id_822. PITOLISANT, A HISTAMINE H3 RECEPTOR ANTAGONIST/INVERSE AGONIST, REDUCES PAIN HYPERSENSITIVITY AND ALTERS MORPHINE ANALGESIA, ANXIETY-LIKE BEHAVIOUR AND METABOLISM IN A SEX-DEPENDENT MANNER IN A MURINE MODEL OF NEUROPATHIC PAIN.
Magdalena Maciuszek1, Magdalena Białoń1, Tomasz Lenda2, Patrycja Mieszczak3, Justyna Barut3, Katarzyna Starowicz1, Katarzyna Popiolek-Barczyk1
1 1Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 Str., 31-343 Krakow, Poland
2 CEPHARES, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 Str, 31-343 Krakow, Poland
3 Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 Str, 31-343 Krakow, Poland
INTRODUCTION: Multimodal pain therapy is a growing trend in chronic pain management, with the histamine 3 receptor (H3R) being a promising target for new analgesics research. We introduce an innovative therapeutic approach utilizing the clinically approved H3R antagonist/inverse agonist, pitolisant (PIT), combined with morphine (M).
AIM(S): This strategy aims to synergistically reduce pain while enabling significant opioid dose reduction and decreased side effects.
METHOD(S): We used chronic constriction injury in male and female mice to model neuropathic pain. Mechanical and thermal thresholds were assessed after PIT administration, and the possible participation of spinal H1R and H2R in these analgesic effects was determined. The neurochemical assessment of monoamines after PIT treatment was performed. The effects of PIT and M co-administration on metabolic and behavioural parameters were evaluated.
RESULTS: PIT reduced hypersensitivity more effectively in males, which correlated with elevated spinal levels of monoamines. Spinal H1R/H2R blockade diminished PIT-induced analgesia. Co-administration of PIT and M at ineffective doses produced significant analgesia in both sexes. PIT alone did not impair locomotor activity, anxiety-like behaviour, and metabolism, while increasing food/water consumption in males. PIT reversed M-induced locomotor impairment in males, but did not mitigate sleep disturbances, anxiety in both sexes; or female-restricted metabolic reductions.
CONCLUSIONS: Our study identifies PIT as a potent antinociceptive and co-analgesic, and propose an innovative pharmacological approach that pairs pitolisant with morphine to harness the potent analgesia of opioids and mitigate their side effects, addressing critical gaps in current chronic pain treatment paradigms.
FINANCIAL SUPPORT: Work was financed by a grant from the National Science Centre, Poland, 2019/35/D/NZ7/01042. The research was carried out with the use of the Center for the Development of New Pharmacotherapies of Central Nervous System Diseases CEPHARES co-financed by the European Regional Development Fund, Measure 4.2 of the Smart Growth Operational Programme 2014-2020.