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Activation of 5-HT1A Receptors Normalizes the Overexpression of Presynaptic 5-HT1A Receptors and Alleviates Diabetic Neuropathic Pain.
Munawar, Neha; Bitar, Milad S; Masocha, Willias.
Afiliación
  • Munawar N; Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Al-Jabriya 046302, Kuwait.
  • Bitar MS; Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Al-Jabriya 046302, Kuwait.
  • Masocha W; Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait University, Al-Jabriya 046302, Kuwait.
Int J Mol Sci ; 24(18)2023 Sep 20.
Article en En | MEDLINE | ID: mdl-37762636
Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 1 / Neuropatías Diabéticas / Neuralgia Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Kuwait Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 1 / Neuropatías Diabéticas / Neuralgia Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Kuwait Pais de publicación: Suiza