Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

Abstract

Thiazolidinedione drugs (TZDs) such as pioglitazone are FDA-approved for the treatment of insulin resistance in type 2 diabetes. However, whether TZDs reduce painful diabetic neuropathy (PDN) remains unknown. Therefore we tested the hypothesis that chronic administration of pioglitazone would reduce PDN in Zucker Diabetic Fatty (ZDFfa/fa) rats. Compared to Zucker Lean (ZLfa/+) controls, ZDF developed: (1) elevated blood glucose, HbA1c, methylglyoxal and insulin; (2) mechanical and thermal hyperalgesia at the hindpaw; (3) increased avoidance of noxious mechanical probes in a mechanical conflict avoidance behavioral assay, the first report of a measure of affective-motivational pain-like behavior in ZDF; and (4) exaggerated lumbar dorsal horn immunohistochemical expression of pressure-evoked phosphorylated extracellular signal-regulated kinase (pERK). Seven weeks of pioglitazone (30 mg · kg−1 · d−1 in food) reduced blood glucose, HbA1c, hyperalgesia, and pERK expression in ZDF. This is the first report to reveal hyperalgesia and spinal sensitization in the same ZDF animals, both evoked by a noxious mechanical stimulus that reflects pressure pain frequently associated with clinical PDN. As pioglitazone provides the combined benefit of reducing hyperglycemia, hyperalgesia, and central sensitization, we suggest that TZDs represent an attractive pharmacotherapy in patients with type 2 diabetes-associated pain.

Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation

“…Therefore, in addition to behavior, we test the hypothesis that intraplantar injection of MG evokes activation of spinal nociresponsive neurons by evaluating the phosphorylation of extracellular signal-regulated kinase (p-ERK) in the spinal cord dorsal horn. P-ERK is an established marker of pain-related central sensitization (Ji et al, 1999 , 2009 ; Gao and Ji, 2009 ) and is exacerbated in conditions of peripheral nerve injury (Morgenweck et al, 2013 ), inflammation (Corder et al, 2013 ), and type 2 diabetes (Griggs et al, 2016 ).…”

Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia

“…Because pain hypersensitivity can persist long after the healing of the initial damage, it causes major health problems around the world [2] . Interestingly, many patients with systemic disorders, such as spinal cord injury (SCI) [3] and diabetes [4] , suffer from hyperalgesia. Almost all of these patients accompany with oxidative stress when excessive amount of reactive oxygen species (ROS) are formed or when the antioxidant capacity is decreased [5] , [6] , and such imbalance may be a key factor to hyperalgesia [7] .…”

Alterations in the Expression of Transcription Factors PPARγ and NFκB in the Brain of Models of Chronic Pain

“…Treatment with PPARγ ligands, such as pioglitazone, in the SNT model indicates that pioglitazone alleviates neuropathic pain through the attenuation of the up-regulation in proinflammatory cytokines [30]. The effect of pioglitazone in reducing pain may be mediated by a decrease in glial activation and through neuropathic non-genomic and genomic activity [31]. It has been shown that inflammatory cytokines and oxidative stress decrease the expression of PPARγ mRNA in adipocytes [32] and thiazolidinediones reverse this effect [33].…”