PhD Scientific Days 2023

Budapest, 22-23 June 2023

Pharmaceutical Sciences II.

Effect of Concomitant Administration of Telmisartan and Morphine on Mononeuropathic Pain and Opioid Antiniciceptive Tolerance in Rats

David Á. Karádi1, Anna R. Galambos1, Péter P. Lakatos2, Joost Apenberg1, Sarah K. Abbood1, Mihály Balogh1,3, Kornél Király1, Pál Riba1, Nariman Essmat1, Edina Szűcs4, Sándor Benyhe4, Zoltán Varga1, Éva Szökő2, Tamás Tábi2, Mahmoud Al-Khrasani1
1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1089, Budapest, Hungary
2 Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
3 Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD, Groningen, The Netherlands
4 Institute of Biochemistry, Biological Research Center, Temesvári krt. 62, H-6726 Szeged, Hungary

Text of the abstract

Introduction
Angiotensin receptor type 1 (AT1) has been proposed as a potential pharmacological target in the treatment of neuropathic pain (NP). In addition, connections between the renin-angiotensin and opioid systems regarding analgesia have been described.
Aims
We hypothesized that simultaneous blockade of AT1 and activation of µ-opioid receptors (MOR) could be beneficial in NP and opioid tolerance. In addition, we aimed to assess the possible colocalization of these structures in key points of pain transmission.
Methods
Male Wistar rats (170-250 g) were used for mononeuropathic (Seltzer ligation) or morphine analgesic tolerance models. Animals received acute or chronic oral treatment with losartan (50, 100 or 150 µmol/kg) or telmisartan (20, 40 or 80 µmol/kg) alone or in combination with subcutaneous morphine (10 µmol/kg). The antiallodynic effect was determined by dynamic plantar aesthesiometer. To assess opioid tolerance, the effect of morphine (31,08 µmol/kg), telmisartan (20 µmol/kg) or their combination was determined in the rat tail-flick (TF) assay following acute and chronic treatments. Morphine-stimulated [35S]-GTPγS binding assay was performed on spinal cord samples obtained from neuropathic animas. Finally, spinal cord and dorsal root ganglion tissue samples obtained from naïve rats were used for RNA Scope® in-situ hybridization, to assess OPRM1 and AGTR1A mRNA presence.
Results
Oral telmisartan or losartan produced acute antiallodynic effect in the higher tested doses. Upon chronic treatment, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a significant leftward shift in the dose-response curve of morphine in [35S]GTPγS binding assay. Telmisartan delayed morphine analgesic tolerance, seen as a significant difference in TF latency between groups on day 10. Colocalization of AT1 and MOR mRNAs were found at sites of particular importance for pain transmission.
Conclusions
Despite the reported decrease in MOR reserve in NP and morphine tolerance, telmisartan restored morphine potency. These findings may provide the preclinical basis for exploiting AT1 blockade as a pharmacological target and raise the possibility of drug-repurposing in pain conditions with opioid impairment.
Funding
TKP 2021 EGA-25; ÚNKP-22-3-II-SE-31; “Semmelweis 250+ Kiválósági PhD Ösztöndíj” EFOP-3.6.3-VEKOP-16-2017-00009