Kappa 3 receptors and levorphanol-induced analgesia.

Levorphanol is a widely used opiate analgesic. Although structurally related to morphine, levorphanol has high affinity for a number of receptor subtypes, including both kappa 1 and kappa 3. Prior reports had implicated a kappa component of levorphanol-induced antinociception. Evidence is now presented suggesting that levorphanol-induced analgesia is produced by a mixture of mu and kappa 3 mechanisms. Levorphanol was a potent analgesic in the tail-flick assay, when given systemically, spinally or supraspinally. Isobolographic analysis of the combined administration of levorphanol, spinally and supraspinally implied synergistic interactions. Naloxonazine reduced levorphanol-induced analgesia, implicating a role for mu1 receptors. The kappa 1 antagonist nor-binaltorphimine at a dose which reversed analgesia induced by U50,488H did not antagonize levorphanol-induced analgesia. Additional studies revealed no cross tolerance in either direction, between levorphanol with the kappa 1 analgesic U50,488H. Together, these results strongly argue against a role for kappa 1 receptors in levorphanol-induced analgesia. However, mice tolerant to the kappa 3 analgesic, naloxone benzoylhydrazone (NalBzoH), showed cross tolerance to levorphanol, implying a role of kappa 3 mechanisms in levorphanol-induced analgesia.     

Increased sensitivity of virus-infected cells to inhibitors of protein synthesis does not correlate with changes in plasma membrane permeability

Semliki Forest virus-infected BHK cells or herpes simplex virus-infected Vero cells were incubated with the protein synthesis inhibitors hygromycin B and gougerotin. Infected cells take up no more [3H]hygromycin or [3H]gougerotin than do mock-infected cells, at a time p.i. at which either compound is more inhibitory to protein synthesis in infected, than in mock-infected cells. The concentrations of hygromycin and gougerotin required to inhibit protein synthesis in intact cells (irrespective of whether they are infected or not) are several orders of magnitude higher than those required in either permeabilized cells or in cell-free systems. Infected cells take up 86Rb+ at the same rate as mock-infected cells, their intracellular content of K+ is the same, and the activity of the Na+ pump is the same. It is concluded that the increased efficacy of hygromycin and gougerotin in virus-infected cells is a consequence of altered intracellular compartmentation and that increases in permeability of the plasma membrane, if any, are so small as to be undetectable by direct methods.     

A statistically significant sex difference in the number of colony-forming cells from human peripheral blood

 The number of colony-forming cells (CFC) in the peripheral blood (PB) of 43 volunteers was examined using a semisolid clonogenic culture assay. In all, 22 male (age 21–39 years) and 21 female individuals (age 21–39 years) were tested, ten of each group twice to examine the intraindividual variability of colony-forming cells in PB. A statistically significant sex difference in the number of CFC, erythroblastic colonies (BFU-E), and granulocyte/macrophage colonies (CFU-GM) in PB was detected in favor of male individuals. No significant difference between female and male PB was found for the number of CFU-GEMM. The intraindividual variability of CFC and BFU-E was significantly higher in female donors. These results support previous reports by others on a potential influence of sex steroids on hematopoiesis. Received: 8 November 1996 / Accepted: 4 April 1997     

An interactive course to enhance self-efficacy of family practitioners to treat obesity

Background  

Physicians' awareness of their important role in defusing the obesity epidemic has increased. However, the number of family practitioners who treat obesity problems continues to be low. Self-efficacy refers to the belief in one's ability to organize and execute the courses of action required to produce given attainments. Thus, practitioners who judge themselves incapable of managing obesity do not even try. We hypothesized that practitioners' self-efficacy and motivation would be enhanced as a result of participating in an interactive course designed to enrich their knowledge of obesity management.     

Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs

Many peptides and transmitters found within the brain also have peripheral sites of action. We now demonstrate that the brain releases functionally active neurotransmitters/neuromodulators directly from the brain into the blood through a saturable P-glycoprotein (Pgp) transport system. Downregulating Pgp1 expression with antisense reduced the brain-to-blood transport of morphine, beta-endorphin and other opioids. Lowering Pgp expression significantly enhanced systemic morphine analgesia and prevented tolerance, but diminished the analgesic activity of centrally administered morphine, implying that supraspinal analgesia resulted from a combination of central and peripheral mechanisms activated by morphine transported from the brain to the blood. Similarly, mice with a disruption of the Mdr1a gene were more sensitive to systemic morphine and less sensitive to morphine given centrally. This ability of the Pgp transport system to pump functionally active compounds from the brain to periphery defines a potentially important mechanism for the central nervous system to modulate peripheral systems.     

Disease modifying activity of HWA 486 in rat adjuvant-induced arthritis

HWA 486 was investigated for its ability to modify the development of adjuvant-induced polyarthritis in Lewis rats. HWA 486 (20 mg/kg/day p.o.), dosed for 8 or 16 days beginning with the day of adjuvant administration, significantly reduced edema, fibrinogen levels, and erythrocyte sedimentation rates (ESR) 42 days later. When HWA 486 (20 mg/kg/day, p.o.) and cyclosporin A (CsA 15 mg/kg/day, p.o.) were tested in the 8-day treatment regimen, the antiarthritic effects of HWA 486 were more sustained. Both compounds reduced the delayed hypersensitivity (DTH) response on day 9 followed by a rebound to an enhanced DTH response on day 21. The PHA-induced mitogenic response of splenocytes from arthritic rats was suppressed on day 9. Treatment with HWA 486 but not CsA restored the splenocyte response to the level of the negative controls.     

Cost effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction.

BACKGROUND. There is a lack of consensus among cardiologists about the potential benefit of thrombolytic therapy for suspected acute myocardial infarction in older patients. To investigate this issue, we constructed a decision-analytic model for patients 75 years of age or older who present with ST-segment elevation within six hours of the onset of symptoms suggesting acute myocardial infarction. METHODS. The variables incorporated in this model were the probability that the patient has an acute myocardial infarction, the probability of in-hospital death among patients with acute myocardial infarction who do not receive thrombolytic therapy, the probability of a fatal or incapacitating complication resulting from thrombolytic therapy, and the expected relative reduction in the risk of death associated with thrombolytic therapy in patients with acute myocardial infarction. Our analyses were based primarily on the use of streptokinase as the thrombolytic agent. RESULTS. Given our base-line assumptions, the probability of dying in the hospital was 21.4 percent if thrombolytic therapy was given and 24.4 percent if it was not given. In one-way sensitivity analyses, thrombolytic therapy decreased the risk of dying if the probability that the patient had an acute myocardial infarction was assumed to be greater than 9 percent, if the probability of dying in the hospital after an acute myocardial infarction without thrombolytic therapy was assumed to be greater than 3 percent, if the rate of fatal or incapacitating complications due to thrombolytic therapy was assumed to be 4 percent or less, or if the relative reduction in the risk of death associated with thrombolytic therapy was assumed to be greater than 1 percent. On the basis of our base-line assumptions, our estimate of the cost effectiveness of streptokinase therapy (the cost per year of life saved) for an 80-year-old patient with suspected acute myocardial infarction was $21,200. For a wide range of assumptions about risks, benefits, and costs, the cost per year of life saved remained less than $55,000. CONCLUSIONS. Within the limitations imposed by the assumptions used in our analysis, thrombolytic therapy with streptokinase was found to be a beneficial and cost-effective treatment for suspected acute myocardial infarction in elderly patients in a wide variety of clinical circumstances.     

Mu 1 opioid receptor involvement in maternal behavior

Previous studies have demonstrated that morphine inhibits the display of maternal behavior in lactating rats. Whether morphine exerts its actions specifically at the mu receptor has not yet been determined. The present study examined this possibility by evaluating whether naloxonazine, an irreversible and selective antagonist of the mu 1 opioid receptor subtype, is able to attenuate morphine's disruptive effect on maternal behavior in primiparous lactating rats. Experiment 1 compared the ability of naloxonazine (AZINE) and naloxone (NAL) to block the action of morphine (MOR) on maternal care. Virgin, Sprague-Dawley rats were mated in our colony and on day 3 postpartum (parturition, day 0) all rats received jugular catheters. On day 6 the mothers received one of the following treatments: MOR alone (10 mg/kg, SC, N = 10); MOR (10 mg/kg, SC) 24 hr after AZINE pretreatment (10 mg/kg, IV, N = 10); MOR (10 mg/kg, SC) 24 hr after NAL pretreatment (10 mg/kg, IV, N = 8); or MOR (10 mg/kg, SC) immediately after NAL (0.5 mg/kg, SC, N = 10). MOR alone completely disrupted maternal behavior (0% responded) which was blocked by prior NAL administration (100%). AZINE pretreatment 24 hr earlier partially blocked MOR disruption of MB (40% responded; significantly different from MOR alone). The response of rats pretreated 24 hr earlier with NAL did not differ from MOR alone. AZINE blocked MOR's effect on pup retrieval to an even greater degree (70% responded vs. 10% in MOR alone). Experiment 2 determined the ability of AZINE to interfere with varying doses of MOR on maternal behavior.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of gambling disorders in a primary care setting

BACKGROUND: Pathologic gambling prevalence seems to be increasing as opportunities for gambling increase. Prevalence may be different in a primary care setting compared with population-based studies. OBJECTIVES: To determine the gambling disorder prevalence in a primary care setting and to investigate associations between gambling disorders and proximity to a casino, substance abuse, health ratings, age, sex, and socioeconomic status. DESIGN: Cross-sectional survey of 1394 patients presenting to their primary care physicians between November 1, 1997, and April 1, 1998. SETTING: Three primary care clinics in Wisconsin. PATIENTS: Adults aged 18 years and older. MAIN OUTCOME MEASURES: Gambling disorders, defined by scores of 3 or greater on the South Oaks Gambling Screen (SOGS), and information about drug use (alcohol, tobacco, and marijuana), overall health, specific health symptoms, age, sex, race, and socioeconomic status. RESULTS: A total of 1051 patients completed the survey. More than 80.0% of the patients had gambled, and 6.2% met the criteria for gambling disorders. Gambling disorders were more prevalent in men, nonwhites, and patients from lower socioeconomic groups. Patients with gambling disorders were more likely to use tobacco and abuse alcohol compared with nonproblem gamblers. No relation was seen between marijuana use and gambling disorders. Patients with gambling disorders rated their health more poorly and reported more severe symptoms of heartburn and backache. CONCLUSIONS: A considerable percentage of patients presenting to primary care clinics are affected by their need to gamble. There is significant comorbidity with tobacco use and alcohol abuse. Primary care physicians should consider asking about gambling habits in high-risk patients.     

Antisense mapping KOR-1: evidence for multiple kappa analgesic mechanisms

In binding assays, both dynorphin B and alpha-neoendorphin are relatively selective for the kappa1b site, unlike U50,488H which has high affinity for both kappa1a and kappa1b sites. In vivo, U50,488H, dynorphin B and alpha-neoendorphin analgesia are reversed by the kappa1-selective antagonist, nor-binaltorphimine (norBNI). Antisense mapping the three exons of KOR-1 revealed that probes targeting all three exons blocked U50,488H analgesia, as expected. However, the selectivity profile of dynorphin B and alpha-neoendorphin analgesia towards the various antisense oligodeoxynucleotides differed markedly from U50,488H, implying a different receptor mechanism of action.