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To determine the prevalence of neuropathic-like pain(NP) and pain sensitisation(PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint.
Learn More >This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.
Learn More >The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated receptor channel that plays a role in peripheral neuropathic pain. Src, a protein tyrosine kinase, can regulate the activation of NMDARs in chronic pain conditions. Pannexin 1 (Panx1), a plasma membrane channel, plays an important role in neuropathic pain and functionally interacts with NMDARs in the pathological condition of epilepsy. In this study, the roles of NMDAR1 (NR1), Src, and Panx1 and their interactions in the trigeminal ganglion (TG) in orofacial ectopic pain attributed to inferior alveolar nerve transection (IANX) were investigated. IANX induced mechanical allodynia in the whisker pad with increased expression levels of NR1, Src phosphorylation (p-Src), and Panx1 in the TG. Double immunostaining revealed that NR1, Src, and Panx1 all colocalized with glutamine synthetase (GS) and neuronal nuclei (NeuN), and they overlapped in the TG, suggesting that they might be structurally connected to one another. In addition, trigeminal injection of memantine, PP2, or Panx attenuated IANX-induced mechanical allodynia in the whisker pad. Continuous intraganglionic administration of memantine (an antagonist of NMDAR) decreased IANX-induced upregulated expression of p-Src and Panx1. Similarly, PP2 (an inhibitor of Src) also decreased Panx1 protein expression but had no effect on NR1. In addition, intraganglionic injection of Panx (a blocker of Panx1) decreased NR1 protein expression but did not affect Src. In general, our findings demonstrated that NR1, Src, and Panx1 all contributed to orofacial ectopic pain following IANX and that they composed a signalling pathway in the TG involved in mechanical allodynia.
Learn More >We have developed and feasibility tested an activity pacing framework for clinicians to standardise their recommendations of activity pacing to patients with chronic pain/fatigue. This study aimed to explore the acceptability and fidelity to this framework in preparation for a future trial of activity pacing.
Learn More >Frequently described as "the worst itch" one can ever experience scabies itch is the hallmark of Sarcoptes scabiei mite infestation. Notably, the itchiness often persists for weeks despite scabicides therapy. The mechanism of scabies itch is not yet fully understood, and effective treatment modalities are still missing which can severely affect the quality of life. The aim of this review is to provide an overview of the scope of itch in scabies and highlight candidate mechanisms underlying this itch. We herein discuss scabies itch, with a focus on the nature, candidate underlying mechanisms and treatment options. We also synthesize this information with current understanding of the mechanisms contributing to non-histaminergic itch in other conditions. Itch is a major problem in scabies and can lead to grave consequences. We provide the latest insights on host-mite interaction, secondary microbial infection, and neural sensitization with special emphasis on keratinocytes and mast cells to better understand the mechanism of itch in scabies. Also, the most relevant current modalities remaining under investigation that possess promising perspectives for scabies itch (i.e. Protease-activated receptor-2 (PAR-2) inhibitor, Mas-related G protein-coupled receptor X2 (MRGPRX2) antagonist) are discussed. Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to control itch in individuals with scabies.
Learn More >Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.
Learn More >Agonists at the nociceptin opioid peptide receptor (NOP) are under investigation as therapeutics for non-addicting analgesia, opioid use disorder, Parkinson's disease, and other indications. NOP full and partial agonists have both been of interest, particularly since NOP partial agonists show a reduced propensity for behavioral disruption than NOP full agonists. Here, we investigated the in vitro pharmacological properties of chemically diverse NOP receptor agonists in assays measuring functional activation of the NOP receptor such as GTPgS binding, cAMP inhibition, GIRK activation, phosphorylation, β-arrestin recruitment and receptor internalization. When normalized to the efficacy of the natural agonist nociceptin/orphanin FQ (N/OFQ), we found that different functional assays that measure intrinsic activity produce inconsistent levels of agonist efficacy, particularly for ligands that were partial agonists. Agonist efficacy obtained in the GTPgS assay tended to be lower than that in the cAMP and GIRK assays. These structurally diverse NOP agonists also showed differential receptor phosphorylation profiles at the phosphosites we examined and induced varying levels of receptor internalization. Interestingly, while the rank order for β-arrestin recruitment by these NOP agonists was consistent with their ability to induce receptor internalization, their phosphorylation signatures at the timepoint we investigated were not indicative of the levels of β-arrestin recruitment or internalization induced by these agonists. It is possible that other phosphorylation sites, yet to be identified, drive the recruitment of NOP receptor ensembles and subsequent receptor trafficking by some nonpeptide NOP agonists. These findings potentially help understand NOP agonist pharmacology in the context of ligand-activated receptor trafficking. Chemically diverse agonist ligands at the nociceptin opioid receptor GPCR showed differential efficacy for activating downstream events after receptor binding, in a suite of functional assays measuring GTPγS binding, cAMP inhibition, GIRK channel activation, β-arrestin recruitment, receptor internalization and receptor phosphorylation. These analyses provide a context for understanding NOP agonist pharmacology driven by ligand-induced differential NOP receptor signaling.
Learn More >Nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-induced oxidative stress, including the production of reactive oxygen species (ROS) and hydrogen peroxide, plays a pivotal role in neuropathic pain. Although the activation and plasma membrane translocation of protein kinase C (PKC) isoforms in dorsal root ganglion (DRG) neurons have been implicated in multiple pain models, the interactions between NOX2-induced oxidative stress and PKC remain unknown.
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