PhD Scientific Days 2025

Poster Session I. - F: Pharmaceutical Sciences and Health Technologies

Preclinical Investigation of the Impact of AT1 Receptor and PPARγ on Morphine Antinociceptive Tolerance

Name of the presenter

Boldizsár Imre

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy

Authors

Imre Boldizsár Jr.^1,2, Dávid Árpád Karádi PhD^1,2, Nariman Essmat^1,2, Zoltán Varga PhD^1,2, Gábor Mórotz PhD^1,2, Mahmoud Al-Khrasani PhD^1,2, Kornél Király PhD^1,2

1: Department of Pharmacology and Pharmacotherapy, Semmelweis University
2: Center for Pharmacology and Drug Research & Development, Semmelweis University

Text of the abstract

Introduction: Opioid analgesics are the mainstay in the management of moderate to severe pain. Their effectiveness is hampered by side effects and analgesic tolerance. Studies indicated that AT1 receptor blockers (ARBs), notably telmisartan, have shown antinociception in chronic pain and delayed morphine tolerance (MT), yet activates peroxisome proliferator-activated receptor gamma (PPARγ).
Aim: Exploring whether morphine analgesic tolerance is mediated by AT1 or PPARγ, telmisartan (TEL) and losartan (LOS) were assessed using in vivo and in vitro assays.
Methods: Male Wistar rats and NMRI mice were used. The rat tail-flick, thermal pain assay was used to test the antinociceptive effects of sc. morphine (31.08µmol/kg), po. TEL (20µmol/kg), or LOS (50µmol/kg), either individually or in combination with morphine 60, 90, 150 and 210 min after treatment on day 1, 4 and 10 in the presence or absence of PPARγ antagonist GW9662. After pain assessment, animals were sacrificed, and their spinal cords were removed for histological analysis. In colocalization studies, naïve rats were used. In the in vitro tolerance assay, mouse vas deferens (MVD) was used. After 60 min equilibration under electrical stimulation, MVD was treated three times with vehicle, 1μM morphine alone or in combination with LOS, and then the effect of 0.5μM morphine was tested.
Results: In the thermal pain assay, morphine treated group exhibited a significant decrease in antinociception by day 10, indicating the development of MT. The cotreatment with TEL or LOS attenuated the development of MT. The effect of ARBs was partially blocked by GW9662. ARBs alone failed to show an antinociceptive effect. Chronic morphine treatment increased spinal IBA1 expression, which was reduced by ARBs; this effect was reversed by GW9662. Colocalization of AT1, MOR and CGRP on small to medium-sized primary afferent neurons was observed. Compared to vehicle-treated MVD, the effect of 0.5μM morphine significantly decreased in tissues exposed to repeated 1μM morphine treatment, indicating the development of MT in the in vitro assay. Treatment of MVD with LOS restored the effect of 0.5μM morphine.
Conclusion: Simultaneous activation of MOR and inhibition of AT1 delayed the development of morphine tolerance in vivo and in vitro assays. The involvement of PPARγ in this scenario was proved.
Funding: TKP2021-EGA-25