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Modulation of GABAergic Synaptic Transmission by NMDA Receptors in the Dorsal Horn of the Spinal Cord.

The dorsal horn (DH) of the spinal cord is an important structure involved in the integration of nociceptive messages. Plastic changes in the properties of neuronal networks in the DH underlie the development of analgesia as well as of hyperalgesia and allodynia in acute and chronic pain states. Two key mechanisms are involved in these chronic pain states: increased electrical activities and glutamate release leading to the recruitment of NMDAr and plastic changes in the synaptic inhibition. Although: (1) the balance between excitation and inhibition is known to play a critical role in the spinal network; and (2) plastic changes in spinal excitation and inhibition have been studied separately, the relationship between these two mechanisms has not been investigated in detail. In the present work, we addressed the role of NMDA receptors in the modulation of GABAergic synaptic transmission in the DH network. Using tight-seal whole-cell recordings on adult mice DH neurons, we characterized the effect of NMDAr activation on inhibitory synaptic transmission and more especially on the GABAergic one. Our results show that, in a subset of neurons recorded in lamina II, NMDAr activation facilitates spontaneous and miniature GABAergic synaptic transmission with a target specificity on GABAergic interneurons. In contrast, NMDA reduced the mean amplitude of evoked GABAergic IPSCs. These results show that NMDAr modulate GABAergic transmission by a presynaptic mechanism of action. Using a pharmacological approach, we investigated the composition of NMDAr involved in this modulation of GABAergic synaptic transmission. We found that the NMDA-induced facilitation was mediated by the activation of NMDAr containing GluN2C/D subunits. Altogether, our results bring new insights on nociceptive information processing in the spinal cord network and plastic changes in synaptic inhibition that could underlie the development and maintenance of chronic pain.

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Elevated highly sensitive C-reactive protein in fibromyalgia associates with symptom severity.

Fibromyalgia (FM), a common pain syndrome, is thought to be a non-inflammatory, nociplastic condition, but evidence implicating neuroinflammation has been increasing. Systemic inflammation may be associated with more severe symptoms in some FM patients. We studied healthy controls and FM patients with and without systemic inflammation detectable using high-sensitivity CRP (hsCRP) measurement.

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A Progress Report and Roadmap for Microphysiological Systems and Organ-On-A-Chip Technologies to Be More Predictive Models in Human (Knee) Osteoarthritis.

Osteoarthritis (OA), a chronic debilitating joint disease affecting hundreds of million people globally, is associated with significant pain and socioeconomic costs. Current treatment modalities are palliative and unable to stop the progressive degeneration of articular cartilage in OA. Scientific attention has shifted from the historical view of OA as a wear-and-tear cartilage disorder to its recognition as a whole-joint disease, highlighting the contribution of other knee joint tissues in OA pathogenesis. Despite much progress in the field of microfluidic systems/organs-on-a-chip in other research fields, current models in use do not yet accurately reflect the complexity of the OA pathophenotype. In this review, we provide: 1) a detailed overview of the most significant recent developments in the field of microsystems approaches for OA modeling, and 2) an OA-pathophysiology-based bioengineering roadmap for the requirements of the next generation of more predictive and authentic microscale systems fit for the purpose of not only disease modeling but also of drug screening to potentially allow OA animal model reduction and replacement in the near future.

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History of Spinal Cord “Pain” Pathways Including the Pathways Not Taken.

Traditional medical neuroanatomy/neurobiology textbooks teach that pain is generated by several ascending pathways that course in the anterolateral quadrant of the spinal cord, including the spinothalamic, spinoreticular and spinoparabrachial tracts. The textbooks also teach, building upon the mid-19th century report of Brown-Séquard, that unilateral cordotomy, namely section of the anterolateral quadrant, leads to contralateral loss of pain (and temperature). In many respects, however, this simple relationship has not held up. Most importantly, pain almost always returns after cordotomy, indicating that activation of these so-called "pain" pathways may be sufficient to generate pain, but they are not necessary. Indeed, Brown-Séquard, based on his own studies, eventually came to the same conclusion. But his new view of "pain" pathways was largely ignored, and certainly did not forestall Spiller and Martin's 1912 introduction of cordotomy to treat patients. This manuscript reviews the history of "pain" pathways that followed from the first description of the Brown-Séquard Syndrome and concludes with a discussion of multisynaptic spinal cord ascending circuits. The latter, in addition to the traditional oligosynaptic "pain" pathways, may be critical to the transmission of "pain" messages, not only in the intact spinal cord but also particularly after injury.

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Interventions to Manage Pain Catastrophizing Following Total Knee Replacement: A Systematic Review.

Pain catastrophizing is a maladaptive cognitive strategy that is associated with increased emotional responses and poor pain outcomes. Total knee replacement procedures are on the rise and 20% of those who have the procedure go on to have ongoing pain. Pain catastrophizing complicates this pain and management of this is important for recovery from surgery and prevention of chronic pain. This study examines the effect of interventions on PC for patients undergoing total knee replacement (TKR).

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Evaluation of Recombinant Botulinum Neurotoxin Type A1 Efficacy in Peripheral Inflammatory Pain in Mice.

Well-established efficacy of botulinum neurotoxin type A (BoNT/A) in aesthetic dermatology and neuromuscular hyperactivity disorders relies on canonical interruption of acetylcholine neurotransmission at the neuromuscular junction at the site of the injection. The mechanisms and the site of activity of BoNT/A in pain, on the other hand, remain elusive. Here, we explored analgesic activity of recombinant BoNT/A1 (rBoNT/A1; IPN10260) in a mouse model of inflammatory pain to investigate the potential role of peripheral sensory afferents in this activity. After confirming analgesic efficacy of rBoNT/A1 on CFA-induced mechanical hypersensitivity in C57Bl6J mice, we used GCaMP6s to perform calcium imaging in the ipsilateral dorsal root ganglion (DRG) neurons in rBoNT/A1 vs. vehicle-treated mice at baseline and following administration of a range of mechanical and thermal stimuli. Additionally, immunohisochemical studies were performed to detect cleaved SNAP25 in the skin, DRGs and the spinal cord. Injection of CFA resulted in reduced mechanical sensitivity threshold and increased calcium fluctuations in the DRG neurons. While rBoNT/A1 reduced mechanical hypersensitivity, calcium fluctuations in the DRG of rBoNT/A1- and vehicle-treated animals were similar. Cleaved SNAP25 was largely absent in the skin and the DRG but present in the lumbar spinal cord of rBoNT/A1-treated animals. Taken together, rBoNT/A1 ameliorates mechanical hypersensitivity related to inflammation, while the signal transmission from the peripheral sensory afferents to the DRG remained unchanged. This strengthens the possibility that spinal, rather than peripheral, mechanisms play a role in the mediation of analgesic efficacy of BoNT/A in inflammatory pain.

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Cluster Analysis Revealed Two Hidden Phenotypes of Cluster Headache.

To investigate the possible subgroups of patients with Cluster Headache (CH) by using K-means cluster analysis.

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Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized controlled trial.

This study aimed to provide preliminary evidence for the efficacy of invasive laser acupuncture (ILA) for chronic non-specific low back pain (CNLBP). This was a single-center, randomized, patient and assessor-blinded, placebo-controlled, parallel-arm, clinical trial with a 1:1:1 allocation ratio that included a full analysis set. Forty-five participants with CNLBP were randomly assigned to the control group (sham laser), 650 group (650 nm-wavelength ILA), or 830 group (830 nm-wavelength ILA) (n = 15/group). All participants received ILA for 10 min, followed by electroacupuncture for 10 min on the same day. The treatment was performed once per day, twice per week for 4 weeks at bilateral BL23, BL24, BL25, and GB30. The primary outcome was the among-group difference of changes in the visual analog scale (VAS) scores at intervention endpoint (week 4). The secondary outcomes were the among-group difference of changes in VAS at 4 weeks after intervention completion (week 8), those in the Korean version of the Oswestry Disability Index (ODI) and the European Quality of Life Five-Dimension- Five-Level (EQ-5D-5L) at intervention endpoint (week 4) and 4 weeks after intervention completion (week 8). The VAS scores of the 650 group decreased significantly compared with those of the control group (p = 0.047; week 4 vs. week 0). The ODI scores of the 650 group (p = 0.018, week 4 vs. week 0; p = 0.006, week 8 vs. week 0) and 830 group (p = 0.014, week 4 vs. week 0) decreased significantly compared with those of the control group. There was no adverse event related to ILA and no significant difference in changes in vital signs among the three groups. The 650 group showed significant improvements in pain intensity and functional disability. The 830 group showed significant improvements in functional disability. Therefore, ILA therapy at 650 nm and 830 nm wavelengths can be used to treat CNLBP.

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Do patients’ pre-treatment expectations about acupuncture effectiveness predict treatment outcome in patients with chronic low back pain? A secondary analysis of data from a randomised controlled clinical trial.

This secondary analysis of a randomised controlled patient-blinded trial comparing effectiveness and side effect briefings in patients with chronic low back pain (CLBP) investigated the association between patients' pre-treatment expectations about minimal acupuncture treatment and pain intensity as outcome during and after the end of the treatment.

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Pain and Analgesic Utilization in Medically Underserved Areas: Five-Year Prevalence Study from the Rochester Epidemiology Project.

There is a paucity of data on pain diagnoses and analgesic utilization in medically underserved areas (MUAs). This study compared the prevalence of pain diagnoses and analgesic medication use between MUAs and non-medically underserved areas (N-MUAs) in Southern Minnesota and Western Wisconsin using the Rochester Epidemiology Project (REP) database.

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