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GATA3-dependent epigenetic upregulation of CCL21 is involved in the development of neuropathic pain induced by bortezomib.

The incidence of bortezomib-induced neuropathic pain hampers the progress of therapy for neoplasia, and also negatively affects the quality of life of patients. However, the molecular mechanism underlying bortezomib-induced neuropathic pain remains unknown. In the present study, we found that the application of bortezomib significantly increased the expression of GATA binding protein 3 (GATA3) in the spinal dorsal horn, and intrathecal administration of GATA3 siRNA attenuated mechanical allodynia. Furthermore, ChIP-sequencing showed that bortezomib treatment induced the redistribution of GATA3 to transcriptional relevant regions. Notably, combined with the results of mRNA microarray, we found that C-C motif chemokine ligand 21 (CCL21) had an increased GATA3 binding and upregulated mRNA expression in the dorsal horn after bortezomib treatment. Next, we found that bortezomib treatment induced CCL21 upregulation in the spinal neurons, which was significantly reduced upon GATA3 silencing. Blockade of CCL21 using the neutralizing antibody or special siRNA ameliorated mechanical allodynia induced by bortezomib. In addition, bortezomib treatment increased the acetylation of histone H3 and the interaction between GATA3 and CREB-binding protein (CBP). GATA3 siRNA suppressed the CCL21 upregulation by decreasing the acetylation of histone H3. Together, these results suggested that activation of GATA3 mediated the epigenetic upregulation of CCL21 in dorsal horn neurons, which contributed to the bortezomib-induced neuropathic pain.

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Designing and conducting proof-of-concept chronic pain analgesic clinical trials.

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Skilled reaching deterioration contralateral to cervical hemicontusion in rats is reversed by pregabalin treatment conditional upon its early administration.

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Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.

Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.

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Short- and Long-Term Effects of Cannabis on Headache and Migraine.

Use of cannabis to alleviate headache and migraine is relatively common, yet research on its effectiveness remains sparse. We sought to determine whether inhalation of cannabis decreases headache and migraine ratings as well as whether gender, type of cannabis (concentrate vs. flower), THC, CBD, or dose contribute to changes in these ratings. Finally, we explored evidence for tolerance to these effects. Archival data were obtained from Strainprint, a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. Latent change score models and multilevel models were used to analyze data from 12,293 sessions where cannabis was used to treat headache and 7,441 sessions where cannabis was used to treat migraine. There were significant reductions in headache and migraine ratings after cannabis use. Men reported larger reductions in headache than women and use of concentrates was associated with larger reductions in headache than flower. Further, there was evidence of tolerance to these effects. Perspective: Inhaled cannabis reduces self-reported headache and migraine severity by approximately 50%. However, its effectiveness appears to diminish across time and patients appear to use larger doses across time, suggesting tolerance to these effects may develop with continued use.

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Calcitonin Gene-Related Peptide Antagonists for the Prevention of Migraine: Highlights From Pivotal Studies and the Clinical Relevance of This New Drug Class.

To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. A literature search was performed in PubMed (January 2009 to November 2019) using the terms (CGRP), , and for clinical trials and studies. Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.

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GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents.

Treating neuropathic pain is challenging and novel non-opioid based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence and in situ hybridization, we found the expression of the orphan GPCR (oGPCR) Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord (DH-SC) following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal (i.th.) CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights to its signaling pathways. CARTp is involved in many diseases including depression, reward and addiction, de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

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Investigating the Effect of Perioperative Chlorzoxazone On Acute Postoperative Pain After Total Hip and Knee Replacement Surgery.

Severe pre- and acute postoperative pain have been associated with development of chronic postoperative pain. Chlorzoxazone (a muscle relaxant) has been suggested to enhance acute postoperative pain recovery but the lack of larger randomized controlled trials have however questioned the continued use. Despite this, chlorzoxazone is still used for acute postoperative pain management following total knee or hip replacement (TKR or THR). The currentrandomized, double blinded, placebo-controlled, parallel group, clinical trial aimed to assess the effect of chlorzoxazone for postoperative pain management following TKR or THR.

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The Risks or Lack Thereof of Migraine Treatments in Vascular Disease.

Patients with migraine have a co-morbidity with vascular diseases such as hypertension, coronary heart disease, and stroke.

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Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan.

We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.

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