Selective changes in nocifensive behavior despite normal cutaneous axon innervation in leptin receptor–null mutant (<i>db/db</i>) mice

Wright, Douglas E.; Johnson, Megan S.; Arnett, Mark G.; Smittkamp, Susan E.; Ryals, Janelle M.

doi:10.1111/j.1529-8027.2007.00144.x

Cited by 38 publications

(33 citation statements)

References 51 publications

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“…In laboratory animals, intraperitoneal injection of exogenous leptin lowers the hot plate withdrawal latency in mice, although intracerebroventricular injection of leptin does not alter the hot plate test in rats (16). Moreover, mice with the leptin receptor null mutation (db/db) demonstrate a decreased sensitivity to mechanical stimulation and a decreased nociceptive response in the affected hind paw during the second phase of a formalin test (17). These data suggest that leptin may have an important and yet unknown role in the mechanisms of pain.…”

Section: Introductionmentioning

confidence: 84%

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Lim

Wang²,

Zhang³

et al. 2009

J. Clin. Invest.

103

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Pain after nerve injury, a phenomenon referred to as neuropathic pain, is a debilitating clinical condition, but the underlying mechanisms remain unclear. As leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions, we examined the role of leptin in neuropathic pain using a rat model of the condition chronic constriction sciatic nerve injury (CCI). We report that leptin critically contributed to pain behaviors following CCI. Specifically, spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. Further examination revealed that levels of both leptin and the long form of the leptin receptor (Ob-Rb) were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor and IL-1β through the JAK/STAT pathway. Furthermore, these CCI-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain. IntroductionPain resulting from injury to the nervous system (neuropathic pain) has several salient clinical features, including hyperalgesia and allodynia beyond the dermatome distribution. Both peripheral and central mechanisms, including glial activation and release of proinflammatory cytokines, have been proposed for the pathogenesis of neuropathic pain (1-3). Despite recent progress, the mechanisms underlying clinical features of neuropathic pain remain unclear. Leptin is an adipocytokine produced mainly by white adipose tissue and well known for its role in metabolic regulation and obesity (4-8). A growing body of evidence indicates that leptin has broad roles in the regulation of neuronal functions (3, 9-11). Furthermore, leptin's signal transduction pathways have much in common with those of proinflammatory cytokines (6,8,12).Recent clinical reports suggest that there might be a link between the plasma leptin level and tissue injury. For example, patients with spinal cord injury, chronic angina pectoris, or acute myocardial infarction display a higher than normal plasma leptin level (13-15). In laboratory animals, intraperitoneal injection of exogenous leptin lowers the hot plate withdrawal latency in mice, although intracerebroventricular injection of leptin does not alter the hot plate test in rats (16). Moreover, mice with the leptin receptor null mutation (db/db) demonstrate a decreased sensitivity to mechanical stimulation and a decreased nociceptive response in the affected hind paw during the second phase of a formalin test (17). These data suggest that leptin may have an important and yet unknown role in the mechanisms of pain.We explored the possibilities ...

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Section: Introductionmentioning

confidence: 84%

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Lim

Wang²,

Zhang³

et al. 2009

J. Clin. Invest.

103

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“…Obrosova, unpublished data), as well as in two animal models of prediabetes and obesity, Zucker fatty rats 55 and high-fat diet-fed C57Bl/6J mice. 56 Data for leptin receptor-deficient (db/db) mice 57,58 and Zucker diabetic fatty rats 59,60 are contradictory, and both normal and reduced thermal sensation in these two animal models have been reported. Surprisingly, a number of mechanisms contributing to increased thermal sensitivity in the rat models with relatively short-term duration of diabetes were also implicated in development of thermal hypoalgesia in rats with diabetes of longer duration or diabetic mice.…”

Section: Pathogenesis and Experimental Treatments Of Diabetes-associamentioning

confidence: 99%

“…51,87 Others found reduced tactile sensitivity, rather than tactile allodynia, in STZ-diabetic C57Bl/6J mice and db/db mice. 58,70 Tactile allodynia also develops in nerve injury models of neuropathic pain 88 -90 (e.g., in the model of sciatic nerve ischemia 90 ). The mechanisms underlying diabetes-induced tactile allodynia have not been studied in detail, although considerable progress has been made in experimental studies performed in the last several years.…”

Section: Diabetes-associated Tactile Allodyniamentioning

confidence: 99%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

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“…a Phenotyping was performed at final age unless indicated otherwise. (Wright et al 2007). Whereas C57BKS db/db mice have persistent hyperglycemia and develop robust neuropathy, db/db mice on the C57BL/6 background have transient hyperglycemia and absent or limited neuropathy (Dauch et al 2012;Ii et al 2005;Sullivan et al 2007;Wang et al 2011).…”

Section: Genetic T2dm Mouse Modelsmentioning

confidence: 99%

Mouse models of diabetic neuropathy

Sullivan

Hayes

Wiggin

et al. 2007

Neurobiology of Disease

165

186

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Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and is associated with significant morbidity and mortality. DPN is characterized by progressive, distal-to-proximal degeneration of peripheral nerves that leads to pain, weakness, and eventual loss of sensation. The mechanisms underlying DPN pathogenesis are uncertain, and other than tight glycemic control in type 1 patients, there is no effective treatment. Mouse models of type 1 (T1DM) and type 2 diabetes (T2DM) are critical to improving our understanding of DPN pathophysiology and developing novel treatment strategies. In this review, we discuss the most widely used T1DM and T2DM mouse models for DPN research, with emphasis on the main neurologic phenotype of each model. We also discuss important considerations for selecting appropriate models for T1DM and T2DM DPN studies and describe the promise of novel emerging diabetic mouse models for DPN research. The development, characterization, and comprehensive neurologic phenotyping of clinically relevant mouse models for T1DM and T2DM will provide valuable resources for future studies examining DPN pathogenesis and novel therapeutic strategies.

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Selective changes in nocifensive behavior despite normal cutaneous axon innervation in leptin receptor–null mutant (db/db) mice

Cited by 38 publications

References 51 publications

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

Mouse models of diabetic neuropathy

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