Browse by Audience
Multisite chronic pain (MSCP) is associated with increased chronic pain impact, but methods for identifying MSCP for epidemiological research have not been evaluated.
Learn More >The primary aim was to quantify and compare the location and extent of pain in people with either episodic migraine, chronic migraine, or cervicogenic headache. A secondary aim was to examine the associations between pain extent and headache features, quality of life, and psychological distress for each headache type.
Learn More >The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1β. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1β secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1β is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.
Learn More >To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs, we performed functional imaging scans on patients treated with erenumab.
Learn More >To preliminarily examine the psychometric properties (i.e., internal consistency reliability, construct validity) and clinical utility of the Patient-Reported Outcomes Measurement Information System (PROMIS) psychological stress experiences scale in a sample of youth with chronic pain.
Learn More >Neuropathic pain is a chronic pain state characterized by nerve damage, inflammation, and nociceptive neuron hyperactivity. As the underlying pathophysiology is complex, a more effective therapy for neuropathic pain would be one that targets multiple elements. Here, we generated recombinant adeno-associated viruses (AAVs) encoding three therapeutic genes, namely, , , and , with various combinations. The efficacy for pain relief was evaluated in a rat spared nerve injury model of neuropathic pain. The maximal analgesic effect was achieved when the AAVs expressing all three genes were administered to rats with neuropathic pain. The combination of two virus constructs expressing the three genes was named KLS-2031 and evaluated as a potential novel therapeutic for neuropathic pain. Single transforaminal epidural injections of KLS-2031 into the intervertebral foramen to target the appropriate dorsal root ganglion produced notable long-term analgesic effects in female and male rats. Furthermore, KLS-2031 mitigated the neuroinflammation, neuronal cell death, and dorsal root ganglion hyperexcitability induced by the spared nerve injury. These results suggest that KLS-2031 represents a promising therapeutic option for refractory neuropathic pain.
Learn More >Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine's bell-shaped dose-response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.
Learn More >Exercise-induced hypoalgesia (EIH) describes acute reductions in pain that occur following exercise. Current evidence suggests that the magnitude of EIH is small-to-moderate at best, warranting exploration of novel avenues to bolster these effects. Transcranial direct current stimulation (tDCS) has been shown to relieve pain and represents a promising intervention that may enhance EIH. This study aimed to determine whether anodal tDCS of the primary motor cortex (M1) can augment EIH in healthy individuals experiencing experimentally-induced musculoskeletal pain. Twenty-four healthy subjects attended two experimental sessions ('Day 0' and 'Day 2'). On Day 0, subjects were injected with nerve growth factor (NGF) into their right extensor carpi radialis brevis to induce persistent elbow pain. On Day 2, each subject received active or sham tDCS over M1 followed by an isometric grip exercise. Pain intensity, muscle soreness, sensitivity (pressure pain thresholds) and conditioned pain modulation were assessed prior to the NGF injection, on Day 2 before tDCS, immediately post-exercise, and 15 minutes post-exercise. Active tDCS expedited the onset of EIH, inducing immediate reductions in pain intensity that were not present until 15 minutes post-exercise in the sham group. However, active tDCS did not reduce muscle soreness or sensitivity when compared to sham tDCS. Perspective: These findings suggest that active tDCS accelerates the onset of EIH in healthy individuals experiencing experimentally-induced pain. This may represent a promising means of enhancing adherence to exercise protocols. However, larger randomised controlled trials in persistent pain populations are required to confirm the clinical impact of these findings.
Learn More >Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
Learn More >Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the Neurologic Pain Signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opiodergic prefrontal modulatory networks.
Learn More >