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Sensory perceptions are coded by complex neural dynamics of regional communication in the brain. Thus, sensory abnormalities such as chronic pain may occur when neural dynamics go awry. Previous studies of cross-network dynamic functional connectivity in chronic pain identified abnormalities but were based on functional MRI which only captures slow temporal features. Here we conducted a magnetoencephalography (MEG) study to investigate fine temporal dynamics of aberrant cross-regional and cross-network communication of the dynamic pain connectome in patients with chronic pain. We also introduced a novel measure, dynamic functional coupling, to quantify the variability of brain communication. The study was performed in 33 people who had chronic pain associated with multiple sclerosis and 30 healthy controls. We found that patients with chronic pain exhibited abnormalities in cross-network functional coupling across multiple frequency bands (theta, alpha, beta, gamma), between the salience network and 3 other networks: the ascending nociceptive pathway, descending anti-nociceptive pathway, and the default mode network. However, these cross-network abnormalities involved different frequency bands in patients with neuropathic versus non-neuropathic chronic pain. Furthermore, cross-network abnormalities were linked to pain severity and pain interference. Our findings implicate broadband cross-network abnormalities as hallmark features of chronic pain in multiple sclerosis.
Learn More >Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Learn More >The dorsal root ganglia is a key structure in nociception and chronic pain disorders. Several gene expression studies of dorsal root ganglia in pre-clinical pain models have been performed, but it is unclear if consistent gene changes are identifiable. We, therefore, compared several recent RNA-Seq datasets on the whole dorsal root ganglia in rodent models of nerve injury. Contrary to previous findings, we show hundreds of common differentially expressed genes and high positive correlation between studies, despite model and species differences. We also find, in contrast to prior studies, that 60% of the common rodent gene response after injury is likely to occur in nociceptors of the dorsal root ganglia. Substantial expression changes are observed at a one-week time-point, with smaller changes in the same genes at a later three to four-week time-point. However, a subset of genes shows a similar magnitude of changes at both early and late time-points, suggesting their potential involvement in the maintenance of chronic pain. These genes are centred around suppression of endogenous opioid signalling. Reversal of this suppression could allow endogenous and exogenous opioids to exert their analgesic functions and may be an important strategy for treating chronic pain disorders. Currently used drugs, such as amitriptyline and duloxetine, do not appear to appropriately modulate many of the critical pain genes and indeed may transcriptionally suppress endogenous opioid signalling further.
Learn More >Atopic dermatitis (AD) is a widespread, chronic skin disease associated with aberrant allergic inflammation. Current treatments involve either broad or targeted immunosuppression strategies. However, enhancing the immune system to control disease remains untested. We demonstrate that patients with AD harbor a blood natural killer (NK) cell deficiency that both has diagnostic value and improves with therapy. Multidimensional protein and RNA profiling revealed subset-level changes associated with enhanced NK cell death. Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context. On the basis of these findings, we used an NK cell-boosting interleukin-15 (IL-15) superagonist and observed marked improvement in AD-like disease in mice. These findings reveal a previously unrecognized application of IL-15 superagonism, currently in development for cancer immunotherapy, as an immunotherapeutic strategy for AD.
Learn More >To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury.
Learn More >Natural killer cells collaborate with type 2 immune cells to modulate atopic dermatitis pathogenesis (Mack , this issue).
Learn More >Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology.
Learn More >Chronic musculoskeletal pain is a major health, social, and economic problem. Most of the subjects who suffer from chronic musculoskeletal pain present processes of central sensitization. Temporal summation and conditioned pain modulation are the two most commonly used clinical measures of this. The objective of this review is to evaluate the effects of physical therapy on temporal summation (TS) and conditioned pain modulation (CPM) in patients with chronic musculoskeletal pain.
Learn More >Biopsychosocial integrated pain team (IPT) care models are being implemented in Veterans Health Administration (VA) and other health care systems to address chronic pain and reduce risks related to long-term opioid therapy, with little evaluation of effectiveness to date. We examined whether IPT improves self-reported pain-related outcomes and opioid misuse.
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