Sigma-1 Receptor Inhibition Reduces Mechanical Allodynia and Modulate Neuroinflammation in Chronic Neuropathic Pain.

Autor: Denaro S; Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Pasquinucci L; Section of Medicinal Chemistry, Department of Drug and Health Sciences, University of Catania, 95123, Catania, Italy., Turnaturi R; Section of Medicinal Chemistry, Department of Drug and Health Sciences, University of Catania, 95123, Catania, Italy., Alberghina C; Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Longhitano L; Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Giallongo S; Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Costanzo G; Section of Medicinal Chemistry, Department of Drug and Health Sciences, University of Catania, 95123, Catania, Italy., Spoto S; Section of Pharmacology and Toxicology, Department of Drug and Health Sciences, University of Catania, 95123, Catania, Italy., Grasso M; Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, 94018, Troina, Italy., Zappalà A; Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Li Volti G; Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Tibullo D; Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Vicario N; Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy. nunziovicario@unict.it., Parenti R; Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy. parenti@unict.it., Parenti C; Section of Pharmacology and Toxicology, Department of Drug and Health Sciences, University of Catania, 95123, Catania, Italy.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 May; Vol. 61 (5), pp. 2672-2685. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1007/s12035-023-03717-w
Abstrakt: Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission. As such, it represents a druggable target to treat neuropathic pain. This study aims at investigating the therapeutic potential of the novel compound (+)-2R/S-LP2, a σ1R antagonist, in reducing painful behaviour and modulating the neuroinflammatory environment. We showed that repeated administration of the compound significantly inhibited mechanical allodynia in neuropathic rats, increasing the withdrawal threshold as compared to CCI-vehicle rats. Moreover, we found that (+)-2R/S-LP2-mediated effects resolve the neuroinflammatory microenvironment by reducing central gliosis and pro-inflammatory cytokines expression levels. This effect was coupled with a significant reduction of connexin 43 (Cx43) expression levels and gap junctions/hemichannels mediated microglia-to-astrocyte communication. These results suggest that inhibition of σ1R significantly attenuates neuropathic pain chronicization, thus representing a viable effective strategy.
(© 2023. The Author(s).)
Databáze: MEDLINE
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