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The σ receptor has attracted intense interest in cancer imaging, psychiatric disease, neuropathic pain and other areas of biology. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone and the tool compound PB28. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ receptor. Crystal structures of two ligands bound to the σ receptor confirmed the docked poses. To investigate the contribution of the σ receptor in pain, two potent σ-selective ligands and one potent σ/σ non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model, suggesting that the σ receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.
Learn More >Chronic nonspecific low back pain (cNLBP) is a leading contributor to disease burden worldwide that is difficult to treat due to its nonspecific aetiology and complexity. The amygdala is a complex of structurally and functionally heterogeneous nuclei that serve as a key neural substrate for the interactions between pain and negative affective states. However, whether the functions of amygdalar subcomponents are differentially altered in cNLBP remains unknown. Little attention has focused on effective connectivity of the amygdala with the cortex in cNLBP. In this study, thirty-three patients with cNLBP and 33 healthy controls (HCs) were included. Resting-state functional connectivity (rsFC) and effective connectivity of the amygdala and its subregions were examined. Our results showed that the patient group exhibited significantly greater rsFC between the left amygdala and left dorsal medial prefrontal cortex (mPFC), which was negatively correlated with pain intensity ratings. Subregional analyses suggested a difference located at the superficial nuclei of the amygdala. Dynamic causal modelling revealed significantly lower effective connectivity from the left amygdala to the dorsal mPFC in patients with cNLBP than in HCs. Both groups exhibited stronger effective connectivity from the left amygdala to the right amygdala. In summary, these findings not only suggested altered rsFC of the amygdala-mPFC pathway in cNLBP but also implicated an abnormal direction of information processing between the amygdala and mPFC in these patients. Our results further highlight the involvement of the amygdala in the neuropathology of cNLBP.
Learn More >High molecular weight hyaluronan (HMWH) is an agonist at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, on nociceptors, where it acts to induce anti-hyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments we studied the CD44 second messengers that mediate HMWH-induced attenuation of pain associated with oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN). While HMWH attenuates CIPN only in male rats, following ovariectomy or intrathecal administration of an oligodeoxynucleotide (ODN) antisense to G-protein coupled estrogen receptor (GPR30) mRNA, female rats are also sensitive to HMWH. Intrathecal administration of ODN antisense to CD44 mRNA markedly attenuates HMWH-induced anti-hyperalgesia in male rats with CIPN induced by oxaliplatin or paclitaxel. Intradermal administration of inhibitors of CD44 second messengers, RhoGTPases (RhoA), phospholipase C (PLC) and PI3Kγ attenuates HMWH-induced anti-hyperalgesia, as does intrathecal administration of an oligodeoxynucleotide (ODN) antisense to PI3Kγ. Our results demonstrate that HMWH-induces anti-hyperalgesia in CIPN, mediated by its action at CD44, and downstream signaling by RhoA, PLC and PI3Kγ.
Learn More >Obstructive sleep apnea (OSA), characterized by low arterial oxygen saturation during sleep, is associated with an increased risk of orofacial pain. In this study, we simulated chronic intermittent hypoxia (CIH) during the sleep/rest phase (light phase) to determine the role of transient receptor potential vanilloid 1 (TRPV1) in mediating enhanced orofacial nocifensive behavior and trigeminal spinal subnucleus caudalis (Vc) neuronal responses to capsaicin stimulation in a rat model of OSA. Rats were subjected to CIH (nadir O, 5%) during the light phase for 8 or 16 consecutive days. CIH yielded enhanced behavioral responses to capsaicin, a TRPV1 agonist, after application to the ocular surface and intraoral mucosa, which was reversed under normoxic conditions. The percentage of TRPV1-immunoreactive trigeminal ganglion neurons was greater in CIH rats than in normoxic rats and recovered under normoxic conditions after CIH. The ratio of large-sized TRPV1-immunoreactive trigeminal ganglion neurons increased in CIH rats. The density of TRPV1 positive primary afferent terminals in the superficial laminae of Vc was higher in CIH rats. The phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells intermingled with central terminal of TRPV1 positive afferents in the Vc. The number of pERK-immunoreactive cells following low-dose capsaicin (0.33 µM) application to the tongue was significantly greater in the middle portion of the Vc of CIH rats than in normoxic rats and recovered under normoxic conditions after CIH. These data suggest that CIH during the sleep (light) phase is sufficient to transiently enhance pain on the ocular surface and intraoral mucosa via TRPV1-dependent mechanisms.
Learn More >Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS induced LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12%-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α2δ-1 with gabapentin, or α2δ-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not α2δ-1 knockout, mice. TBS significantly increased the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or α2δ-1Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via α2δ-1-dependent NMDAR activation. α2δ-1-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury.Spinal dorsal horn synaptic plasticity is a hallmark of chronic pain. Although sensory nerves display rhythmic bursting discharges at theta frequencies during painful conditions, the significance of this naturally occurring firing activity in the induction of spinal synaptic plasticity is largely unknown. In this study, we found that theta-burst stimulation (TBS) of sensory nerves induced LTP mainly in excitatory dorsal horn neurons and that the prevalence of TBS-induced LTP was potentiated by nerve injury. This TBS-driven synaptic plasticity required α2δ-1 and its interaction with NMDARs. Furthermore, TBS of sensory nerves induced persistent pain, which was maintained by α2δ-1-bound NMDARs. Thus, TBS-induced LTP at primary afferent-dorsal horn neuron synapses is an appropriate cellular model for studying mechanisms of chronic pain.
Learn More >Adolescents with chronic pain often experience symptom disbelief and social rejection by others secondary to "medically unexplained" symptoms. Although chronic pain is common in adolescents, limited research has conceptualized these social experiences as pain-related stigma in this population. The purpose of this study was to identify and describe pain-related stigma among adolescents with chronic pain and their parents using focus group methodology.
Learn More >The incidence of inflammatory bowel disease with its two main manifestations, colitis ulcerosa and Crohn's disease, is rising globally year after year. There is still a tremendous need to study the underlying pathomechanisms and a well-established tool in order to better understand the disease are colitis models in rodents. Since the concept of the 3Rs was proposed by Russell and Burch, this would include pain medication in animal models of intestinal inflammation as a reduction of suffering. This review argues against pain medication because the administration of pain medication in its current form has an impact on the inflammatory process and the immune response, thus falsifying the results and the reproducibility and therefore leading to misconceptions.
Learn More >This study aimed to characterise recovery from pain and mental health symptoms, and identify whether treatment use facilitates recovery.
Learn More >Risk of herpes zoster (HZ) is increased with Janus kinase inhibitor use. We evaluated clinical study data relating to HZ management in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) receiving tofacitinib.
Learn More >Pain is a clinical feature of COVID-19, however data about persistent pain after hospital discharge, especially among ICU survivors is scarce. The aim of this study is to explore the incidence and characteristics of new-onset pain and its impact on Health-Related Quality of Life (HRQoL), and to quantify the presence of mood disorders in critically ill COVID-19 survivors.
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