Effects of electroacupuncture at 2 and 100 Hz on rat type 2 diabetic neuropathic pain and hyperalgesia-related protein expression in the dorsal root ganglion

Objective： To investigate the analgesic effects of electroacupuncture （EA） at 2 and 100 Hz on type 2 diabetic neuropathic pain （DNP） and on the expressions of the P2X3 receptor and calcitonin gene-related peptide （CGRP） in the dorsal root ganglion （DRG）. Methods： Rat type 2 DNP was induced by a high calorie and high sugar diet fed for 7 weeks, plus a single intraperitoneal injection of streptozotocin （STZ） after 5 weeks. EA at 2 and 100 Hz was carried out once every day after 7 weeks for 7 consecutive days. Body weight, serum fasting insulin （FINS）, fasting blood glucose （FBG）, insulin sensitivity index （ISI）, and paw withdrawal latency （PWL） were measured. The expressions of L4-L6 DRG P2X3 receptors and CGRP were assessed by immunofluorescence. Results： Type 2 DNP was successfully induced as shown by the increased body weight, FINS, and FBG, as well as the reduced ISI and PWL. Expressions of P2X3 receptors and CGRP in L4-L6 DRGs increased. EA at both 2 and 100 Hz relieved type 2 DNP, but the analgesic effect of EA was stronger at 2 Hz. P2X3 receptor expression decreased in L4-L6 DRGs following EA at 2 Hz and in L5 and L6 DRGs following EA at 100 Hz. EA at both 2 and 100 Hz down-regulated CGRP overexpression in L4-L6 DRGs. Conclusions： These findings indicate that EA at 2 Hz is a good option for the management of type 2 DNP. The EA effect may be related to its down-regulation of the overexpressions of the DRG P2X3 receptors and CGRP in this condition.

Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory

tDiabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area;however,the underlying molecular events remain poorly understood.Here we found that an axon guidance molecule,Netrin-3(Ntn-3),was expressed in the sensory neurons of mouse dorsal root ganglia(DRGs),and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model.Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice.In contrast,the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice.In con-clusion,our studies identified Ntn-3 as an important regula-tor of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating that Ntn-3 is a potential druggable target for DNP treatment.

Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China

Background Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain （DPNP） in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain. Methods This double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory （BPI） 24-hour average pain severity ratings ≥4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator＇s judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol： 5 Dimensions, Athens Insomnia Scale, and safety measures. Results Of 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively,completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups （P=0.124）. Duloxetinetreated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1,2, and 4 （P=0.004, P=0.009, and P=0.006, respectively） but not at weeks 8 （P=0.125） and 12 （P=0.107）. Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now, and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction on the Brief Pain Inventory average pain score relative to placebo. Duloxetine-treated patients reported nausea, somnolence, anorexia, and dysuria significantly more than placebo. Conclusions Although the primary study endpoint was not achieved, the overall observed response pattern suggests the efficacy of duloxetine in the treatment of Chinese patients with diabetic peripheral neuropathic pain. The safety profile for duloxetine is similar to that reported in other global trials.

Compounds of traditional Chinese medicine and neuropathic pain

Neuropathic pain(NP)has become a serious global health issue and a huge clinical challenge without available effective treatment.P2 receptors family is involved in pain transmission and represents a promising target for pharmacological intervention.Traditional Chinese medicine(TCM)contains multiple components which are effective in targeting different pathological mechanisms involved in NP.Different from traditional analgesics,which target a single pathway,TCMs take the advantage of multiple components and multiple targets,and can significantly improve the efficacy of treatment and contribute to the prediction of the risks of NP.Compounds of TCM acting at nucleotide P2 receptors in neurons and glial cells could be considered as a potential research direction for moderating neuropathic pain.This review summarized the recently published data and highlighted several TCMs that relieved NP by acting at P2 receptors.