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Descending control from supraspinal neuronal networks onto spinal cord neurons can modulate nociceptionEndogenous opioids in these brain circuits participate in pain modulationA differential opioidergic role for brain nuclei involved in supraspinal pain modulation has not been previously reported WHAT THIS ARTICLE TELLS US THAT IS NEW: In vivo electrophysiologic recordings from the dorsal horn of the spinal cord in male rats reveal differential effects of morphine at the anterior cingulate cortex, right amygdala, and the ventromedial medulla on evoked pain responsesThese data differentiate supraspinal opioid circuit regulation of spinal nociceptive processing and suggest that the regulation of sensory and affective components of pain are likely separate BACKGROUND:: The anterior cingulate cortex and central nucleus of the amygdala connect widely with brainstem nuclei involved in descending modulation, including the rostral ventromedial medulla. Endogenous opioids in these circuits participate in pain modulation. The hypothesis was that a differential opioidergic role for the brain nuclei listed in regulation of spinal neuronal responses because separable effects on pain behaviors in awake animals were previously observed.
Learn More >Knee osteoarthritis (OA) pain is the most common joint pain. Currently, dysfunction in the central nervous system rather than knee joint degeneration is considered to be the major cause of chronic knee OA pain; however, the underlying mechanism remains unknown. The aim of this study was to explore whether spinal NF-κB plays a critical role in chronic knee OA pain. In this study, we used a model induced by the intra-articular injection of monosodium iodoacetate (MIA). Spinal NF-κB and the phosphorylation and activation status of NF-κB p65/RelA (p-p65) were inhibited by the intrathecal injection of the inhibitor PDTC in this model. After behavioral assessment, the knee was dissected for histopathology, and the spinal cord was dissected and examined for NF-κB, p-p65 and cytokine expression. Furthermore, the quantity and activity of neurons, astrocytes and microglial cells and their colocalization with p-p65 in the spinal dorsal horn were investigated. Our findings included the following: (1) histology, the pathological changes in the joints of the knee OA model were basically consistent with knee OA patients; (2) the protein and transcription levels of NF-κB/p65 and p-p65 increased before day 14, appeared to decrease on day 21 and increased again on day 28, and the tendency of weight bearing was similar; (3) on days 21 and 28, the intrathecal injection of PDTC markedly prevented the MIA-induced reduction in the PWT; (4) real-time PCR demonstrated that the expression of TNF-α and IL-33 was suppressed in the knee OA model by the intrathecal injection of PDTC; And (5) immunofluorescence revealed that astrocytes were activated and that p-p65 was mainly increased in astrocytes. Our findings indicate that the spinal NF-κB/p65 pathway in astrocytes modulates neuroimmunity in rat model of intra-articular MIA-induced advanced osteoarthritis.
Learn More >Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus-response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold.The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively.It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing.
Learn More >A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to pain-free controls across different pain conditions. However, this has yet to be systematically investigated.
Learn More >We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.
Learn More >: Migraine is the second leading cause of disability worldwide, yet many patients are unable to tolerate, benefit from, or afford pharmacological treatment options. Non-pharmacological migraine therapies exist, especially to reduce opioid use, which represents a significant unmet need. Mindfulness-based interventions (MBI) have potential as a non-pharmacological treatment for migraine, primarily through the development of flexible attentional capacity across sensory, cognitive, and emotional experiences.: The authors review efficacy and potential mechanisms of MBIs for migraine, including mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT).: While most mindfulness research studies for migraine to date have been pilot trials, which are small and/or lacked rigor, initial evidence suggests there may be improvements in overall headache-related disability and psychological well-being. Many research questions remain to help target the treatment to patients most likely to benefit, including the ideal dosage, duration, delivery method, responder characteristics, and potential mechanisms and biomarkers. A realistic understanding of these factors is important for patients, providers, and the media. Mindfulness will not "cure" migraine; however, mindfulness may be an important tool as part of a comprehensive treatment approach to help patients "mindfully" engage in valued life activities.
Learn More >Growing evidence suggests a critical role of astrocytes for pain regulation. The water channel protein aquaporin 4 (AQP4), a functional regulator of astrocytes, is involved in various neurological disorders. However, the pathophysiological roles of AQP4 in pain conditions remain unclear. In the present study, we investigated the effect of AQP4 gene knockout in central sensitization induced by complete Freund's adjuvant (CFA). The behavioral analysis revealed that mechanical allodynia and thermal hyperalgesia were more severe in AQP4 null mice than those of wild-type controls over the course of 11 days following CFA intraplantar injection. CFA caused activation of astrocytes with upregulated expression levels of AQP4 and glutamate transporter 1 (GLT1) in the dorsal horn of the spinal cord. AQP4 deficiency reduced GLT1 up-regulation, causing persistent expression of the neuronal activation marker Fos within superficial dorsal horn neurons, including glutamatergic neurons. However, AQP4 deletion did not affect CFA-evoked proinflammatory cytokine expression in the spinal cord. Together, these results have shown that AQP4 absence intensifies CFA-induced spinal central sensitization, which is associated with reduced compensatory up-regulation of GLT1, subsequently increasing glutamatergic overexcitation. Therefore, targeting spinal cord AQP4 may serve as a potential strategy for treatment of peripheral inflammation-evoked hyperalgesia.
Learn More >It has recently been shown that epidermal growth factor receptor (EGFR) contributes to the pathogenesis of pain. We scanned genetic markers within genes coding for receptors of the EGFR family (EGFR, ERBB2, ERBB3 and ERBB4) and their ligands (AREG, BTC, EGF, EPGN, EREG, HBEGF, MUC4, NRG1, NRG2, NRG3, NRG4 and TGFA) for association with self-reported pain intensity in patients with chronic facial pain who participated in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. We found that only epiregulin (EREG) was associated with pain. The strongest effect was observed for a minor allele at rs6836436 in EREG, which was associated with lower chronic pain intensity. However, the same allele was associated with higher facial pain intensity among cases with recent onset of facial pain. Similar trends were observed in an independent cohort of UK Biobank (UKB) where the minor allele at rs6836436 was associated with a higher number of acute pain sites but a lower number of chronic pain sites. Expression quantitative trait loci (eQTL) analyses established rs6836436 as a loss-of-function variant of EREG. Lastly, we investigated the functional role of epiregulin using mouse models of chronic and acute pain. Injecting mice with an EREG monoclonal antibody (mAb) reversed established mechanosensitivity in the complete Freund's adjuvant (CFA) and spared nerve injury (SNI) models of chronic pain. However, the EREG mAb prolonged allodynia when administered during the development of CFA-induced mechanosensitivity and enhanced pain behavior in the capsaicin model of acute pain.
Learn More >This proposed systematic review will identify the existing evidence on medication-overuse headache in children and adolescents.
Learn More >Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks (RSNs) and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in TSOP and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with: 1) stronger rsFCs of the posterior cingulate cortex (PCC), with the ventromedial prefrontal cortex (vmPFC) and with the pregenual anterior cingulate cortex (pgACC); 2) weaker rsFC of the anterior insula with the angular gyrus. However, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. Perspective: This article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in heath and in the presence of chronic pain.
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