Characterization of Mechanical Allodynia and Skin Innervation in a Mouse Model of Type-2 Diabetes Induced by Cafeteria-Style Diet and Low-Doses of Streptozotocin

Abstract

Background: Painful distal symmetrical polyneuropathy (DPN) is a frequent complication of type-2 diabetes mellitus (T2DM) that commonly presents as neuropathic pain and loss of skin nerve fibers. However, there are limited therapies to effectively treat DPN and many of the current animal models of T2DM-induced DPN do not appear to mirror the human disease. Thus, we validated a DPN mouse model induced by a cafeteria-style diet plus low-doses of streptozotocin (STZ).Methods: Female C57BL/6J mice were fed either standard (STD) diet or obesogenic cafeteria (CAF) diet for 32 weeks, starting at 8 weeks old. Eight weeks after starting diets, CAF or STD mice received either four low-doses of STZ or vehicle. Changes in body weight, blood glucose and insulin levels, as well as oral glucose- and insulin-tolerance tests (OGTT and ITT) were determined. The development of mechanical hypersensitivity of the hindpaws was determined using von Frey filaments. Moreover, the effect of the most common neuropathic pain drugs was evaluated on T2DM-induced mechanical allodynia. Finally, the density of PGP -9.5+ (a pan-neuronal marker) axons in the epidermis from the hindpaw glabrous skin was quantified.Results: At 22–24 weeks after STZ injections, CAF + STZ mice had significantly higher glucose and insulin levels compared to CAF + VEH, STD + STZ, and STD + VEH mice, and developed glucose tolerance and insulin resistance. Skin mechanical sensitivity was detected as early as 12 weeks post-STZ injections and it was significantly attenuated by intraperitoneal acute treatment with amitriptyline, gabapentin, tramadol, duloxetine, or carbamazepine but not by diclofenac. The density of PGP-9.5+ nerve fibers was reduced in CAF + STZ mice compared to other groups.Conclusion: This reverse translational study provides a painful DPN mouse model which may help in developing a better understanding of the factors that generate and maintain neuropathic pain and denervation of skin under T2DM and to identify mechanism-based new treatments.

Artificial light at night alters progression of cold neuropathy in a sex-dependent manner in a mouse model of type II diabetes mellitus

“…It is possible that the initial phase of hypersensitivity was not replicated in these studies due to the acute period of T2DM induction. In contrast to the absence of hypoesthesia in female mice in this study, another study reported long-term allodynia using the same T2DM induction protocol as this study, although their study examined female C57BL/6 mice (Castañeda-Corral et al, 2021).…”

Response profile in a rat model of exercise‐induced hypoalgesia is associated with duloxetine, pregabalin and diclofenac effect on constriction‐induced neuropathy

“…The doses were selected based on those used in previous studies on pregabalin (Bardin et al, 2010;Chen et al, 2001;Eutamene et al, 2000;Goncalves & Dickenson, 2012;Kiso et al, 2008;Peng et al, 2012), duloxetine (Bardin et al, 2010;Iyengar et al, 2004;Kiso et al, 2008) and diclofenac (Granados-Soto et al, 2004;Khan et al, 2018;Sukriti & Pandhi, 2004). However, we cannot rule out the possibility that different doses could produce different results, specifically in the case of diclofenac as varied doses were used in other studies (Allchorne et al, 2012;Castaneda-Corral et al, 2020).…”

Sexual Dimorphism in the Mechanism of Pain Central Sensitization

“…Moreover, chronic pain has also been investigated in metabolic disorder neuropathies [ 52 , 53 ]. Preclinical models of chronic pain induced by metabolic disorder neuropathies are based on chemical and surgical approaches, genetic, and diet alterations.…”