Indirect involvement of α2-adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I1 receptor ligand LNP599 in a rat model of experimental neuropathy - UTU Research Portal

A1 Refereed original research article in a scientific journal

Indirect involvement of α2-adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I1 receptor ligand LNP599 in a rat model of experimental neuropathy

Authors: Wei, Hong; Vuorenpää, Anne; Laurila, Jonne; Domanskyi, Andrii; Koivisto, Ari; Pertovaara, Antti

Publisher: Elsevier Inc.

Publication year: 2024

Journal: Brain Research Bulletin

Journal name in source: Brain research bulletin

Journal acronym: Brain Res Bull

Article number: 111089

Volume: 217

ISSN: 0361-9230

eISSN: 1873-2747

DOI: https://doi.org/10.1016/j.brainresbull.2024.111089

Web address : https://doi.org/10.1016/j.brainresbull.2024.111089

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/458292854

Abstract

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I₁-receptor agonist LNP599 and whether the attenuation involves co-activation of α₂-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 I₁ receptor agonist) and clonidine (α₂-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 I₁ 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 α₂-adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I₁ receptor/α₂-adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α_2A- or other subtypes of α₂-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 I₁ receptors, but rather due to indirect activation of spinal α₂-adrenoceptors.

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Funding information in the publication:
This study was supported by the Sigrid Jusélius Foundation, Helsinki, Finland.