Mechanism of Pain in Diabetic Peripheral Neuropathy. Effect of Glucose on Pain Perception in Humans

Morley, Gerald K.; Mooradian, A. D.; Levine, A. S.; Morley, J. E.

doi:10.1097/00132586-198512000-00024

Cited by 44 publications

(56 citation statements)

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“…Hyperglycemia directly affects nociceptive thresholds on rat peripheral nerves and dorsal root ganglia (27). Similarly, in both type II diabetes patients or in healthy human volunteers, intravenous infusion of glucose significantly decreases pain thresholds (30). Given that sEH is implicated in β-islet function, we asked if inhibition of sEH changed pain-related behavior by modulating the glycemic status of rats (31,32).…”

Section: Resultsmentioning

confidence: 99%

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Inceoglu

Wagner

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. The progressive damage to the peripheral nervous system is irreversible although strict control of hyperglycemia may prevent further damage. Current treatments include tricyclic antidepressants, anticonvulsants, and opioids, depending on the severity of the pain state. However, available therapeutics have drawbacks, arguing for the need to better understand the pathophysiology of neuropathic pain and develop novel treatments. Here we demonstrate that stabilization of a class of bioactive lipids, epoxygenated fatty acids (EpFAs), greatly reduces allodynia in rats caused by streptozocin-induced type I diabetes. Inhibitors of the soluble epoxide hydrolase (sEHI) elevated and stabilized the levels of plasma and spinal EpFAs, respectively, and generated dose-dependent antiallodynic effects more potently and efficaciously than gabapentin. In acute experiments, positive modulation of EpFAs did not display differences in insulin sensitivity, glucose tolerance, or insulin secretion, indicating the efficacy of sEHIs are not related to the glycemic status. Quantitative metabolomic analysis of a panel of 26 bioactive lipids demonstrated that sEHI-mediated antiallodynic effects coincided with a selective elevation of the levels of EpFAs in the plasma, and a decrease in degradation products coincided with the dihydroxy fatty acids in the spinal cord. Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain.analgesic drug | soluble epoxide hydrolase inhibitor | cytochrome P450 | glucose homeostasis | motor depressant

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Section: Resultsmentioning

confidence: 99%

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Inceoglu

Wagner

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Aside from the latter point, many researchers have noticed the presence of mechanical hyperalgesia in STZ-induced diabetic animals. In fact, high glucose per se (26), changes of neurotransmitters (27), alterations of opioid metabolism and receptors (28,29), or physiologically increased responsiveness or abnormalities of ion channels of neurons (15,18,30,31,32) have been proposed as contributing factors to hyperalgesia. Many reports have supported the significant effect of PKC modulators on the generation of pain; PKC may contribute to primary afferent C-fiber excitability, because phorbol esters can depolarize cultured DRG neurons with C-fiber properties (33).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

et al. 2003

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Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKC␤ inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKC␤-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKC␤ and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.

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“…Many clinical and experimental studies have suggested that diabetes or hyperglycemia alters pain sensitivity (4). Diabetic neuropathy can be associated with a sensation of burning or tactile hypersensitivity (4).…”

mentioning

confidence: 99%

Antinociceptive Effect of Vitamin K2 (Menatetrenone) in Diabetic Mice

Onodera

Zushida

Kamei

2001

Japanese Journal of Pharmacology

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ABSTRACT-The antinociceptive effect of vitamin K2 (menatetrenone) in diabetic mice was examined using a tail-pressure test. Intraperitoneal injection of menatetrenone (10 -100 mg/ kg) produced a dosedependent increase in the nociceptive threshold in diabetic mice. There was no significant difference between non-diabetic and diabetic mice in the menatetrenone-induced changes in the nociceptive threshold. The results suggest the therapeutical usefulness of menatetrenone for treating painful diabetic neuropathy and osteoporosis.

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Mechanism of Pain in Diabetic Peripheral Neuropathy. Effect of Glucose on Pain Perception in Humans

Cited by 44 publications

References 0 publications

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

Antinociceptive Effect of Vitamin K2 (Menatetrenone) in Diabetic Mice

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