Activation of 5-HT1A Receptors Normalizes the Overexpression of Presynaptic 5-HT1A Receptors and Alleviates Diabetic Neuropathic Pain

Abstract

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.