intrathecal administration of the ERK phosphorylation inhibitor U0126 dramatically reduces the scratching behaviors induced by histamine and DNFB, but not by chloroquine. Furthermore, administration of the histamine receptor H1 antagonist chlorpheniramine decreases the scratching behaviors and ERK activation induced by histamine, but has no effect on DNFB-induced itch responses. Finally, the patch-clamp recording shows that in histamine-, chloroquine- and DNFB-treated mice the spontaneous excitatory postsynaptic current (sEPSC) of dorsal horn neurons is increased, and the decrease of action potential threshold is largely prevented by bathing of U0126 in histamine- and DNFB-treated mice but not those treated with chloroquine.. Our results demonstrate a critical role for ERK activation in itch sensation at the spinal level.

Topics: Animals; Butadienes; Chloroquine; Dinitrofluorobenzene; Disease Models, Animal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Histamine; Male; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; Neuroglia; Nitriles; Oligopeptides; Phosphorylation; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Pruritus; Receptors, Histamine H1; Sensation; Spinal Cord; Time Factors