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Patients with neuropathic pain have altered proteomic and neuropeptide constituents in cerebrospinal fluid (CSF) compared to controls. Tonic spinal cord stimulation (SCS) has demonstrated differential expression of neuropeptides in CSF before and after treatment suggesting potential mechanisms of action. Burst-SCS is an evidence-based paraesthesia free waveform utilised for neuropathic pain with a potentially different mechanistic action to tonic SCS. This study examines the dynamic biological changes of CSF at a cellular and proteome level after Burst-SCS.
Learn More >Long-term opioid use has negative health care consequences. Opioid-naïve adults are at risk for prolonged and persistent opioid use after surgery. While these outcomes have been examined in some adolescent and teenage populations, little is known about the risk of prolonged and persistent postoperative opioid use after common surgeries compared to children who do not undergo surgery and factors associated with these issues among pediatric surgical patients of all ages.
Learn More >Pain is a principal contributor to the global burden of arthritis with peripheral sensitization being a major cause of arthritis-related pain. Within the knee joint, distal endings of dorsal root ganglion neurons (knee neurons) interact with fibroblast-like synoviocytes (FLS) and the inflammatory mediators they secrete, which are thought to promote peripheral sensitization. Correspondingly, RNA-sequencing has demonstrated detectable levels of pro-inflammatory genes in FLS derived from arthritic patients. This study confirms that stimulation with tumor necrosis factor (TNF-α), results in expression of pro-inflammatory genes in mouse and human FLS (derived from OA and RA patients), as well as increased secretion of cytokines from mouse TNF-α stimulated FLS (TNF-FLS). Electrophysiological recordings from retrograde labelled knee neurons co-cultured with TNF-FLS, or supernatant derived from TNF-FLS, revealed a depolarized resting membrane potential, increased spontaneous action potential firing and enhanced TRPV1 function, all consistent with a role for FLS in mediating the sensitization of pain-sensing nerves in arthritis. Therefore, data from this study demonstrate the ability of FLS activated by TNF-α to promote neuronal sensitization, results that highlight the importance of both non-neuronal and neuronal cells to the development of pain in arthritis.
Learn More >Spontaneous and pharmacologically-provoked migraine attacks are frequently preceded by nonheadache symptoms called premonitory symptoms. Here, we systematically evaluated premonitory symptoms in migraine patients and healthy controls following glyceryl trinitrate (GTN) infusion. In women with migraine without aura (n=34) and age-matched female controls (n=24) we conducted systematically a semi-structured interview assessing 21 possible premonitory symptoms every 15 minutes in the 5 hours following GTN infusion (0.5 µg/kg/min over 20 min). Migraine-like headaches occurred in 28/34 (82.4%) migraineurs (GTN responders). After GTN, 26/28 (92.9%) responders, 6/6 (100%) non-responders, and 13/24 (54.2%) controls reported at least one possible premonitory symptom. Concentration difficulties (p=0.011), yawning (p=0.009), nausea (p=0.028), and photophobia (p=0.001) were more frequently reported by those migraineurs who developed a migraine-like attack versus healthy controls. Importantly, concentration difficulties were exclusively reported by those who developed a migraine-like attack. Thus, our findings support the view that GTN is able to provoke the naturally occurring premonitory symptoms, and show that yawning, nausea, photophobia, and concentration difficulties are most specific for an impending GTN-induced migraine-like headache. We suggest that these symptoms may also be helpful as early warning signals in clinical practice with concentration difficulties exclusively reported by those who develop a migraine-like attack.
Learn More >Itch is an unpleasant sensation that emanates primarily from the skin. The chemical mediators that drive neuronal activity originate from a complex interaction between keratinocytes, inflammatory cells, nerve endings and the skin microbiota, relaying itch signals to the brain. Stress also exacerbates itch via the skin-brain axis. Recently, the microbiota has surfaced as a major player to regulate this axis, notably during stress settings aroused by actual or perceived homeostatic challenge. The routes of communication between the microbiota and brain are slowly being unraveled and involve neurochemicals (i.e., acetylcholine, histamine, catecholamines, corticotropin) that originate from the microbiota itself. By focusing on itch biology and by referring to the more established field of pain research, this review examines the possible means by which the skin microbiota contributes to itch.
Learn More >The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, α2δ-1 or Cava2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT: It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.
Learn More >Robust activation of glial cells has been reported to occur particularly during the pathogenesis of bone cancer pain (BCP). Researchers from our group and others have shown that histone deacetylases (HDACs) play a significant role in modulating glia-mediated immune responses; however, it still remains unclear whether HDACs are involved in the activation of glial cells during the development of BCP.
Learn More >Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETRs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch.
Learn More >Attentional distraction from pain has been shown to be largely ineffective for obtaining a hypoalgesic effect in patients with chronic pain when compared to a control condition. It has been hypothesized that this may be due to the non-engaging types of distraction that have been used so far. Moreover, it is suggested that the hypoalgesic effects of distraction may be attenuated by pain-related cognitions and emotions, as they may increase the attention to pain.
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