Indirect involvement of α 2 -adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I 1 receptor ligand LNP599 in a rat model of experimental neuropathy.

Autor: Wei H; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Vuorenpää A; Pain Research Unit, Orion Pharma, Orion Corporation, Turku, Finland., Laurila J; Faculty of Medicine, Institute of Biomedicine, University of Turku, Turku, Finland., Domanskyi A; Pain Research Unit, Orion Pharma, Orion Corporation, Turku, Finland., Koivisto A; Pain Research Unit, Orion Pharma, Orion Corporation, Turku, Finland. Electronic address: ari-pekka.koivisto@orionpharma.com., Pertovaara A; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: antti.pertovaara@helsinki.fi.
Jazyk: angličtina
Zdroj: Brain research bulletin [Brain Res Bull] 2024 Oct 15; Vol. 217, pp. 111089. Date of Electronic Publication: 2024 Sep 26.
DOI: 10.1016/j.brainresbull.2024.111089
Abstrakt: Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I 1 -receptor agonist LNP599 and whether the attenuation involves co-activation of α 2 -adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb. Additionally, GTPγS radioligand binding assay, β-arrestin recruitment and intracellular cAMP levels were used for receptor profiling in vitro. LNP599 (imidazoline I 1 receptor agonist) and clonidine (α 2 -adrenoceptor agonist) produced equal dose-related mechanical antihypersensitivity effects in both sexes. LNP599 attenuated heat nociception preferentially in males, while clonidine reduced heat nociception equally in males and females. Carbophenyline (another imidazoline I 1 receptor agonist) had no significant effect on mechanical hypersensitivity or heat nociception in males or females. Mechanical antihypersensitivity and heat antinociception induced by LNP599 in SNI males was prevented by pretreatments with yohimbine or atipamezole (two α 2 -adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I 1 receptor/α 2 -adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α 2A - or other subtypes of α 2 -adrenoceptors. However, LNP599 was a weak partial agonist for 5-HT 2B receptors and bound to sigma-1 and sigma-2 receptors that all are involved in modulation of spinal nociception. The results indicate that the suppression of neuropathic pain hypersensitivity by LNP599 is not due to action on spinal imidazoline I 1 receptors, but rather due to indirect activation of spinal α 2 -adrenoceptors.
Competing Interests: Declaration of Competing Interest Three of the authors (A.V., A.D., and A.K.) are employees of a pharmaceutical company (Orion Pharma). One of the authors (J.L.) has received funding from a pharmaceutical company (Orion Pharma). Other authors (H.W. and A.P.) declare no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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