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Biomedical subjects

D Paul

Publications and source records attributed to D Paul.

At least 109 records · Page 6Linked to original sources
PubMed1992

Evidence of hyperglycemic hyperalgesia by quinpirole.

Male albino rats were tested for antinociception following injections (IP) with saline, quinpirole (Quin) (1 mg/kg), morphine sulfate (M.S.) (5 mg/kg), or both Quin and M.S. (1 mg/kg and 5 mg/kg, respectively). Quin reduced and M.S. increased tail-flick latency as compared to controls. Tail-flick latencies of the animals injected with both drugs were significantly reduced as compared M.S. alone. Quin increased blood glucose levels by 96 percent, as compared to saline controls. In competitive binding studies Quin displaced 3H-DAGO (IC50 = 29.8 microM). CD-1 mice demonstrated a naloxone-reversible analgesia following ICV Quin (100 micrograms). These data are consistent with the hypothesis that the hyperglycemic effects of Quin attenuate M.S. analgesia while the antinociceptive effects of Quin may be mediated through opioid receptors.

Animals↗
PubMed1992

Ion channels in single bilayers induced by rat connexin32.

The gap junction channel mediates an important form of intercellular communication, but its detailed study is hindered by inaccessibility in situ. We show here that connexin32, the major protein composing junctional channels in rat liver, forms ion channels in single bilayer membranes. The properties of these reconstituted connexin32 channels are characterized and compared with those of gap junction channels. The demonstration that connexin32 forms channels in single membranes has implications for assembly and regulation of junctional channels, and permits detailed study of the gating, permeability and modulation of this channel-forming protein.

Animals↗
PubMed1992

Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines.

Subtractive hybridization, selecting for mRNAs expressed in normal human mammary epithelial cells (NMECs) but not in mammary tumor cell lines (TMECs), led to the cloning of the human gap junction gene connexin 26 (Cx26), identified by its sequence similarity to the rat gene. Two Cx26 transcripts derived from a single gene are expressed in NMECs but neither is expressed in a series of TMECs. Northern analysis using rat Cx probes showed that Cx43 mRNA is also expressed in the normal cells, but not in the tumor lines examined. Connexin genes Cx31.1, Cx32, Cx33, Cx37, and Cx40 are not expressed in either normal cells or the tumor lines examined. In cell-cell communication studies, the normal cells transferred Lucifer yellow, while tumor cells failed to show dye transfer. Both Cx26 and Cx43 proteins were immunolocalized to membrane sites in normal cells but were not found in tumor cells. Further analysis demonstrated that Cx26 is a cell-cycle regulated gene expressed at a moderate level during G1 and S, and strongly up-regulated in late S and G2, as shown with lovastatin-synchronized NMECs. Cx43, on the contrary is constitutively expressed at a uniform low level throughout the cell cycle. Treatment of normal and tumor cells with a series of drugs: 5dB-cAMP, retinoic acid, okadaic acid, estradiol, or TGFb had no connexin-inducing effect in tumor cells. However, PMA induced re-expression of the two Cx26 transcripts but not of Cx43 in several TMECs. Thus Cx26 and Cx43 are both downregulated in tumor cells but respond differentially to some signals. Modulation of gap-junctional activity by drug therapy may have useful clinical applications in cancer.

Amino Acid Sequence↗
PubMed1992

Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice.

Nalbuphine is a mixed opioid agonist/antagonist analgesic. It labels mu receptors most potently where it acts as an antagonist. Nalbuphine is analgesic in the tail-flick assay after systemic (ED50, 41.8 mg/kg s.c.), i.c.v. (ED50, 21.3 micrograms) or intrathecal administration (ED50, 11.2 micrograms). Analgesia elicited by systemic nalbuphine was reversed by nor-binaltorphimine, but not by beta-funaltrexamine or naltrindole despite their ability to antagonize morphine and [D-Pen2,D-Pen5]enkephalin analgesia, respectively. This insensitivity toward beta-funaltrexamine and naltrindole argued strongly against either a mu or delta component of analgesia. Nor-binaltorphimine antagonized systemic nalbuphine analgesia over 10-fold more potently after intrathecal injection of the antagonist than after i.c.v. administration, implying a role for kappa 1 receptors at the spinal level. The presence of analgesic cross-tolerance between nalbuphine and both naloxone benzoylhydrazone and nalorphine indicated an analgesic role for kappa 3 receptors, which act supraspinally. Additional studies revealed synergistic interactions between spinal kappa 1 and supraspinal kappa 3 receptors when nalbuphine was given both intrathecally and i.c.v. In conclusion, these studies suggest that nalbuphine elicits analgesia through a complex interaction of supraspinal kappa 3 and spinal kappa 1 mechanisms.

Analgesia↗
PubMed1991

Genetic influences in opioid analgesic sensitivity in mice.

Studies of various strains of mice revealed marked differences in their analgesic sensitivity towards morphine (mu), U50,488H (kappa 1) and naloxone benzoylhydrazone (NalBzoH; kappa 3). Sensitivity to mu and kappa analgesia varied independently of the other. Analgesic sensitivity to morphine remained relatively consistent among 3 different nociceptive assays for each strain. However, the sensitivity of an individual strain to NalBzoH remained highly dependent upon the assay used. CD-1 mice were sensitive to NalBzoH in all 3 assays, but in BALB/c mice NalBzoH produced analgesia only in the hot plate and cold water tail-flick assays. In Swiss-Webster mice, NalBzoH was active in the radiant heat and cold water tail-flicks but inactive in the hot plate. Although the levels of mu, kappa 1 and kappa 3 binding in whole brain homogenates did vary somewhat, they did not correlate with analgesic sensitivity. These results suggests that the genetic controls over mu and kappa analgesia operate independently and further illustrate the many difficulties in evaluating potential analgesics.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus.

Opiates modulate pain perception at a number of different levels within the central nervous system and the importance of synergistic spinal and supraspinal influences have been well documented. In the present study we demonstrate synergistic interactions between the periaqueductal gray and locus coeruleus. Administered either systemically or intracerebroventricularly (i.c.v.), ethylketocyclazocine elicits a potent naloxonazine-sensitive analgesia, indicating a mu 1 action. mu 1 Receptors also play a major role in opioid analgesic mechanisms in the periaqueductal gray and the locus coeruleus. However, microinjection of EKC into either the periaqueductal gray or locus coeruleus failed to elicit an analgesic response at any dose tested (0.1-20 micrograms) and, in additional studies, antagonized the analgesic actions of coadministered morphine or [D-Ser2,Leu5]enkephalin-Thr6 (DSLET). However, the simultaneous administration of EKC into both the periaqueductal gray (10 micrograms) and the locus coeruleus (10 micrograms; total combined dose 20 micrograms) produced a potent naloxonazine-sensitive analgesia greater than that observed with 50 micrograms i.c.v. These results suggest that EKC is a partial mu 1 agonist which lacks the efficacy to elicit analgesia when microinjected into either of the two brain regions alone. However, when exposed to several regions at once, either through simultaneous microinjections into the periaqueductal gray and locus coeruleus or by injection into the ventricle, EKC is a potent mu 1 analgesic. These results point out the existence of synergistic supraspinal interactions between the periaqueductal gray and the locus coeruleus, similar to the spinal/supraspinal interactions observed previously.

Analgesics↗
PubMed1991

Comparison of naloxonazine and beta-funaltrexamine antagonism of mu 1 and mu 2 opioid actions.

beta-Funaltrexamine (beta-FNA) irreversibly blocks morphine analgesia, lethality and its inhibition of gastrointestinal transit, confirming that these actions involve mu receptors. In dose-response studies, beta-FNA antagonized all the actions with similar potencies (ID50 values of 12.1, 11.3 and 12.3 mg/kg, respectively). beta-FNA also reduced intra-cerebroventricular and intrathecal DAMGO analgesia equally well (ID50 values of 6.09 and 7.7 mg/kg, respectively). Naloxanazine blocked systemic morphine analgesia (ID50 value 9.5 mg/kg) and supraspinal DAMGO analgesia (ID50 value 6.1 mg/kg) as potently as beta-FNA. However, against spinal DAMGO analgesia, morphine's inhibition of gastro-intestinal transit or lethality, naloxonazine (ID50 values 38.8, 40.7 and 40.9 mg/kg, respectively) was significantly less active than beta-FNA (p less than 0.05). beta-FNA remains a valuable tool in the classification of mu opioid actions. Within the mu category, actions can be defined as either mu 1 (naloxonazine-sensitive) or mu 2 (naloxonazine-insensitive).

Animals↗
PubMed1991

Microclones derived from the mouse chromosome 7 D-E bands map within the proximal region of the c14CoS deletion in albino mutant mice.

A group of radiation-induced perinatal-lethal deletions that include the albino (c) locus on mouse chromosome 7 causes failure of expression of various hepatocyte-specific genes when homozygous (S. Gluecksohn-Waelsch, 1979, Cell 16:225-237). The transcription of such genes could be controlled in trans by a regulatory gene(s) located within the proximal region of the C14CoS deletion. To identify this potential regulatory gene, a microclone library was established from microdissected D and E bands of chromosome 7. Three nonoverlapping microclones (E305, E336B, and E453B) hybridizing with wildtype but not with C14CoS/C14CoS DNA were isolated. E336B represents a single-copy DNA fragment, whereas E305 and E453B hybridized with 3 and 10 EcoRI DNA restriction fragments, respectively. All fragments map exclusively within the deletion. The microclones hybridized to DNA of viable C6H/C14CoS deletion heterozygotes but not to DNA of homozygotes for the lethal mutation c10R75M, which belongs to the same complementation group as c14CoS. DNA of viable homozygous mutant C62DSD, which carries a deletion breakpoint proximal to that of c6H, hybridized only with E453B. This microclone identified 6 EcoRI restriction fragments in C62DSD/C62DSD DNA. The results demonstrate that of the isolated microclones, E453B identifies a locus (D7RT453B) that maps closest to the hsdr-1 (hepatocyte-specific developmental regulation) locus (S. Gluecksohn-Waelsch, 1989, Mouse Newslett. 83: 149), which maps between the proximal breakpoints of deletions c10R75M and c62DSD.

Albinism↗
PubMed1991

Induction of chromosome aberrations and sister chromatid exchange by indirectly acting mutagens in immortal mouse and rat hepatocyte lines.

Two immortalized, differentiated mouse (FMH-202) and rat (NRL-Cl-A) hepatocyte lines were examined for their capacity to activate the indirectly acting mutagens aflatoxin B1 (AFB1), cyclophosphamide (CP), benzo[a]pyrene (BaP) and 7,12-dimethylbenz[a]anthracene (DMBA) into DNA reactive metabolites as determined by the induction of structural chromosome aberrations (CA) and sister chromatid exchange (SCE). The rat and mouse hepatocyte lines were able to efficiently activate either AFB1, BaP and DMBA, or BaP and DMBA, respectively, as shown by significant clastogenic responses. SCE induction was apparent in both cell lines in response to each of the compounds. Due to the observed long-term maintenance of various liver specific functions (at least 3-4 years) as well as the capability to metabolize xenobiotics (at least 30 passages) these cells may be a suitable assay system for the detection of indirectly acting mutagens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Assessment of knowledge and skills about growth monitoring amongst child development project officers.

Knowledge and skills about growth monitoring (GM) amongst Child Development Project Officers (CDPOs) were assessed by interview technique. Majority (94%) of subjects had correct knowledge that GM helps in early detection of growth retardation while about 83% felt that a flattened growth curve indicates no weight gain. The percentages of CDPOs who were able to interpret and read correctly about what ascending descending and flattened growth curves indicate were 83, 71 and 50% respectively. There is thus a need of in-service training of CDPOs in GM activities.

Child Health Services↗
PubMed1991

Pharmacological characterization of nalorphine, a kappa 3 analgesic.

Nalorphine is an unusual opiate. Whereas low doses of nalorphine antagonize morphine analgesia, higher nalorphine doses are analgesic, with ED50 values (95% CL) of 13.4 (11.5, 15.8) mg/kg in the writhing and 39.5 (26.6, 60.1) mg/kg in the tail-flick assay. Although nalorphine analgesia is sensitive to naloxone, implying an opioid mechanism, neither beta-funaltrexamine, naltrindole nor nor-binaltorphomine antagonized nalorphine analgesia in the tail-flick assay at doses which reversed equianalgesic doses of their respective selective agonists. Nalorphine and the kappa 3 opiate naloxone benzoylhydrazone demonstrated analgesic cross-tolerance regardless of whether the mice were treated chronically with either nalorphine or naloxone benzoylhydrazone. Animals tolerant to nalorphine were not tolerant to either morphine or U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(pyrrolindinyl)-cyclohexyl]- benzeneacetamide). Furthermore, nalorphine retained its analgesic potency in animals tolerant to U50,488H. Nalorphine exerts its analgesia predominantly through supraspinal mechanisms. Against systemically administered nalorphine, the opiate antagonist WIN44,441 ([2,6,11S-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6, 11-trimethyl-2,6-methano-e-benazocine-11-yl)-3-pentanone methylsulfonate) reversed nalorphine analgesia 1500-fold more potently when administered i.c.v. (ID50, 0.1 ng) than when given intrathecally (ID50,159 ng). Together these results indicate that nalorphine analgesia in the tail-flick assay does not involve mu, delta or the U50,488H-sensitive kappa 1 receptor and strongly suggest a role for supraspinal kappa 3 receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Blockade of morphine analgesia by both pertussis and cholera toxins in the periaqueductal gray and locus coeruleus.

Rats demonstrating analgesia following microinjection of morphine into the periaqueductal gray (PAG) or locus coeruleus (LC) were injected with either pertussis toxin, cholera toxin or saline into the same brain region. Both pertussis and cholera toxin blocked the analgesic effect of morphine at both injection sites for up to 7 days after toxin treatment. These results indicate that morphine analgesia is a complex response involving systems dependent upon Gs as well as Gi or Go proteins.

Analgesia↗
PubMed1990

Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA.

Persistent infection by hepatitis B virus (HBV) is epidemiologically correlated with the prevalence of hepatocellular carcinoma, but its role in tumor development is not yet understood. To study the putative oncogenic potential of HBV, a non-malignant immortal mouse hepatocyte line FMH202 harboring metallothionein promoter-driven simian virus 40 large tumor antigen was transfected with HBV DNA. All stably transfected clones which replicated HBV displayed malignant growth characteristics in soft agar and were tumorigenic upon inoculation in nude mice. The nude mice tumors were histologically classified as differentiated or anaplastic hepatocellular carcinomas. As with human liver carcinomas, rearrangements of in vitro integrated HBV sequences were observed in the nude mouse tumors, and in tumor-derived cell lines. In one case, expression of viral core and surface antigens was blocked in the tumors, correlating with hypermethylation of the HBV genome. However, the expression of X gene was maintained in most tumors and tumor-derived cell lines. X protein was detected in nuclei by immune fluorescence and by immune blot. These results provide the first demonstration that HBV displays oncogenic potential in an experimental system. This system could be useful to functionally identify HBV genes which convey a tumorigenic phenotype.

Animals↗
PubMed1990

Basic fibroblast growth factor and transforming growth factor-alpha are hepatotrophic mitogens in vitro.

Basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF alpha) have been identified as potent hepatotrophic mitogens. bFGF and TGF alpha induce DNA synthesis in fetal and adult rat hepatocytes in primary culture and support fetal rat hepatocyte multiplication in chemically defined medium. No additional exogenous growth or progression factors are required by the cells for traversing the cell cycle or for cell division. These mitogenic polypeptides, previously identified in various cell types including liver and endothelial cells, platelets, and macrophages may act locally in a paracrine mode in controlling hepatocyte multiplication in the liver during development and regeneration.

Animals↗
PubMed1990

Precocious induction of tyrosine aminotransferase mRNA by hydrocortisone in cultured fetal rat hepatocytes at different developmental stages.

Tyrosine-aminotransferase (TAT) is encoded by a liver-specific gene known to be expressed perinatally. Fetal rat hepatocytes (gestation day 19) in primary cultures, in which TAT gene expression is normally undetectable, are induced by hydrocortisone to express TAT-mRNA in a dose-dependent manner (greater than 10(-7) M). In hepatocytes incubated with hydrocortisone, TAT-mRNA levels were marginal after 24 hours, reaching maximal levels at 48 hours. After a pre-incubation of hepatocytes for 24 hours in the absence of hydrocortisone followed by exposure to hydrocortisone (24-48 hours). TAT-mRNA levels were high. Hepatocytes derived from fetuses of gestation days 14 and 17 displayed comparable levels of TAT-mRNA in response to hydrocortisone. These results demonstrate that cultured hepatocytes of gestational stages as early as day 14, which initially do not respond to hydrocortisone by TAT gene induction, undergo a "maturation" process during the initial 24 hours following cultivation, resulting in the acquisition of precocious competence for TAT gene transcription in response to hydrocortisone. This suggests that one or more factor(s), required for hydrocortisone-inducible TAT gene transcription, and not available in fetal liver until birth (Gluecksohn-Waelsch: Cell, 18:225-237, 1979) appear in fetal hepatocytes upon cultivation during this "maturation" period, thus permitting precocious TAT gene expression in vitro.

Animals↗
PubMed1990

Pirenperone does not attenuate morphine analgesia in spinal rats.

The selective serotonin type-2 (S2) receptor blocker pirenperone (0.24 mg/kg, SC) attenuates morphine-produced tail-flick antinociception in intact rats, but not in rats with transected spinal cords. These results suggest that S2 receptor blockade does not affect intraspinal opioid antinociception. Together with evidence that there are virtually no S2 receptors in the dorsal spinal cord, supraspinal S2 receptors are implicated in the mediation of morphine-produced antinociception.

Analgesics↗