Drug discrimination distinguishes pharmacologically distinct κ-opioid receptor agonists in rats

Ligand-dependent signaling has emerged as a central concept in κ-opioid receptor (KOR) pharmacology, yet whether differences among KOR agonists are reflected in their discriminative stimulus effects remains unclear. The present study compared the discriminative stimulus effects of pharmacologically distinct KOR agonists and examined the contribution of intracellular signaling-related mechanisms to the discriminative stimulus produced by the prototypical KOR agonist U50,488H. Male Fischer 344 rats were trained to discriminate (±)U50,488H (5.0 mg/kg, s.c.) from saline under a two-lever fixed-ratio 10 schedule of food reinforcement. Substitution tests were conducted with KOR agonists and representative psychoactive drugs. Antagonism by nor-binaltorphimine and modulation by lithium and the phosphodiesterase 10A inhibitor PF-2545920 were also evaluated. U69,593 completely substituted for the discriminative stimulus effects of U50,488H, whereas the pharmacologically distinct agonist nalfurafine failed to substitute. Nor-binaltorphimine completely antagonized the discriminative stimulus effects of U50,488H. None of the representative psychoactive drugs examined produced complete substitution. Lithium significantly attenuated the discriminative stimulus effects of U50,488H, whereas PF-2545920 had no significant effect. These findings demonstrate that pharmacologically distinct KOR agonists produce qualitatively different discriminative stimulus effects despite acting at the same receptor. The results are consistent with the possibility that ligand-dependent intracellular signaling may contribute to qualitative differences in KOR-mediated interoceptive effects and demonstrate the utility of drug discrimination as an in vivo approach for distinguishing pharmacological differences among KOR agonists.