Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor...

Although the terms "agonist" and "antagonist" have been used to classify sigma-1 receptor (σ₁R) ligands, an unambiguous definition of the functional activity is often hard. In order to determine the pharmacological profile of σ₁R ligands, the most common method is to assess their potency to alleviate opioid analgesia. It has been well established that σ₁R agonists reduce opioid analgesic activity, while σ₁R antagonists have been demonstrated to enhance opioid analgesia in different pain models.

In the present study, we evaluated the pharmacological profile of selected σ₁R ligands using a novel object recognition (NOR) test, to see if any differences in cognitive functions between σ₁R agonists and antagonists could be observed. We used the highly selective PRE-084 and S1RA as reference σ₁R agonist and antagonist, respectively. Furthermore, compound KSK100 selected from our ligand library was also included in this study. KSK100 was previously characterized as a dual-targeting histamine H₃/σ₁R antagonist with antinociceptive and antiallodynic activity in vivo. Donepezil (acetylcholinesterase inhibitor and σ₁R agonist) was used as a positive control drug.

Both tested σ₁R agonists (donepezil and PRE-084) improved learning in the NOR test, which was not observed with the σ₁R antagonists S1RA and KSK100.

The nonlinear dose-response effect of PRE-084 in this assay does not justify its use for routine assessment of the functional activity of σ₁R ligands.