Activation of extracellular signal-regulated kinase is critical for the discriminative stimulus effects induced by U-50,488H.

We previously demonstrated that the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H were associated with its aversive effects in rats. However, its molecular signaling mechanisms are not fully understood. The aim of this study was to investigate the intracellular signaling that plays a role in mediating the discriminative stimulus effect induced by U-50,488H.

Sigma-1 receptor function is critical for both the discriminative stimulus and aversive effects of the kappa-opioid receptor agonist U-50488H.

The present study was undertaken to identify possible similarities between the effects of kappa-opioid receptor agonist, N-methyl-D-aspartate-receptor antagonist, and sigma receptor agonist on the discriminative stimulus effects of U-50488H, and the possible involvement of sigma receptors in the discriminative stimulus and aversive effects of U-50488H. The kappa-opioid receptor agonist U-50488H produced significant place aversion as measured by the conditioned place preference procedure, and this effect was completely abolished by treatment with the putative sigma-1 receptor antagonist NE-100. In addition, phencyclidine (+)-SKF-10047 and (+)-pentazocine, which are sigma receptor agonists, generalized to the discriminative stimulus effects of U-50488H in rats that had been trained to discriminate between U-50488H (3.

Role of dopamine D2 and D3 receptors in mediating the U-50,488H discriminative cue: comparison with methamphetamine and cocaine.

Substitutions of the dopamine D(2) or D(3) receptor agonists for the discriminative stimulus effect induced by U-50,488H, methamphetamine (METH) and cocaine in rats were examined. The D(2) receptor agonist R-propylnorapomorphine [(-)-NPA] failed to substitute for U-50,488H cue, while the D(3) receptor-preferred agonist (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) produced dose-related increases in drug-appropriate responding up to 0.03 mg/kg, which fully substituted.