Editors' Note: Rich, insightful conversations about current research go on every day in journal clubs around the world. The goal of our new Journal Club feature is to capture those discussions and air them for the broader pain community.
Thanks to Carter Jones for submitting the first Journal Club. We are pleased to present his summary of the discussion from the University of California San Diego clinical pain journal club, whose members took up a recent paper from Tan and colleagues concerning the role of dendritic spine remodeling in a model of diabetic neuropathic pain.
Paper: Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain. Tan AM, Samad OA, Fischer TZ, Zhao P, Persson A-K, Waxman SG. J Neurosci. 2012 May 16; 32(20):6795-807
Presented by: Leo Lombardo, MD, UC San Diego Pain Medicine Fellow
Synopsis of paper and discussion written by: R. Carter W. Jones III, MD, PhD, Assistant Professor of Anesthesiology, UC San Diego
This article identified morphologic changes occurring in dendritic spines, the sites of postsynaptic communication on neurons of the spinal cord dorsal horn that coincide with the development of behavioral and electrophysiologic manifestations of increased excitability in spinal nociceptive neurons that may contribute to pain in patients with diabetes. This is a common clinical problem and one that is often poorly addressed by current therapies, consequently insight into the underlying mechanisms, such as provided by this study, is crucial to advancing treatment of diabetic neuropathy.
In this study, the authors use a common preclinical model of diabetes, parenteral administration of a pancreatic beta cell toxin, streptozotocin. Within a few days, animals developed significant hyperglycemia. A few weeks following treatment, the animals developed significant mechanical hypersensitivity, assessed by squeezing pressure and punctate von Frey hair application to the hindpaw. Interestingly, alterations in the morphology of spines on dendrites of wide dynamic range (WDR) neurons found in the deep lamina of the dorsal horn of the spinal cord appeared coincident with the full development of behavioral changes. The authors went on to demonstrate that the altered spine morphology, with a predominance of “mushroom” type spines compared to a mixture of “mushroom” and “straight” spines found in sham treated rats, was associated with a change in the excitability of spinal WDR neurons assessed electrophysiologically, including a greater percentage of neurons possessing spontaneous activity, increased responsivity to mechanical stimuli, and larger receptive fields. This finding alone is significant in that it demonstrates, for the first time, that in addition to other maladaptive changes that have been implicated in diabetic neuropathy, including the expression of potassium-chloride cotransporter 2, sodium channels, and growth factors (as mentioned in the article), there are structural changes in nociceptive neurons in the spinal cord that impact their function and connectivity.
The authors go on to investigate the potential therapeutic role for inhibition of a Rho GTPase, Rac1, that has been previously implicated in cancer progression and dendritic remodeling in other models of neuropathic pain (Tan et al., 2008; Tan et al., 2011). Intrathecal treatment with an inhibitor of Rac1, NSC23766, after the development of tactile allodynia, WDR neuron hyperexcitability, and altered dendritic spine morphology, returned these parameters back to baseline with no distinguishable difference compared to sham treated rats. Given that Rac1 is present in many cell-types and plays a role in many different disease processes, administration of Rac1 inhibitors for diabetic neuropathy, although promising, raises concerns for potential side effects that would need to be evaluated before widespread clinical use.
Although the findings of this study are circumstantial and no direct causal link was demonstrated between dendrite morphology, electrophysiology, and Rac1 inhibition, the close temporal association of their findings suggests that altered dendritic morphology of WDR neurons is an additional and potentially important mechanism underlying diabetic neuropathy. Moreoever, Rac1 poses a potentially valuable therapeutic target to reverse this particular aspect of diabetic neuropathy. It would be interesting to evaluate the effect of Rac1 inhibition on other aspects implicated in this disease, e.g. microglial activation. In addition, Rac1 is a target of botulinum toxin, therefore it would be interesting to study the effects of botulinum toxin on Rac1 and WDR neuron dendritic morphology in this model of diabetes.
The clinical problem of diabetic neuropathy is complex. Although tight glucose control can prevent or delay the development of neuropathy, our clinical experience suggests that neuropathy often presents in patients with good glucose control and sometimes even in patients with impaired glucose tolerance who don’t yet meet criteria for diabetes. Indeed, data from primate models of diabetes has demonstrated hyperplasia of cutaneous innervation early in the disease. The model chosen in this study, one that is commonly used to study diabetic neuropathy, is inherently artificial by producing a rapid and profound hyperglycemia that does not reflect the typical clinical situation. There was concern in the discussion group that this may lead to identification of mechanisms and potential therapeutic strategies based on the preclinical model that are not supported by clinical studies. Clearly, more research will need to be done to identify morphologic changes in spinal cord nociceptive neurons and the importance of Rac1 as major players in diabetic neuropathy in human patients.
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