ABSTRACT
Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up-down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h2 = 0.23-0.40). All strains displayed oxycodone-induced analgesia that peaked at 15-30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h2 = 0.10-0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone-induced analgesia.
Subject(s)
Analgesia , Opioid-Related Disorders , Rats , Animals , Oxycodone/pharmacology , Analgesics, Opioid/pharmacologyABSTRACT
Monocyte differentiation induced by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is interrupted during the course of acute promyelocytic leukemia (APL). One form of APL is associated with the translocation t(11;17), which joins the promyelocytic leukemia zinc finger (PLZF) and retinoic acid receptor alpha (RARalpha) genes. Because PLZF is coexpressed in the myeloid lineage with the vitamin D(3) receptor (VDR), the interplay between PLZF and VDR was examined. It was found that PLZF interacts directly with VDR. This occurred at least partly through contacts in the DNA-binding domain of VDR and the broad complex, tram-trak, bric-a-brac/pox virus zinc finger (BTB/POZ) domain of PLZF. Moreover, PLZF altered the mobility of VDR derived from nuclear extracts when bound to its cognate binding site, forming a slowly migrating DNA-protein complex. Overexpression of PLZF in a monocytic cell line abrogated 1,25(OH)(2)D(3) activation from both a minimal VDR responsive reporter and the promoter of p21(WAF1/CIP1), a target gene of VDR. Deletion of the BTB/POZ domain significantly relieved PLZF-mediated repression of 1,25(OH)(2)D(3)-dependent activation. In addition, stable, inducible expression of PLZF in U937 cells inhibited the ability of 1,25(OH)(2)D(3) to induce surface expression of the monocytic marker CD14 and morphologic changes associated with differentiation. These results suggest that PLZF may play an important role in regulating the process by which 1,25(OH)(2)D(3) induces monocytic differentiation in hematopoietic cells.
Subject(s)
Calcitriol/pharmacology , Cell Differentiation/drug effects , DNA-Binding Proteins/pharmacology , Monocytes/drug effects , Receptors, Calcitriol/drug effects , Transcription Factors/pharmacology , Binding Sites , Cell Nucleus/chemistry , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , DNA/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression , Humans , Kruppel-Like Transcription Factors , Lymphoma, Large B-Cell, Diffuse , Promoter Regions, Genetic , Promyelocytic Leukemia Zinc Finger Protein , Receptors, Calcitriol/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic/drug effects , Transfection , U937 Cells , Zinc FingersABSTRACT
Tube cystostomy was used to treat 13 goats and two sheep with obstructive urolithiasis. The cystostomy tube was intermittently occluded 3 to 4 days after placement to determine if urine could be voided through the urethra. If the animal showed no discomfort during urination after the cystostomy tube had been occluded for several days, the tube was removed. This procedure was successful in relieving urethral obstruction in 12 animals. The mean time until the animal could urinate freely and until the cystostomy tube was removed was 11.5 and 14.4 days respectively. Follow-up was available for 10 animals; seven were alive with no recurrence of urinary obstruction. One goat died from unrelated to urinary obstruction 1 year postoperatively. One goat died from unknown causes, and one goat died after urinary obstruction recurred.
