Articles: neuropathic-pain.
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Postherpetic neuralgia (PHN) is a common and exceptionally drug-resistant neuropathic pain condition. In this cross-sectional skin biopsy study, seeking information on the responsible pathophysiological mechanisms we assessed how ophthalmic PHN affects sensory and autonomic skin innervation. We took 2-mm supraorbital punch skin biopsies from the affected and unaffected sides in 10 patients with ophthalmic PHN. ⋯ Although skin biopsy showed reduced epidermal and dermal myelinated fiber density in specimens from the affected side, the epidermal/dermal myelinated nerve fiber ratio was lower in the affected than in the unaffected side (p < 0.001), thus suggesting a predominant epidermal unmyelinated nerve fiber loss. Conversely, autonomic skin innervation was spared. Our study showing that ophthalmic PHN predominantly affects unmyelinated nerve fiber and spares autonomic nerve fiber might help to understand the pathophysiological mechanisms underlying this difficult-to-treat condition.
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Neurobiology of disease · Jan 2015
BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation.
The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. ⋯ Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury.
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Although burst spinal cord stimulation (SCS) has been reported to reduce neuropathic pain, no study has explicitly investigated how the different parameters that define burst SCS may modulate its efficacy. The effectiveness of burst SCS to reduce neuronal responses to noxious stimuli by altering stimulation parameters was evaluated in a rat model of cervical radiculopathy. ⋯ Burst SCS can be optimized by adjusting relevant stimulation parameters to modulate the charge delivered to the spinal cord during stimulation. The efficacy of burst SCS is dependent on the charge per burst.
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Rufinamide is a structurally novel, antiepileptic drug approved for the treatment of Lennox-Gastaut syndrome. Its mechanism of action involves inhibition of voltage-gated Na+ channels (VGSCs) with possible membrane-stabilizing effects. VGSCs play a significant role in the pathogenesis of neuropathic pain. ⋯ Rufinamide treatments significantly blocked the TTX-R Na+ channel activity as evident from significant reduction in I(Na) density and hyperpolarizing shift in activation and inactivation curves as compared to diabetic control. This suggests that rufinamide acts on TTX-R Na+ channels, reduces channel activity and attenuates nerve functional and behavioral parameters in diabetic rats. Altogether, these results indicate therapeutic potential of rufinamide in the treatment of diabetic neuropathy.
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Journal of pain research · Jan 2015
Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.
Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. ⋯ It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.