Preclinical characterization of the efficacy and safety of histamine H3 receptor antagonist, LINS01022, as a novel analgesic for chronic neuropathic pain treatment.

Abstract

Neuropathic pain is a disorder that represents a significant clinical challenge, while is refractory to therapeutic interventions. Given that the histamine H3 receptor (H3R) is a promising target for new analgesics, we aimed to determine the effects of a novel H3R antagonist (pKi=8.2), LINS01022 (1-(2,3-dihydrobenzofuran-2-yl)methylpiperazine), in neuropathic pain model (chronic constriction injury). Recognizing the significant impact of sex on chronic pain, all experiments were conducted in male and female mice. We investigated the effects of a single intraperitoneal (i.p.) LINS01022 injections (10, 20, 30 mg/kg) on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli to determine dose-, time-, and sex-dependent analgesic profile. To characterize LINS01022 (20 mg/kg) influence on the metabolism parameters, we conducted behavioral profiling studies using an innovative, high-resolution Promethion Metabolic Cages system. Mechanical and thermal thresholds were also assessed after repeated LINS01022 (20 mg/kg/day) treatment, and the possible participation of spinal glutamine, glutamate and γ-aminobutyric acetic acid, and supraspinal glia activation was determined. Additionally, we investigated the LINS01022 influence on locomotor activity (open-field). LINS01022 reduced hypersensitivity in a dose- and time-dependent manner, with greater efficacy in males, and this analgesic effect was not corelated with changes in neurotransmitters level or glia activation. Importantly, the H3R antagonist did not impair locomotor activity and metabolic parameters. This research provides the first evaluation of LINS01022's analgesic efficacy and its favourable safety profile in neuropathic pain. These results suggest that a novel H3R antagonist is a promising drug candidate and a valuable pharmacological tool for further investigation.