Spinal Serotonin and 5HT6 Receptor Levels During Development of Neuropathy and Influence of Blockade of these Receptors on Thermal Hyperalgesia in Diabetic Mice

Abstract

Little is known about the role of 5-HT6 receptors in the pathophysiology of neuropathic pain. The aim of this study is firstly, to investigate the influence of spinal and systemic 5-HT6 receptors on thermal hyperalgesia, one of the most significant symptoms of neuropathy occurring in diabetes; and secondly to determine spinal lumbar serotonin and 5-HT6 receptor levels during development of diabetic neuropathy in mice. Diabetes was produced in Balb/c mice with a single injection of streptozocin (150 mg/kg, i.p.). Using the hot plate test, the 5-HT6 antagonist SB-258585 was given systemically (3, 10, 30 mg/kg) and intrathecally (0.01, 0.1, 1 nmol/mouse) to determine its effect on thermal hyperalgesia. Furthermore, on days 7 and 15 of diabetes, development of thermal hyperalgesia was evaluated in relation to changes in spinal serotonin and 5-HT6 receptor levels by using LC/MS/MS and Western blot analyses, respectively. Two-way analysis of variance and unpaired t-tests were used to evaluate data from hot-plate tests and 5-HT levels/ 5-HT6 receptor expression, respectively. Thermal hyperalgesia was observed in neuropathic mice, starting from day 5 after streptozocin administration. On day 15, systemic, but not intrathecal, SB-258585 attenuated thermal hyperalgesia in neuropathic mice. Spinal serotonin levels did not change during development of hyperalgesia after induction of diabetes, whereas spinal 5-HT6 receptor levels were significantly reduced on days 7 and 15. Our findings show that systemic, but not spinal, blockade of 5-HT6 receptors may exert antihyperalgesic effects in neuropathic mice and suggest that systemic 5-HT6 receptors contribute to the pathophysiology of diabetic neuropathy.

The serotonergic system dysfunction in diabetes mellitus

“…Systemic, but not spinal, inhibition of 5-HT 6 receptors relieved thermal hyperalgesia in diabetic mice. These results indicate that 5-HT 6 receptor antagonists may be therapeutic targets for pharmacotherapy of diabetic neuropathy ( Sari et al, 2019 ).…”

“…Spinal nerve damage results in a loss of descending serotonergic neurons ( Leong et al, 2011 ); in contrast, it does not alter spinal 5-HT 6 receptor expression ( Morgado et al, 2011 ). Differentiation from nerve injury-caused neuropathy, and 5-HT 6 receptor expression is obviously downregulated in diabetes-induced neuropathy, which can be due to the effect of intrathecal injection of 5-HT 6 receptor antagonist SB-258585 to ameliorate thermal hyperalgesia in diabetic rats ( Sari et al, 2019 ). Systemic, but not spinal, inhibition of 5-HT 6 receptors relieved thermal hyperalgesia in diabetic mice.…”

Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?

“…In this study, the intrathecal administration of a cell-penetrating mimetic peptide that disrupts the physical interaction between the 10 amino-acyl residues of the C-terminus of the 5-HT 6 receptor and mTOR protein [52], also suppressed mechanical hyperalgesia in STZ diabetic rats [56]. The attenuation of thermal hyperalgesia in STZ diabetic mice after systemic administration of SB258585 and the absence of changes in spinal serotonin levels during the course of diabetes further support a role for 5-HT 6 receptor constitutive activity in diabetic neuropathic pain [57]. In addition to 5-HT 6 receptor-dependent mTOR activation, mTOR has been shown to be involved in glucose homeostasis by regulating pan-creatic β-cell function [58] and neuronal function.…”

The Antinociceptive Responses of MTDZ to Paclitaxel−Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches

“…In regard to the serotonergic pathway, MTDZ was found to specifically target 5-HT 1A/1B receptors. Descending pain pathways often involve serotonin receptors, with neuropathic pain in particular affecting transmission through descending serotonergic pathways by altering 5−HT 1A/1B receptors [ 25 ]. Notably, the dorsal horn, where pain processing occurs, predominantly contains the 5−HT 1 receptor subtype [ 25 ].…”

“…Descending pain pathways often involve serotonin receptors, with neuropathic pain in particular affecting transmission through descending serotonergic pathways by altering 5−HT 1A/1B receptors [ 25 ]. Notably, the dorsal horn, where pain processing occurs, predominantly contains the 5−HT 1 receptor subtype [ 25 ]. Selective modulation of the 5−HT 1A subtype may exert a significant inhibitory effect against mechanical hyperalgesia [ 26 ].…”