Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature.

Autor: Gold MS; Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Pineda-Farias JB; Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Close D; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Patel S; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Johnston PA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Stocker SD; Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Journigan VB; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Sep; Vol. 181 (18), pp. 3527-3543. Date of Electronic Publication: 2024 May 24.
DOI: 10.1111/bph.16429
Abstrakt: Background and Purpose: We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin-induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT).
Experimental Approach: Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin-induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry.
Key Results: VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose-dependently attenuated cold hypersensitivity in oxaliplatin-treated mice at 3, 10 and 30 mg·kg -1 (n = 7, P < 0.05). VBJ103 (30 mg·kg -1 ) antinociception was influenced by neither the TRPA1 antagonist HC-030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg -1 , but not 100 or 300 mg·kg -1 , n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg -1 ) dose-dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 μL; n = 5) did not alter CBT.
Conclusions and Implications: We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target.
(© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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