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

BACKGROUND

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

METHODS

In the present study, we evaluated the pharmacological profile of selected σR ligands using a novel object recognition (NOR) test, to see if any differences in cognitive functions between σR agonists and antagonists could be observed. We used the highly selective PRE-084 and S1RA as reference σR 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 H/σR antagonist with antinociceptive and antiallodynic activity in vivo. Donepezil (acetylcholinesterase inhibitor and σR agonist) was used as a positive control drug.

RESULTS

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

CONCLUSIONS

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