Browse by Audience
P2X7 receptor antagonists have potential for treating various CNS diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signaling in pain and the lack of a corresponding preclinical mechanistic biomarker.
Learn More >Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds , , , and ), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely , , and , demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal () injection.
Learn More >The importance of the dynamic interplay between the opioid and the serotonin neuromodulatory systems in chronic pain is well recognized. In this study, we investigated whether these two signalling pathways can be integrated at the single-cell level via direct interactions between the mu-opioid (MOP) and the serotonin 1A (5-HT) receptors. Using fluorescence cross-correlation spectroscopy (FCCS), a quantitative method with single-molecule sensitivity, we characterized in live cells MOP and 5-HT interactions and the effects of prolonged (18 h) exposure to selected non-peptide opioids: morphine, codeine, oxycodone and fentanyl, on the extent of these interactions. The results indicate that in the plasma membrane, MOP and 5-HT receptors form heterodimers that are characterized with an apparent dissociation constant Kdapp = (440 ± 70) nM). Prolonged exposure to all non-peptide opioids tested facilitated MOP and 5-HT heterodimerization and stabilized the heterodimer complexes, albeit to a different extent: Kd, Fentanylapp = (80 ± 70) nM), Kd,Morphineapp = (200 ± 70) nM, Kd, Codeineapp = (100 ± 70) nM and Kd, Oxycodoneapp = (200 ± 70) nM. The non-peptide opioids differed also in the extent to which they affected the mitogen-activated protein kinases (MAPKs) p38 and the extracellular signal-regulated kinase (Erk1/2), with morphine, codeine and fentanyl activating both pathways, whereas oxycodone activated p38 but not ERK1/2. Acute stimulation with different non-peptide opioids differently affected the intracellular Ca levels and signalling dynamics. Hypothetically, targeting MOP-5-HT heterodimer formation could become a new strategy to counteract opioid induced hyperalgesia and help to preserve the analgesic effects of opioids in chronic pain.
Learn More >A sucrose downshift causes a temporary suppression of consumption accompanied by psychological pain, a negative emotion triggered by reward loss. When administered systemically before downshift sessions, opioid agonists reduce and opioid antagonists enhance such behavioral suppression. However, little is known about the effects of signals of opioid drugs on behavior during a reward downshift episode. Research showed that morphine administration can induce a direct effect (e.g., hypoalgesia) followed by a compensatory effect (e.g., hyperalgesia). Therefore, a signal for morphine could elicit either a direct or a compensatory effect. Male Wistar rats were exposed to ten 5-min sessions of access to 32% sucrose in context A, followed by three sessions of access to 4% sucrose in context B. In parallel, animals received pairings between context B and morphine (5 mg/kg, sc) occurring each day immediately after sucrose sessions (contexts were counterbalanced). Control conditions included a saline control (no morphine injected), an unpaired control (morphine injected after exposure to B) tested in A (Experiment 1), and an unpaired control tested in B (Experiment 2). In both experiments, behavioral suppression induced by the 32-to-4% sucrose downshift was attenuated when the downshift occurred in a context previously paired with morphine. These data are consistent with the hypothesis that reward downshift is accompanied by an emotion of negative valence that can be counteracted by the conditioned release of endogenous opioids triggered by signals of morphine, much like it is attenuated by systemic morphine administration. Alternative hypotheses are also discussed.
Learn More >Osteoarthritis (OA) is one of the leading chronic conditions in the older population. People with OA are more likely to have one or more other chronic conditions than those without. However, the temporal associations, clusters of the comorbidities, role of analgesics and the causality and variation between populations are yet to be investigated. This paper describes the protocol of a multinational study in four European countries (UK, Netherlands, Sweden and Spain) exploring comorbidities in people with OA.
Learn More >Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation.
Learn More >Recent cross-sectional studies have identified differences in autobiographical memory (AM) among individuals with chronic pain, but temporal relationship between the two is unknown. Moreover, AM has yet to be studied in patients undergoing major surgery. The present study addressed these gaps by conducting a prospective, longitudinal study of memory performance, postsurgical pain, and psychosocial factors in 97 adult participants scheduled for major surgery. Memories were evaluated using the Autobiographical Memory Test before and one month after surgery when participants were asked to recall personal events related to positive and pain-related word cues. Responses were coded for level of specificity, emotional valence, and surgery-related content. Questionnaires assessing presence/absence of pain and psychological functioning were administered before and at 1-, 3-, 6-, and 12-month follow-ups. Generalized estimating equations modelled pain at each postsurgical timepoint with memory variables as predictors. As hypothesized, higher numbers of specific pain memories recalled before surgery predicted lower odds of pain across all timepoints (OR=0.58, 95% CI [0.37-0.91]). Participants who took longer to recall pain memories before surgery (OR=2.65, 95% CI [1.31-5.37])) and those who produced more surgery-related content at the one-month assessment (OR=1.31, 95% CI [1.02-1.68]) had greater odds of reporting postsurgical pain up to 12 months later. These findings indicate that pre-surgical AM biases are risk factors for development and maintenance of postsurgical pain. To the extent that these biases are causal, presurgical interventions that modify the quality and content of patients' memories may prove to be promising strategies in the prevention of chronic postsurgical pain.
Learn More >Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein-coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.
Learn More >Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer's disease are susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in Alzheimer's disease patients will affect the pain processing. Here we leverage animal behavior, neural activity recording, optogenetics, chemogenetics and Alzheimer's disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to the pain response. The 5× familial Alzheimer's disease (5×FAD) mice show alleviated mechanical allodynia which can be regained by genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation as well as the dendritic spine reduction of ACC pyramidal neurons in 5×FAD mice can be mimicked by Rac1 or actin polymerization inhibitor in Wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer's disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.
Learn More >Australian people living with chronic pain (n=206; 90% female) and carers (n=10; 40% female) described their pain care priorities (eDelphi, Round 1). A coding framework was inductively derived from 842 pain care priorities (9 categories, 52 priorities) including: validation; communication; multidisciplinary approaches; holistic care; partnerships; practitioner knowledge; self-management; medicines and diagnosis.
Learn More >