Increased sensitization to morphine-induced oral stereotypy in aged rats.

Sensitization develops to the stereotypic biting behavior that appears with the repeated administration of high dose morphine to rats. Because there is evidence that this behavior is dopamine-mediated and that there are age-related changes in dopamine systems, we compared the development and expression of morphine-induced biting behavior in aged (24 months) and young rats (5 months). Animals were treated with four sensitizing 10 mg/kg doses of morphine or saline, followed by three weekly challenges with 4 mg/kg doses of morphine or saline. By the fourth sensitizing morphine dose and after the administration of each low dose challenge, the biting time was significantly greater for aged than for young morphine pre-treated rats. After the first weekly low dose challenge, the aged but not young animals expressed more biting than when they did after the last 10 mg/kg dose. These results indicate that sensitization to morphine-induced oral stereotypy is significantly greater in aged as compared to young rats. Age-related enhanced sensitivity to morphine-induced oral stereotypy might be related to age-induced increases in vulnerability to opioid-induced insults to the basal ganglia, and may be a model for certain diseases of this pathway.

Effects of morphine on brain-stimulation reward thresholds in young and aged rats.

Mesolimbic opioid systems are altered with aging; however, the effects of these changes on the rewarding actions of opioids have not been examined. The present experiment assessed differences in the responsiveness of brain reward pathways in young and aged rats to the effects of morphine using the brain-stimulation reward (BSR) model. Aged (24 months) and young (5 months) male F344/BNF1 rats were stereotaxically implanted with a bipolar stainless steel electrode into the lateral hypothalamic (LH) region of the medial forebrain bundle. Thresholds were determined using the rate-independent psychophysical method. Each animal was tested after the administration of saline or morphine at 0.5, 1, 2.5, 5 and 10 mg/kg doses. A significant difference in the mean baseline threshold between aged (99.8+/-6 microA) and young rats (149.1+/-14 microA) was observed. Although in both groups morphine lowered the BSR threshold, there were no significant differences between the groups except at the 10-mg/kg dose, the difference did approach significance. This study indicates that there are baseline differences in the rewarding threshold in the two groups, that morphine lowers the threshold in young and aged animals and that the hedonic effects produced by morphine, for the most, part remain preserved in aged animals.

Sp and GATA factors are critical for Apolipoprotein AI downstream enhancer activity in human HepG2 cells.

The factors that bind to the hepatic-specific human apolipoprotein AI (apoAI) 48-bp downstream enhancer (DSE) were identified and characterized by electrophoretic mobility shift assays. A significant homology was shown between the histone 4 (H4) promoters and the hepatic-specific human apoAI DSE at Sp1 and H4TF2 binding sites. Human HepG2 nuclear extracts were used to form four specific complexes with the DSE (referred to as apoAI DSE-1, -2, -3, and -4). The apoAI DSE-1 and -2 complexes showed similar binding specificity to the Sp/H4TF1 consensus site within the apoAI DSE. The apoAI DSE-1 complex was predominantly recognized by anti-Sp1 and Sp3 sera in gel shift assays, indicating that the DSE was recognized by multiple Sp family members. Nuclear extracts that were prepared from retinoic acid treated HepG2 cells showed increased levels of Sp factors in gel shift and Western blot assays. The apoAI DSE-2 complex was identified as H4TF1 and formed in the absence of magnesium chloride. The apoAI DSE-3 complex bound to a consensus GATA element within the DSE that was recognized by recombinant human GATA-6 as well. The apoAI DSE-3 complex was completely disrupted by a GATA-4 antibody in EMSA. GATA-4 and -6 were detected in nuclear extracts prepared from retinoic acid treated HepG2 cells using Western blot assays. The highest apoAI DSE-3 levels were observed with retinoic acid treated HepG2 cell nuclear extracts in EMSA. ApoAI DSE-4 is a multi-factor complex that includes an Sp/H4TF1 factor and either H4TF2 or apoAI DSE-3. Because apoAI DSE mutations revealed transcription defects in transient transfection assays, we conclude that the entire DSE sequence is required for full apoAI transcriptional activity in HepG2 cells.

Dapsone-induced acute pancreatitis.

OBJECTIVE: To report a case of acute pancreatitis associated with dapsone use. CASE SUMMARY: An 87-year-old white man was prescribed dapsone for dermatitis herpetiformis. Four weeks later, he developed acute abdominal pain requiring hospitalization. The patient had elevated serum amylase and lipase levels. Laboratory test results for other possible etiologies were negative. His symptoms resolved when dapsone was discontinued. Dapsone was reintroduced for exacerbation of dermatitis herpetiformis 4 months later. The patient again had severe abdominal pain with high amylase and lipase levels. Again, symptoms resolved following dapsone discontinuation. DISCUSSION: Only 1 other case of pancreatitis associated with dapsone was found in a MEDLINE search of the literature (1966-June 2003) using the key terms dapsone and pancreatitis. An objective causality assessment revealed dapsone to be a probable cause of acute pancreatitis, based on the Naranjo probability scale. Drugs should always be considered as causative factors for pancreatitis in patients without known risk factors. Dapsone is increasingly used as a second line of treatment of Pneumocystis carinii pneumonia (PCP). The recognition of dapsone-induced pancreatitis is of particular importance in these patients. CONCLUSIONS: While dapsone is traditionally used for the treatment of leprosy and dermatitis herpetiformis, its use for PCP prophylaxis, malaria, brown recluse spider bites, and acne is not uncommon. Pancreatitis is an uncommon adverse effect of dapsone, and greater awareness of this association will prompt a high index of suspicion in an appropriate clinical setting. Further reporting of cases and clinical research of drug-induced pancreatitis is indicated.