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Articles, Neurobiology of Disease

Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain

Andrew M. Tan, Omar A. Samad, Tanya Z. Fischer, Peng Zhao, Anna-Karin Persson and Stephen G. Waxman
Journal of Neuroscience 16 May 2012, 32 (20) 6795-6807; DOI: https://doi.org/10.1523/JNEUROSCI.1017-12.2012
Andrew M. Tan
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Omar A. Samad
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Tanya Z. Fischer
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Peng Zhao
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Anna-Karin Persson
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Stephen G. Waxman
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Abstract

Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure–function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV–V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N6-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.

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The Journal of Neuroscience: 32 (20)
Journal of Neuroscience
Vol. 32, Issue 20
16 May 2012
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Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain
Andrew M. Tan, Omar A. Samad, Tanya Z. Fischer, Peng Zhao, Anna-Karin Persson, Stephen G. Waxman
Journal of Neuroscience 16 May 2012, 32 (20) 6795-6807; DOI: 10.1523/JNEUROSCI.1017-12.2012

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Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain
Andrew M. Tan, Omar A. Samad, Tanya Z. Fischer, Peng Zhao, Anna-Karin Persson, Stephen G. Waxman
Journal of Neuroscience 16 May 2012, 32 (20) 6795-6807; DOI: 10.1523/JNEUROSCI.1017-12.2012
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