P3.26. INVESTIGATION OF THE ANALGESIC POTENCY, METABOLIC IMPACT, AND EFFECTS ON LOCOMOTOR ACTIVITY OF THE NOVEL HISTAMINE H₃ RECEPTOR ANTAGONIST, LINS01022, IN A MURINE MODEL OF NEUROPATHIC PAIN
Mateusz Królewski1, Magdalena Maciuszek1, Magdalena Białoń1, Nathalia A. Fiocchi2, Flavia B. Lopes2, João Paulo S. Fernandes2, Katarzyna Popiołek-Barczyk1
1 Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 street, 31-343 Cracow, Poland
2 Department of Pharmaceutical Sciences, Federal University of São Paulo, Diadema, Brazil
INTRODUCTION: Neuropathic pain is a chronic condition that is often resistant to standard analgesics. A growing body of evidence suggests that the histaminergic system is a potential therapeutic target for pain management. Here, we have used a novel compound LINS01022 (1-(2,3-dihydrobenzofuran-2-yl)methylpiperazines), characterised as a potent H3R antagonist (with nanomolar affinity pKi=8.2)).
AIM(S): To investigate the analgesic potency of novel H3R antagonist, LINS01022, and its influence on metabolic parameters and locomotor activity in a mouse model of neuropathic pain.
METHOD(S): Neuropathic pain was induced using the chronic constriction injury (CCI) to the sciatic nerve. At day 14th after nerve injury, mice received a single intraperitoneal (i.p.) injection of LINS01022 [10, 20, and 30 mg/kg]. The control group was injected with the vehicle. The presence of mechanical hypersensitivity was determined by a von Frey test, 15, 45, 90, and 150 min after injections. Metabolic parameters [consumption of oxygen; production of carbon dioxide; respiratory exchange ratio; expenditure energy, and locomotor activity (meters, speed)] were measured using the Promethion metabolic cages system. CCI-exposed mice were injected with LINS01022 [20 mg/kg] or vehicle and monitored for 72 hours in metabolic cages. Naïve animals served as healthy controls.
RESULTS: Our data revealed an analgesic effect of LINS01022 at all tested doses compared to vehicle-treated controls. The administration of LINS01022 did not show any disturbances in metabolic parameters and locomotor activity.
CONCLUSIONS: Our studies bring the first evidence for the analgesic potency of the novel H3R antagonist. Moreover, the new compound did not reveal any influence on metabolic parameters and locomotion. @e suggest that LINS01022 is a promising compound with analgesic potency and a favourable safety profile and can be used as a novel pharmacological tool to deepen our knowledge of the histaminergic system in pathological conditions of the central nervous system
FINANCIAL SUPPORT: Work was financed by a grant from the National Science Centre, Poland, SONATA 2019/35/D/NZ7/01042; and São Paulo Research Foundation - FAPESP grant 2023/03485-7National Council for Scientific and Technological Development - CNPq grant 307829/2021-9