The effects of kappa opioid agonist RU-1205 on local field potentials and behavior in the discriminative stimulus paradigm

Kappa opioid receptors play a pivotal role in regulating both physiological and cognitive processes. RU-1205, a benzimidazole derivative acting as a specific kappa opioid receptor agonist, has demonstrated the capacity to modulate neuronal activity. However, the nuanced effects of RU-1205 on neuronal activity remain incompletely understood.

The aim of the study was to identify and elucidate the effects of the kappa opioid agonist RU-1205 on local field potentials and behavior in the discriminative stimulus paradigm.

Materials and methods. The experiments were conducted in male rats weighing 260–280 g. The animals were surgically implanted with cortical electrodes (F — frontal, O — occipital, P — parietal) as well as deep electrodes in specific brain regions, including the medial prefrontal cortex (mPFC), hippocampus (Hipp), nucleus accumbens (NAc), ventral tegmental area (VTA) and amygdala (Amy). LFP signals were obtained and analyzed after the administration of the compound RU-1205 (350 μg/5 μl intracerebroventricular injections) using spectral and coherence analysis methods. Drug discrimination paradigm was employed to evaluate the similarity of the compound RU-1205 to the selective kappa opioid receptor agonist U-50488 and the p38 MAPK inhibitor SB203580 (including in combination with the opioid receptor blocker naloxone).

Results. Electrophysiological changes observed include an increase in power of theta frequencies (4–8 Hz) in F, P and mPFC leads, along with a reduced power of delta frequencies (0.5–4 Hz) in O and Hipp leads, and a suppression of gamma activity (30–50 Hz) in F and mPFC leads, all with statistical significance (p <0.05). Post-administration of RU-1205 resulted in a decreased coherence between pairs of electrodes: P–O, P–F, F–O, and mPFC–Hipp (all p <0.05). It was found that the compound RU-1205 is similar to U-50488 and does not exhibit p38 inhibitory activity in the discriminative stimulus paradigm.

Conclusion. Compared to the selective kappa-opioid agonist U-50488, the compound RU-1205 induces less significant changes in LFP activity without electrophysiological and behavioral signs of beta-arrestin pathway activation. The overall data suggest that RU-1205 is a functionally selective agonist of kappa-opioid receptors.

1. Cahill CM, Taylor AM, Cook C, Ong E, Morón JA, Evans CJ. Does the kappa opioid receptor system contribute to pain aversion?. Frontiers in pharmacology. 2014;5:253. DOI: 10.3389/fphar.2014.00253

2. Kalitin KY, Grechko OY, Spasov AA, Sukhov AG, Anisimova VA, Matukhno AE. GABAergic mechanism of anticonvulsive effect of chemical agent RU-1205. Bulletin of Experimental Biology and Medicine. 2017;164(11):582–588.

3. Kalitin KY, Spasov AA, Grechko OY, Sukhov AG, Vislobokov AI, Anisimova VA, Matukhno AE. Anticonticonvulsant and membranotropic activity of RU-1205 compound. Éksperimentalnaya i Klinicheskaya Farmakologiya. 2017;80(9):28–34. DOI: 10.30906/0869-2092-2017-80-9-28-34

4. van Wijk BCM, de Bie RMA, Beudel M. A systematic review of local field potential physiomarkers in Parkinson's disease: from clinical correlations to adaptive deep brain stimulation algorithms. J Neurolog. 2023;270(2):1162–1177. DOI: 10.1007/s00415-022-11388-1

5. Melnikova T, Tsukarzi E, Mosolov S. Interhemispheric Connections Dynamics of Symmetric Cortical Areas According Coherence Analysis of EEG in Therapy-resistant Depressive Patients in Transcranial Magnetic Stimulation. Curr Ther Mental Dis. 2019;(2):2–8. DOI: 10.21265/PSYPH.2019.73.85.001

6. Ona G, Sampedro F, Romero S, Valle M, Camacho V, Migliorelli C, Mañanas MÁ, Antonijoan RM, Puntes M, Coimbra J, Ballester MR, Garrido M, Riba J. The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A. Int J Neuropsychopharmacol. 2022;25(1):54–63. DOI: 10.1093/ijnp/pyab063

7. Simón-Arceo K, González-Trujano ME, Coffeen U, Fernández-Mas R, Mercado F, Almanza A, Contreras B, Jaimes O, Pellicer F. Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats. J Ethnopharmacol. 2017;206:115–124. DOI: 10.1016/j.jep.2017.05.016

8. Tortella FC, Rose J, Robles L, Moreton JE, Hughes J, Hunter JC. EEG spectral analysis of the neuroprotective kappa opioids enadoline and PD117302. The Journal of pharmacology and experimental therapeutics. 1997;282(1):286–293.

9. Cahill CM, Taylor AM, Cook C, Ong E, Morón JA, Evans CJ. Does the kappa opioid receptor system contribute to pain aversion? Front Pharmacolog. 2014;5:253. DOI: 10.3389/fphar.2014.00253

10. Crowley NA, Kash TL. Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2015;62:51–60. DOI: 10.1016/j.pnpbp.2015.01.001

11. Spasov AA, Zvartau EE, Grechko OY, Eliseeva NV, Semenova YV, Dravolina OA, Vasiliev PM, Anisimova VA. Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205. Research Results in Pharmacology. 2020;6(3):59–65. DOI: 10.3897/rrpharmacology.6.54558

12. Grechko OY, Spasov AA, Kalitin KY, Zhukovskaya ON, Anisimova VA. Comparative study of the influence of benzimidazole derivative RU-1205, diazepam, and sodium valproate on the seizure threshold, anticonvulsant tolerance, and rebound. Éksperimentalnaya i Klinicheskaya Farmakologiya. 2016;79(12):3–6. DOI: 10.30906/0869-2092-2016-79-12-3-6

13. Zan GY, Wang Q, Wang YJ, Chen JC, Wu X, Yang CH, Chai JR, Li M, Liu Y, Hu XW, Shu XH, Liu JG. p38 mitogen-activated protein kinase activation in amygdala mediates κ opioid receptor agonist U50,488H-induced conditioned place aversion. Neuroscience. 2016;320:122–128. DOI: 10.1016/j.neuroscience.2016.01.052

14. Hramov AE, Frolov NS, Maksimenko VA, Kurkin SA, Kazantsev VB, Pisarchik AN. Functional networks of the brain: from connectivity restoration to dynamic integration. Uspekhi Fizicheskikh Nauk. 2021;191(6):614–650. DOI: 10.3367/UFNe.2020.06.038807

15. Colpaert FC. Drug Discrimination: Methods of Manipulation, Measurement, and Analysis. In: Bozarth MA, editor. Methods of Assessing the Reinforcing Properties of Abused Drugs. Springer, New York, NY; 1987. DOI: 10.1007/978-1-4612-4812-5_17

16. Lee JY, Choi MJ, Choe ES, Lee YJ, Seo JW, Yoon SS. Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats. Behavioural Brain Research. 2016;306:197–201. DOI: 10.1016/j.bbr.2016.03.029

17. Manvich DF, Webster KA, Foster SL, Farrell MS, Ritchie JC, Porter JH, Weinshenker D. The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. Sci Rep. 2018;8(1):3840. DOI: 10.1038/s41598-018-22116-z

18. Kalitin KY, Spasov AA, Mukha OY. Aversion-related effects of kappa-opioid agonist U-50488 on neural activity and functional connectivity between amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens. Research Results in Pharmacology. 2023;9(4):21–9. DOI: 10.18413/rrpharmacology.9.10051

19. Stujenske JM, Likhtik E, Topiwala MA, Gordon JA. Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. Neuron. 2014;83(4):919–33. DOI: 10.1016/j.neuron.2014.07.026

20. Courtin J, Karalis N, Gonzalez-Campo C, Wurtz H, Herry C. Persistence of amygdala gamma oscillations during extinction learning predicts spontaneous fear recovery. Neurobiol Learn Mem. 2014;113:82–89. DOI: 10.1016/j.nlm.2013.09.015

21. Likhtik E, Stujenske JM, Topiwala MA, Harris AZ, Gordon JA. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat Neurosci. 2014;17(1):106–113. DOI: 10.1038/nn.3582

22. Merino E, Raya-Salom D, Teruel-Martí V, Adell A, Cervera-Ferri A, Martínez-Ricós J. Effects of Acute Stress on the Oscillatory Activity of the Hippocampus-Amygdala-Prefrontal Cortex Network. Neurosci. 2021;476:72–89. DOI: 10.1016/j.neuroscience.2021.09.009

23. Zhou H, Zhu J, Jia J, Xiang W, Peng H, Zhang Y, Liu B, Mu Y, Lu Y. The antidepressant effect of nucleus accumbens deep brain stimulation is mediated by parvalbumin-positive interneurons in the dorsal dentate gyrus. Neurobiol Stress. 2022;21:100492. DOI: 10.1016/j.ynstr.2022.100492

24. Okonogi T, Sasaki T. Theta-Range Oscillations in Stress-Induced Mental Disorders as an Oscillotherapeutic Target. Front Behav Neurosci. 2021;15:698753. DOI: 10.3389/fnbeh.2021.698753

25. Ploski JE, Vaidya VA. The neurocircuitry of posttraumatic stress disorder and major depression: Insights into overlapping and distinct circuit dysfunction—A tribute to Ron Duman. Biologic Psychiatry. 2021;90(2): 109–117. DOI: 10.1016/j.biopsych.2021.04.009

26. Drevets WC. Neuroimaging abnormalities in the amygdala in mood disorders. Ann N Y Acad Sci. 2003;985(1):420–444. DOI: 10.1111/j.1749-6632.2003.tb07098.x

27. Voruganti LP, Awad AG. Is neuroleptic dysphoria a variant of drug-induced extrapyramidal side effects? Canad J Psychiatry. 2004;49(5):285–289. DOI: 10.1177/070674370404900502

28. Wang J, Li D, Li X, Liu FY, Xing GG, Cai J, Wan Y. Phase-amplitude coupling between θ and γ oscillations during nociception in rat electroencephalography. Neurosci Letters. 2011;499(2):84–87. DOI: 10.1016/j.neulet.2011.05.037

29. Rustamov N, Wilson EA, Fogarty AE, Crock LW, Leuthardt EC, Haroutounian S. Relief of chronic pain associated with increase in midline frontal theta power. Pain Rep. 2022;7(6):e1040. DOI: 10.1097/PR9.0000000000001040

30. Xiao Z, Martinez E, Kulkarni PM, Zhang Q, Hou Q, Rosenberg D, Talay R, Shalot L, Zhou H, Wang J, Chen ZS. Cortical Pain Processing in the Rat Anterior Cingulate Cortex and Primary Somatosensory Cortex. Front Cell Neurosci. 2019;13:165. DOI: 10.3389/fncel.2019.00165

31. Reakkamnuan C, Cheaha D, Kumarnsit E. Nucleus accumbens local field potential power spectrums, phase-amplitude couplings and coherences following morphine treatment. Acta Neurobiol Exp (Wars). 2017;77(3):214–224. DOI: 10.21307/ane-2017-055

32. Ahmadi Soleimani SM, Mohamadi M A H MH, Raoufy MR, Azizi H, Nasehi M, Zarrindast MR. Acute morphine administration alters the power of local field potentials in mesolimbic pathway of freely moving rats: Involvement of dopamine receptors. Neurosci Letters. 2018;686:168–174. DOI: 10.1016/j.neulet.2018.09.016

33. Wang GW, Cai JX. Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats. Behav Brain Res. 2006;175(2):329–336. DOI: 10.1016/j.bbr.2006.09.002

34. McDaniel KL, Mundy WR, Tilson HA. Microinjection of dynorphin into the hippocampus impairs spatial learning in rats. Pharmacol Biochem Behav. 1990;35(2):429–435. DOI: 10.1016/0091-3057(90)90180-p

35. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018;17(4):243–260. DOI: 10.1038/nrd.2017.229

36. Kalitin KY, Mukha OY, Spasov AA. Electrophysiological effects of kappa-opioid analgesic, RU-1205, using machine learning methods. Pharmacy & Pharmacology. 2023;11(5):432–442. DOI: 10.19163/2307-9266-2023-11-5-432-442

37. Birdsong WT, Williams JT. Recent progress in opioid research from an electrophysiological perspective. Mol Pharmacol. 2020;98(4):401–409. DOI: 10.1124/mol.119.119040

38. Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzwanker S, Schmiedel F, Katte TA. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci Signal. 2020;13(625):eaaz3140. DOI: 10.1126/scisignal.aaz3140