u-0126 and ifenprodil

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

We have recently characterized a form of ex vivo depotentiation (depotentiationex vivo), which correlates tightly with fear extinction, at thalamic input synapses onto the lateral amygdala. Here, we examined the effects of learning-attenuating drugs, reported to impair fear extinction when microinjected into the basolateral amygdala, on depotentiationex vivo. U0126, a mitogen-activated protein kinase inhibitor, and cycloheximide, a protein synthesis inhibitor, blocked depotentiationex vivo. However, ifenprodil, an NR2B-containing NMDA receptor inhibitor, did not alter depotentiationex vivo, although it blocked amygdala long-term potentiation. These findings indicate that amygdala depotentiation shares some molecular processes with learning and further suggest that different forms of synaptic plasticity in the basolateral amygdala mediate fear extinction.

Topics: Adrenergic alpha-Antagonists; Amygdala; Animals; Butadienes; Cycloheximide; Electric Stimulation; Enzyme Inhibitors; Extinction, Psychological; Fear; In Vitro Techniques; Long-Term Synaptic Depression; Male; Microelectrodes; Mitogen-Activated Protein Kinases; Nitriles; Piperidines; Protein Biosynthesis; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Cocaine-induced changes in glutamatergic synaptic transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play a key role in cocaine behavioral effects. Activation of ionotropic glutamate receptor NMDA receptor (NMDAR) in the VTA is critical for the development of cocaine psychomotor sensitization. However, the role of NMDAR in the NAc, a brain area critical for the expression of cocaine psychomotor sensitization, remains to be explored. Here, we show that repeated noncontingent cocaine injections increased NAc NMDAR subunits, NR1, NR2A, and NR2B 21 d, but not 1 d, after withdrawal from cocaine. These changes were associated with an increase in the GluR1 subunit of the AMPA receptor. We also found a time-dependent increase in extracellular signal-regulated kinase (ERK) activity which correlated with the increased expression of NMDAR subunits. Furthermore, the increase in GluR1 and ERK activity was blocked after inhibition of NR2B-containing NMDAR during the development of cocaine psychomotor sensitization or when the MEK (mitogen-activated protein/ERK kinase) inhibitor was microinjected into the NAc 21 d after withdrawal from cocaine. Together, these results suggest that the development of cocaine psychomotor sensitization triggers a delayed increase in the expression of NMDAR subunits in the NAc, which in turn enhances the activity of ERK. Enhanced ERK activity drives the increased expression of the GluR1 subunits, which increases the excitability of NAc neurons after prolonged withdrawal from cocaine and results in enduring expression of psychomotor sensitization.

Topics: Analysis of Variance; Animals; Butadienes; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug Administration Schedule; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Locomotion; Male; Nitriles; Nucleus Accumbens; Piperidines; Psychomotor Performance; Rats; Receptors, N-Methyl-D-Aspartate; Subcellular Fractions; Time Factors