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Finding effective, accessible treatment options such as professional-delivered cognitive behavioral therapy (CBT) for medically complex individuals is challenging in rural communities.
Learn More >The Short-Term Kinetics of sICAM-1 after Induction of Acute Experimental Pain in Healthy Volunteers.
Intercellular adhesion molecule-1 (ICAM-1) mediates extravasation of leukocytes, releasing proinflammatory cytokines or endogenous opioids in the inflamed tissue. Thus, ICAM-1 is a crucial component of peripheral antinociception. Previously, we demonstrated a significant correlation between the soluble form of ICAM (sICAM-1) in serum and pain intensity reported by chronic pain patients. The present study examines the role and kinetics of sICAM-1 in experimentally induced acute pain. Three groups of 10 subjects were exposed to 10 min of high (capsaicin-enhanced) or low-intensity heat pain or cold pain, respectively. Thermal stimuli were induced using a device for quantitative sensory testing. Topical capsaicin significantly increased heat pain intensity without the risk of thermal tissue damage. Pain intensity was recorded every minute during testing. sICAM-1 concentrations in serum were determined by ELISA before, immediately after, and 60 min after test termination. Among all experimental groups, sICAM-1 significantly decreased immediately after pain induction. After 60 min, sICAM-1 concentrations returned towards initial values. Interestingly, a linear correlation was found between the extent of sICAM-1 changes and the initial concentrations. Whereas high initial values led to a distinct decrease of sICAM-1, low concentrations tended to increase. There was no statistically significant correlation between levels or alterations of serum sICAM-1 and pain intensity reported by the test subjects. In contrast to our previous findings in chronic pain patients, the present results show that sICAM-1 values do not correlate with the intensity of acute experimental pain. However, we were able to detect short-term changes of sICAM-1 after induction of nociceptive thermal stimuli, suggesting that this marker is part of a demand-oriented homeostatically controlled system.
Learn More >Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by SARM1 is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved program of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy (SNA), we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain (NfL) released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 KO mice prevented loss of axonal function, assessed by sensory nerve action potential (SNAP) amplitudes of the tail nerve, in a gene dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibers induced by paclitaxel and provided partial protection of axonal function assessed by SNAP amplitude and mechanical allodynia.
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 >To assess the effectiveness of an educational intervention with or without the addition of the therapeutic alliance in patients with nonspecific chronic low back pain (LBP) and low risk of poor prognosis.
Learn More >There is considerable public interest in whether Europe is facing an opioid crisis comparable to the one in the U.S. and the contribution of opioid prescriptions for pain to a potential opioid crisis.
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 >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 >Neuropathic pain is a common disorder of the somatosensory system that affects 7%-10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.
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