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Painful diabetic neuropathy (PDN) is a severely debilitating chronic pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of chronic pain induced by peripheral tissue inflammation or nerve injury. In this study we investigated whether CXCL13/CXCR5 mediates PDN and the underlying spinal mechanisms. We used the db/db type 2 diabetes mice, which showed obvious hyperglycemia and obese, long-term mechanical allodynia, and increased expression of CXCL13, CXCR5 as well as pro-inflammatory cytokines TNF-α and IL-6 in the spinal cord. Furthermore, in the spinal cord of db/db mice there is significantly increased gliosis and upregulated phosphorylation of cell signaling kinases, including pERK, pAKT and pSTAT3. Mechanical allodynia and upregulated pERK, pAKT and pSTAT3 as well as production of TNF-α and IL-6 were all attenuated by the noncompetitive NMDA receptor antagonist MK-801. If spinal giving U0126 (a selective MEK inhibitor) or AG490 (a Janus kinase (JAK) -STAT inhibitor) to db/db mice, both of them can decrease the mechanical allodynia, but only inhibit pERK (by U0126) or pSTAT3 (by AG490) respectively. Acute administration of CXCL13 in C57BL/6J mice resulted in exacerbated thermal hyperalgesia and mechanical allodynia, activation of the pERK, pAKT and pSTAT3 pathways and increased production of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), which were all attenuated by knocking out of Cxcr5. In all, our work showed that chemokine CXCL13 and its receptor CXCR5 in spinal cord contribute to the pathogenesis of PDN and may help develop potential novel therapeutic approaches for patients afflicted with PDN.
Learn More >The neurosteroid dehydroepiandrosterone sulphate (DHEAS) activates the sigma-1 receptor, inhibits gamma-aminobutyric acid A (GABA) and glycine receptors, and induces hyperalgesic effects. Although its effects have been studied in various tissues of the nervous system, its synaptic mechanisms in nociceptive pathways remain to be elucidated.
Learn More >Dopamine-beta-hydroxylase (DBH) enzyme activity is modulated at the genetic level by the presence of several polymorphisms. Among these, the 19-bp insertion/deletion (I/D) polymorphism (rs72393728/rs141116007) was investigated in several genetic association studies for its correlation with the susceptibility to develop episodic migraine, but conflicting results were achieved. In the present study we analyzed this genetic variant in a carefully characterized population of migraineurs encompassing both episodic and chronic migraine (with and without medication overuse) with the aim to perform a replication study and verify any possible correlation with migraine endophenotypes. Genotyping of the DBH 19-bp I/D polymorphism was performed on 400 migraine patients and 204 healthy individuals. The associations between genotypic frequencies and the clinical and sociodemographic features of migraineurs were then investigated. The DBH 19-bp I/D polymorphism did not correlate with migraine susceptibility or most clinical variables, with the exception of a statistically significant correlation within the subgroup of patients affected by chronic migraine were the individuals carrying the deleted (D) allele were significantly more prone to abuse in analgesics. As a result of this finding, the DBH 19-bp I/D polymorphism does not influence migraine susceptibility, but it might contribute to the development of medication overuse in patient with chronic migraine.
Learn More >Children who develop greater negatively-biased recall of pain (ie, recalled pain is higher than the initial pain report) following surgery are at risk for developing chronic pain; therefore, identifying risk factors for the development of biased pain memories is important. Higher anxiety has been implicated in the development of greater negatively-biased recall of pain; however, studies have not examined anxiety at multiple time points before and after a surgery and its relationship to children's postsurgical pain memories after 1 year. This prospective study examined a cohort of 237 children and adolescents undergoing major surgery. Anxiety sensitivity, pain catastrophizing, and pain anxiety were assessed at baseline, 48 to 72 hours after surgery, and at 6- and 12-month follow-ups. Pain intensity at rest, movement-evoked pain intensity, and pain unpleasantness were assessed daily in hospital. Memories for pain were elicited via telephone 1-year post surgery. Findings revealed that children who had higher levels of anxiety at baseline and 48 to 72 hours after surgery developed greater negatively-biased recall of pain intensity 12 months after surgery. Specifically, higher anxiety sensitivity at baseline and greater tendencies to catastrophize about pain at baseline and in the immediate acute recovery phase were most strongly linked to greater negatively-biased recall of pain. Greater negatively-biased recall of pain was related to higher pain intensity at 6 and 12 months post surgery. Findings support conceptual models of anxiety and pain memory biases and can inform intervention efforts to reduce anxiety in the pre- and post-op periods to minimize negative biases in pain memories.
Learn More >The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.
Learn More >NADPH oxidase (NOX2) is an enzyme that induces reactive oxygen species (ROS) and serves as a switch between the pro-inflammatory and neurorestorative microglial/macrophage phenotypes; such changes play an important role in neuropathic pain and motor dysfunction. Increased NOX2 expression after spinal cord injury (SCI) has been reported, and inhibition of NOX2 improves motor function. However, the underlying mechanisms of NOX2 in post-traumatic pain and motor deficit remain unexplored. In the present study, we report that depletion of NOX2 (NOX2) or inhibition of NOX2 using NOX2ds-tat significantly reduced mechanical/thermal cutaneous hypersensitivity and motor dysfunction after moderate contusion SCI at T10 in male mice. Western blot (WB, 3 mm lesion area) and immunohistochemistry (IHC) showed that SCI elevates NOX2 expression predominantly in microglia/macrophages up to 8 weeks post-injury. Deletion of NOX2 significantly reduced CD11b/CD45F4/80 macrophage infiltration at 24h post-injury detected by flow cytometry and 8-OHG ROS production at 8 weeks post-injury by IHC in both lesion area and lumbar enlargement. NOX2 deficiency also altered microglial/macrophage pro-inflammatory and anti-inflammatory balance towards the neurorestorative response. WB analysis showed robust increase of Arginase-1 and YM1 proteins in NOX2 mice. Furthermore, qPCR analysis showed significant up-regulation of anti-inflammatory cytokine IL-10 levels in NOX2 mice, associated with reduced microRNA-155 expression. These findings were confirmed in CD11b microglia/macrophages isolated from spinal cord at 3 days post-injury. Taken together, our data suggest an important role for IL-10/miR-155 pathway in regulating NOX2-mediated SCI-dysfunction. Thus, specific targeting of NOX2 may provide an effective strategy for treating neurological dysfunction in SCI patients.
Learn More >The present study investigated the role of the amygdala NMDA receptors/NOS pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala (CeA), chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was intraperitoneally administered to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (0.05-0.1 µg/rat) or L-NAME, the NO synthase inhibitor, (0.1-0.5 µg/rat) were microinjected into the CeA, the higher doses potentiated an ineffective dose of morphine (3 mg/kg). Microinjection of the same doses of D-AP5 and L-NAME without morphine had no effect. Co-microinjection of the ineffective doses of L-NAME (0.1 µg/rat) and D-AP5 (0.05 µg/rat) with a 5-min interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cAMP-response element-binding protein (CREB) and phosphorylated CREB (pCREB) in the amygdala tissues. Our results showed that neuropathic pain increased the pCREB/CREB ratio in the amygdala, while this ratio was decreased following morphine-induced anti-allodynia. The potentiative effect of the co-administration of D-AP5/L-NAME on an ineffective dose of morphine also decreased the amygdala pCREB/CREB levels. Therefore, it seems that the amygdala pCREB/CREB signaling pathway plays a critical role in processing neuropathic pain. Moreover, the glutamate NMDA receptors and NO system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is hard to treat and the exact mechanisms are still unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. The findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.
Learn More >In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies.
Learn More >The present study's objective is to understand the causal mechanisms underpinning the recovery of individuals with whiplash-associated disorders (WAD). We applied Bayesian Networks (BN) to answer two study aims: (1) to identify the causal mechanism(s) of recovery underpinning neck-specific exercise, and (2) quantify if the cyclical pathway of the fear avoidance model (FAM) is supported by the present data.
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