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Descending control of nociception (DCN; also known as conditioned pain modulation [CPM], the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pain modulation on the application of a DCN paradigm involving low-intensity test stimuli occurs in the direction of hyperalgesia in healthy mice and rats, whereas the use of high-intensity stimuli produces analgesia. To elucidate the physiological mechanisms underlying hyperalgesic DCN, we administered agonists and antagonists of norepinephrine (NE) and serotonin (5-HT) receptors, key neurochemical players in the production of analgesic DCN. We find that 3 different monoamine reuptake inhibitors-the NE-selective reboxetine, the 5-HT-selective fluoxetine, and the dual NE/5-HT agonist duloxetine-all abolish hyperalgesic DCN when administered into the spinal cord (but not systemically), with no effect on heat or mechanical pain sensitivity. The reversal by reboxetine of hyperalgesic DCN is mediated by α2-adrenergic receptors (ie, blocked by atipamezole), and the fluoxetine reversal is mediated by 5-HT7 receptors (ie, blocked by SB269970). By contrast, analgesic DCN was found to be reversed by atipamezole and SB269970 themselves, with no effect of reboxetine or fluoxetine. Thus, hyperalgesic DCN seems to be the neurochemical opposite to analgesic DCN. These data further validate and help elucidate a preclinical paradigm that mimics dysfunctional CPM and thus may form the basis of translational experiments that aim to reveal preventative pharmacological strategies for individuals predisposed to persistent pain.
Learn More >Self-management support is considered an important component in the physiotherapeutic treatment of people with chronic low back pain. The stratified blended physiotherapy intervention e-Exercise Low Back Pain is an example of a self-management intervention. More insight may contribute to improving blended interventions to stimulate self-management after treatment and thus hopefully prevent chronicity and/or relapses in patients with chronic low back pain.
Learn More >Opioid-induced hyperalgesia (OIH) is a paradoxical effect of opioids that is not consensually recognized in clinical settings. We conducted a revision of clinical and preclinical studies and discuss them side by side to provide an updated and renewed view on OIH. We critically analyze data on the human manifestations of OIH in the context of chronic and post-operative pain. We also discuss how, in the context of cancer pain, though there are no direct evidence of OIH, several inherent conditions to the tumor and chemotherapy provide a substrate for the development of OIH. The review of the clinical data, namely in what concerns the strategies to counter OIH, emphasizes how much OIH rely mechanistically on the existence of µ-opioid receptor (MOR) signaling through opposite, inhibitory/antinociceptive and excitatory/pronociceptive, pathways. The rationale for the maladaptive excitatory signaling of opioids is provided by the emerging growing information on the functional role of alternative splicing and heteromerization of MOR. The crossroads between opioids and neuroinflammation also play a major role in OIH. The latest pre-clinical data in this field brings new insights to new and promising therapeutic targets to address OIH. In conclusion, although OIH remains insufficiently recognized in clinical practice, the appropriate diagnosis can turn it into a treatable pain disorder. Therefore, in times of scarce alternatives to opioids to treat pain, mainly unmanageable chronic pain, increased knowledge and recognition of OIH, likely represent the first steps towards safer and efficient use of opioids as analgesics.
Learn More >Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the Multidisciplinary Approach to the study of chronic Pelvic Pain (MAPP) research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex-vivo Toll-Like Receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. Here we attempt to confirm these findings in the multisite MAPP Symptom Patterns Study using TLR4 stimulated whole blood (female IC/BPS patients with COPC n =99; without n=36). Samples were collected in tubes preloaded with TLR4 agonist, incubated for 24 hours, and resulting supernatant assayed for seven cytokines/chemokines. These were subject to a principal components analysis and the resulting components used as dependent variables in general linear models. Controlling for patient age, body mass index, and site of collection, we found that greater ex-vivo TLR4 stimulated cytokine/chemokine release was associated with the presence of COPCs (p < 0.01), extent of widespread pain (p < 0.05), but not experimental pain sensitivity (p > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity (p < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex-vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.
Learn More >Pain can be regarded as an emergent property of multiple interacting, dynamically changing brain networks and thus needs a targeted treatment approach. A novel high-definition transcranial infraslow pink-noise stimulation (HD-tIPNS) technique was developed to modulate the key hubs of the three main nociceptive pathways simultaneously, ie, the pregenual anterior cingulate cortex (pgACC) (descending inhibitory pathway), the dorsal anterior cingulate cortex (dACC) (medial nociceptive pathway), and both somatosensory cortices (S1) (lateral nociceptive pathway). This study aimed to evaluate safety and verify whether a single session of HD-tIPNS may disrupt functional and effective connectivity between targeted cortical regions.
Learn More >In virtual reality, avatar embodiment can spur perceptions and behaviours related the avatars' characteristics. We tested whether embodying superhero-like avatars can change self-perceptions in people with chronic low back pain (CLBP).
Learn More >To systematically review the effectiveness and safety of telemedicine combined with usual care (in-person visits) compared to usual care for the therapeutic management and follow-up assessment of neurologic diseases.
Learn More >CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.
Learn More >Previous research suggests that individuals with post-traumatic stress disorder (PTSD) have higher risk of chronic pain symptoms. It remains unknown whether risk of chronic pain symptoms occurs in the offspring of parents with PTSD. This study aimed to explore the risk of chronic pain conditions and depression in the offspring of parents with PTSD.
Learn More >Hevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin was sufficient to induce persistent mechanical allodynia in naïve mice. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal antibody may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.
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