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To use a mouse model of imiquimod-induced psoriasis to investigate the relationship between pruritus and mast cells, nerve growth factor (NGF) and endogenous pruritogenic peptides, which are highly expressed in the skin of psoriasis patients.
Learn More >The emergence of several fentanyl-related substances in the recreational drug marketplace has resulted in a surge of opioid overdose deaths in the United States. Many of these substances have never been examined in living organisms under controlled conditions. In the present study, seven fentanyl-related substances were tested in adult male Swiss Webster mice for their effects on locomotion and antinociception and compared to those of fentanyl and morphine. In locomotor activity tests, fentanyl (1, 10 mg/kg), morphine (100, 180 mg/kg), isobutyrylfentanyl (10 mg/kg), crotonylfentanyl (10 mg/kg), para-fluorobutyrylfentanyl (10, 100 mg/kg), para-methoxybutyrylfentanyl (10 mg/kg), thiophenefentanyl (100 mg/kg), and benzodioxolefentanyl (0.1 mg/kg) produced significant (p ≤ 0.05) dose-dependent increases in locomotion. Valerylfentanyl, however, was without effects on locomotion up to 100 mg/kg. In warm-water tail-withdrawal tests, all substances produced significant (p ≤ 0.05) dose-dependent increases in antinociception with increasing ED values (CI) of isobutyrylfentanyl [0.0768 mg/kg (0.044-0.128)] > fentanyl [0.0800 mg/kg (0.0403-0.164)] > para-methoxybutyrylfentanyl [0.106 mg/kg (0.0516-0.195)] > crotonylfentanyl [0.226 mg/kg (0.176-0.292)] > para-fluorobutyrylfentanyl [0.908 mg/kg (0.459-1.58)] > thiophenefentanyl [4.66 mg/kg (3.65-5.95)] > valerylfentanyl [6.43 mg/kg (3.91-10.5)] > morphine [7.82 mg/kg (5.42-11.0)] > benzodioxolefentanyl [46.3 mg/kg (25.8-83.4)]. Naltrexone (1 mg/kg) increased antinociceptive ED values several fold in decreasing magnitudes of isobutyrylfentanyl (233x) > para-methoxybutyrylfentanyl (37.7x) > thiophenefentanyl (34.6x) > valerylfentanyl (11.9x) > para-fluorobutyrylfentanyl (10.9x) > benzodioxolefentanyl (8.42x) > crotonylfentanyl (6.27x) > fentanyl (3.95x) > morphine (1.48x). These findings establish that locomotor and antinociceptive effects of several fentanyl-related substances are similar to those of morphine and fentanyl and are mediated by opioid receptors.
Learn More >To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification.
Learn More >NKTR-181, a new molecular entity, full mu-opioid receptor agonist with an inherently slow rate of CNS entry, was designed to provide analgesia while reducing abuse potential. The objective of this phase 3, enriched-enrollment, randomized-withdrawal trial was to evaluate the analgesic efficacy, safety, and tolerability of NKTR-181 in patients with chronic low-back pain (CLBP). Adults with moderate-to-severe CLBP refractory to non-opioid analgesics achieving an analgesic NKTR-181 dosage (100-400 mg twice daily) during the open-label titration period were randomized to continued NKTR-181 treatment, double-blind, or switched to placebo. The study was conducted at 55 sites in the United States. Of 1189 patients exposed to NKTR-181 during the titration period, 610 were randomized to NKTR-181 100-400 mg every 12 hours or placebo for 12-weeks. The primary outcome measure was the change in weekly pain score (scale, 0-10) at 12-weeks from randomization baseline. Secondary outcome measures included responder rates defined by ≥30% and ≥50% improvement in pain score from screening to 12 weeks. Among 610 randomized patients, the mean pain score decreased from 6.73 to 2.32 during open-label titration. After randomization, the least-squares mean change in pain score was +0.92 for NKTR-181 vs. +1.46 for placebo (P=0.002). The ≥30%-improvement responder rate of NKTR-181 vs. Placebo was 71.2% vs. 57.1% (P<0.001), and the ≥50%-improvement responder rate was 51.1% vs. 37.9% (P=0.001). NKTR-181 was well tolerated with a low incidence (<3%) of CNS-related AEs during the randomized treatment phase. In patients with moderate-to-severe CLBP, NKTR-181 demonstrated significant analgesic efficacy and a favorable safety/tolerability profile, with a low incidence of CNS AEs.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Complex Regional Pain Syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation which is explained by local and systemic activation of a pro-inflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin converting enzyme (ACE) in patients treated for hypertension increases the odds to develop CRPS. This hint lead us to investigate the serum protease network activity in CRPS patients vs. respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate CRPS patients, as well as healthy (HC) and pain (painful diabetic neuropathy; dPNP) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in HC and dPNP is shifted to higher values for DBK1-8 and lower values for DBK 1-5 at one hour of incubation in CRPS patients. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators like BK might be different in CRPS patients; having a look at the the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.
Learn More >Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the "G" allele at rs6471859 produces a cryptic 3'UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.
Learn More >The purpose of this review is to explore the effects of the opioid crisis on pediatric patients in the postoperative setting and provide recommendations for well-tolerated opioid prescribing practices.
Learn More >Vulvodynia is a debilitating, chronic vulvar pain condition. Community-based case-control studies have consistently shown associations between early-life chronic stressors and vulvodynia onset.
Learn More >The goal of this project was to use computational models to investigate which types of primary sensory neurons are modulated by dorsal root ganglion stimulation (DRGS) to provide pain relief.
Learn More >Current definitions of pain do not necessitate tissue damage. This is important because it does justice to the pain patient in whom a nociceptive source is not detectable. However, in conjunction with exciting findings regarding supraspinal pain modulation and a (perceived) failure of identifying nociceptive sources in individual patients, this might have led to a devaluation of the role of nociception for chronic pain. In this review, the relative importance of nociception versus psychological factors for chronic pain is examined by scrutinizing the example of pain present several months following surgical joint replacement for severe osteoarthritis.
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