Role of vanilloid VR1 receptor in thermal allodynia and hyperalgesia in diabetic mice

Kamei, Junzo; Zushida, Ko; Morita, Kayo; Sasaki, Mitsumasa; Tanaka, Shun‐ichi

doi:10.1016/s0014-2999(01)01059-7

Cited by 82 publications

(54 citation statements)

References 14 publications

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“…The tail-flick test, where the time to movement of the tail from a noxious heat source is measured, reflects activity of a simple spinal reflex arc and provides information on peripheral nerve and spinal function in isolation from higher nociceptive processing and cognitive systems (23). The tail-flick response latency data in diabetic rats and mice are quite contradictory (4,23,25,29,30). In our previous study (4), the tail-flick response latency was increased in 12-week diabetic NOD mice compared with nondiabetic NOD mice.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

et al. 2006

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Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg ⅐ kg ؊1 ⅐ day ؊1 i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADPribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.

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Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

et al. 2006

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“…Similar to human painful diabetic neuropathy, animal models such as streptozotocin (STZ) 1 -induced diabetic mice or rats demonstrate early functional and biochemical abnormalities including thermal hyperalgesia and mechanical allodynia (3)(4)(5)(6). It has been suggested that hyperactivity of small, unmyelinated C-fibers results in hyperalgesia and allodynia in this model (6,7). Khan et al (4) reported that A-fiber afferents in diabetic rats developed abnormal spontaneous discharges and increased sensitivity to mechanical stimuli, suggesting a role of large A-fiber neurons in addition to nociceptive C-fibers in the development of diabetic neuropathic pain.…”

mentioning

confidence: 89%

Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Hong

Wiley

2005

Journal of Biological Chemistry

211

136

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Diabetes mellitus is associated with one or more kinds of stimulus-evoked pain including hyperalgesia and allodynia. The mechanisms underlying painful diabetic neuropathy remain poorly understood. Previous studies demonstrate an important role of vanilloid receptor 1 (VR1) in inflammation and injury-induced pain. Here we investigated the function and expression of VR1 in dorsal root ganglion (DRG) neurons isolated from streptozotocin-induced diabetic rats between 4 and 8 weeks after onset of diabetes. DRG neurons from diabetic rats showed significant increases in capsaicin-and protonactivated inward currents. These evoked currents were completely blocked by the capsaicin antagonist capsazepine. Capsaicin-induced desensitization of VR1 was down-regulated, whereas VR1 re-sensitization was upregulated in DRG neurons from diabetic rats. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate blunted VR1 desensitization, and this effect was reversible in the presence of the PKC inhibitor bisindolylmaleimide I. Compared with the controls, VR1 protein was decreased in DRG whole-cell homogenates from diabetic rats, but increased levels of VR1 protein were observed on plasma membranes. Of interest, the tetrameric form of VR1 increased significantly in DRGs from diabetic rats. Increased phosphorylation levels of VR1 were also observed in DRG neurons from diabetic rats. Colocalization studies demonstrated that VR1 expression was increased in large myelinated A-fiber DRG neurons, whereas it was decreased in small unmyelinated C-fiber neurons as a result of diabetes. These results suggest that painful diabetic neuropathy is associated with altered cell-specific expression of the VR1 receptor that is coupled to increased function through PKC-mediated phosphorylation, oligomerization, and targeted expression on the cell surface membrane.Painful neuropathy is one of the most common complications in early to intermediate stages of diabetes mellitus. Diabetic patients frequently exhibit one or more kinds of stimulusevoked pain, including increased responsiveness to noxious stimuli (hyperalgesia) as well as a hyper-responsiveness to normally innocuous stimuli (allodynia) that are often concurrent with a paradoxical loss of stimulus-evoked sensation (1, 2). The underlying mechanisms of painful diabetic neuropathy remain elusive. Similar to human painful diabetic neuropathy, animal models such as streptozotocin (STZ) 1 -induced diabetic mice or rats demonstrate early functional and biochemical abnormalities including thermal hyperalgesia and mechanical allodynia (3-6). It has been suggested that hyperactivity of small, unmyelinated C-fibers results in hyperalgesia and allodynia in this model (6, 7). Khan et al. (4) reported that A-fiber afferents in diabetic rats developed abnormal spontaneous discharges and increased sensitivity to mechanical stimuli, suggesting a role of large A-fiber neurons in addition to nociceptive C-fibers in the development of diabetic neuropathic pain.Capsaicin, the pungent ingredient in hot p...

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“…Among others, the streptozotocin-induced type-1 diabetes model in rodents is characterised by early functional abnormalities, including thermal hyperalgesia [5,28], associated with spinal deregulation of TRPV1 [5,29], SP [3] and GABA [25,26].…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats

2011

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Aims/hypothesis Diabetes is considered the leading cause of neuropathies in developed countries. Dysfunction of nerve growth factor (NGF) production and/or utilisation may lead to the establishment of diabetic neuropathies. Electroacupuncture has been proved effective in the treatment of human neuropathic pain as well as in modulating NGF production/activity. We aimed at using electroacupuncture to correct the development of thermal hyperalgesia and the tissue alteration of NGF and sensory neuromodulators in a rat model of type 1 diabetes. Methods Adult rats were injected with streptozotocin to induce diabetes and subsequently treated with lowfrequency electroacupuncture for 3 weeks. Variation in thermal sensitivity was studied during the experimental course. Hindpaw skin and spinal cord protein content of NGF, NGF receptor tyrosine kinase A (TrkA), substance P (SP), transient receptor potential vanilloid 1 (TRPV1) receptor and glutamic acid decarboxylase-67 (GAD-67) were measured after electroacupuncture treatments. The skin and spinal cord cellular distribution of TrkA was analysed to explore NGF signalling. Results Early after streptozotocin treatment, thermal hyperalgesia developed that was corrected by electroacupuncture. The parallel increases in NGF and TrkA in the spinal cord were counteracted by electroacupuncture. Streptozotocin also induced variation in skin/spinal TrkA phosphorylation, increases in skin SP and spinal TRPV1 and a decrease in spinal GAD-67. These changes were counteracted by electroacupuncture. Conclusions/interpretation Our results point to the potential of electroacupuncture as a supportive therapy for the treatment of diabetic neuropathies. The efficacy of electroacupuncture might depend on its actions on spinal/peripheral NGF synthesis/utilisation and normalisation of the levels of several sensory neuromodulators.

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Role of vanilloid VR1 receptor in thermal allodynia and hyperalgesia in diabetic mice

Cited by 82 publications

References 14 publications

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats

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