Receptors in the dorsal horn and intrathecal drug administration.
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Animals↗
Biomedical subjects
C W Stevens
Publications and source records attributed to C W Stevens.
Partially transformed, anchorage-independent human diploid fibroblasts result from overexpression of the c-sis oncogene: mitogenic activity of an apparent monomeric platelet-derived growth factor 2 species.
A human c-sis cDNA in an expression vector was introduced into human diploid fibroblasts by transfection or electroporation. Fibroblast clones showing an aberrant, densely packed colony morphology were isolated and found to overexpress a 3.6-kilobase sis mRNA species and associated immunoprecipitable platelet-derived growth factor (PDGF) 2 proteins. Parallel analyses in cell clones of sis mRNA expression and colony formation in agar indicated that, above a threshold, a linear, positive correlation existed between sis overexpression and acquired anchorage independence. The sis-overexpressing cells formed transient, regressing tumor nodules when injected into nude mice, consistent with the finite life span which they retained. Protein products generated from the transfected c-sis construct in two overexpressing clones were immunoprecipitated with anti-human PDGF antibodies. One clone contained an apparent PDGF dimer of 21 kilodaltons; the second clone contained only an apparent PDGF monomer of 12 kilodaltons, which was shown to account for all of the mitogenic activity present in the cells, essentially all of which was concentrated in the membrane fraction. The results demonstrate a clear link between sis overexpression and acquisition of a partially transformed, anchorage-independent phenotype, and when combined with previous observations of sis overexpression in human tumors, clearly implicate sis overexpression as a genetic mechanism which contributes to human cell transformation.
Cell Adhesion↗
Spinal infusion of opiate and alpha-2 agonists in rats: tolerance and cross-tolerance studies.
Intrathecal morphine or ST-91, an alpha-2 agonist, produce potent antinociception in a number of animal models. Using osmotic minipumps and a new Y-catheter technique, we show that chronic intrathecal (i.t.) infusion of morphine (2, 6 or 20 nmol/microliter/hr) or ST-91 (3, 10 or 30 nmol/microliter/hr) in rats produces a dose-dependent increase in hot-plate latency 1 day after pump implant. By 4 to 5 days after initiation of chronic infusion of either drug, hot-plate latencies do not differ from saline-infused controls. Rats rendered tolerant to one of the three chronic i.t. morphine doses (2, 6 or 20 nmol/microliter/hr) and tested at 7 days after initiation of infusion with a bolus i.t. dose of morphine, show a dose-dependent rightward shift in hot-plate dose-response curves. The two lower doses of chronic i.t. infusions of morphine produce parallel shifts of the subsequent i.t. administered morphine dose-response curves, but the highest chronic i.t. dose of morphine (20 nmol/microliter/hr) produces a significantly greater slope of the subsequent i.t. administered morphine dose-response curve. Animals exposed to chronic i.t. infusion of one of three doses of ST-91 (3, 10 or 30 nmol/microliter/hr) display a parallel, dose-dependent rightward shift to a subsequent bolus i.t. injection of ST-91. Rats rendered tolerant to chronic i.t. infusions of ST-91 showed no difference in the response to i.t. administered morphine hot-plate dose-response curves as compared to saline infused controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Primary invasive carcinoma of the vagina.
A retrospective study of 29 patients with invasive carcinoma of the vagina was completed at The Milton S. Hershey Medical Center, Pennsylvania State University, for a ten-year period from 1976-1986. The overall incidence was 1.3% of all gynecologic malignancies. Twenty-four patients (83%) had squamous cell carcinoma and five (17%) had adenocarcinoma. Squamous cell carcinoma was most commonly located in the upper anterior and lateral vaginal vaults, whereas adenocarcinoma was found more often in the lower anterior and lateral vaginal vaults. The majority of the patients (96%) were managed by a combination of whole-pelvis irradiation and brachytherapy. Twenty-four percent of the patients had a recurrence in the vagina only, indicating the need for better local control. The overall survival rate was 48%. Patients with previous hysterectomy were more likely to develop serious treatment-related complications.
Adenocarcinoma↗
Chronic antagonist infusion does not increase morphine antinociception in rat spinal cord.
Chronic spinal infusion of the opiate antagonists naloxone or naltrexone fail to influence the antinociceptive effect of subsequent intrathecal morphine on the hot plate test in rats compared to saline-infused controls. These results contrast the functional supersensitivity to morphine seen after long-term systemic opiate antagonist administration and support the hypothesis that dopaminergic interactions, lacking in the spinal cord, are necessary for antagonist-induced opioid receptor upregulation.
Animals↗
Intrathecal dynorphins suppress hindlimb electromyographic activity in rats.
Intrathecal administration of dynorphin A-(1-17) produced suppression of hindlimb electromyographic activity in rats. This effect was seen also with the [D-Ala2]dynorphin (A-(1-17) analog. Intrathecal saline or the prototypical kappa opiate agonist, U50488, did not produce any change in electromyographic activity. These results, along with others, suggest that dynorphin or degradation fragment(s) of dynorphin, induces inhibition of ventral horn output and may possibly have toxic effects on ventral horn cells of the spinal cord.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Spinal antinociceptive action of three representative opioid peptides in frogs.
Spinal administration of low doses of dynorphin, beta-endorphin or Met-enkephalin produces a potent, dose-dependent increase in the nociceptive threshold in the unanesthetized frog, Rana pipiens. Nociceptive thresholds were determined by using the acetic acid test, previously shown to be a sensitive indicator of antinociception in this amphibian species. Of particular interest, spinally administered dynorphin produces a potent antinociception in frogs without any signs of motor dysfunction seen after spinally administered dynorphin in mammalian species.
Analgesics↗
Use of second-look laparotomy in the management of patients with ovarian epithelial malignancies.
Between June 1976 and January 1986, 94 evaluable patients with stage I-IV disease underwent second-look laparotomy as part of their treatment for ovarian epithelial carcinomas. Stage and residual tumor size after initial debulking surgery demonstrated a significant association with absence of disease at reexploration. Forty-nine patients (52%) had no evidence of disease at second-look laparotomy. Thirty patients (32%) had macroscopic residual tumor, and 15 patients (16%) had microscopic disease at reexploration. Patients with a negative second-look laparotomy had an excellent prognosis; uncorrected 2- and 5-year survival rates exceed 90%. None of the patients with stage I or II disease developed recurrent tumor after a negative second-look laparotomy. However, 7 of the 25 (28%) patients with stage III disease and a negative second-look have demonstrated recurrent carcinomas. Recurrences were documented from 15.4 to 51.7 months after second-look laparotomy and were located within the abdominal cavity. Life table methods demonstrated improved survival for patients with microscopic disease as compared to those with gross tumor at second-look survey. Both groups had similar mean patient ages and tumor stage distributions. Patients with microscopic residual disease had uncorrected 2- and 5-year survival rates of 76 and 64%. The 2-year uncorrected survival rate for patients with gross tumor at second-look laparotomy was 25%. Thirty patients with macroscopic disease at second-look laparotomy underwent a repeat attempt at tumor debulking. Seventeen patients completed second-look surgery with residual disease less than 1 cm in maximum dimensions. Life table methods demonstrated improved survival when residual disease was less than 1 cm. Regardless of residual tumor size after reexploration, patients with gross tumor had a worse survival than those with microscopic disease.
Adult↗
Issues in drug management. Part 2. The use of receptor-selective agents as analgesics in the spinal cord: trends and possibilities.
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Analgesics↗
Spinal action of dermorphin, an extremely potent opioid peptide from frog skin.
Studies on the characteristics of spinally administered dermorphin, a novel heptapeptide isolated from the skin of South American Phyllomedusa frogs, indicated that this agent is 3-5000X more active spinal morphine on the hot plate, tail flick and writhing tests. This agent displays naloxone reversibility and cross tolerance to spinal morphine, and possesses all of the characteristics of a mu opiate receptor agonist.
Analgesics, Opioid↗
Simple catheter preparation for permitting bolus intrathecal administration during chronic intrathecal infusion.
This paper briefly describes a simple method for preparing a polyethylene "Y" catheter in which the stem of the "Y" is inserted into the intrathecal space, one arm of the "Y" is externalized for intrathecal injection and the other arm of the "Y" connected to an osmotic infusion pump. This simple preparation permits the chronic infusion of drug into the spinal space and without further surgical preparation, permits bolus injection of drugs through the same catheter.
Animals↗
Dynorphin A and related peptides administered intrathecally in the rat: a search for putative kappa opiate receptor activity.
The intrathecal delivery of dynorphin A (1-17) and (1-13) induces, with rapid onset, a severe motor dysfunction characterized by flaccid extension of the hindlimbs and complete loss of muscle tone. This motor effect does not appear to be mediated via opiate receptors as high doses of naloxone neither block nor reverse motor dysfunction, and it is produced by dynorphin A fragments inactive at opiate receptors. At doses just below those which produce motor dysfunction, dynorphin A has no effect on nociceptive responses in the hot-plate, tail-flick and writhing tests. The selective, kappa opiate agonist, U50488H, produces a significant, dose-dependent inhibition of writhing, which is antagonized by pretreatment with naloxone, but has no effect on hot-plate and tail-flick latency. The kappa agent U50488H does not produce motor dysfunction with doses as high as 300 nmol/rat. It appears that the potent kappa opiate activity exhibited by dynorphin A in vitro may not reflect in vivo effects of dynorphin after intrathecal administration.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Benzo[a]pyrene diol-epoxides: different mutagenic efficiency in human and bacterial cells.
Monolayer cultures of diploid human fibroblasts and suspensions of S. typhimurium TA100 cells were treated with [3H]-labelled enantiomeric forms of benzo[a]pyrene anti and syn 7,8-dihydrodiol 9,10-epoxides. In both cell types, all of the enantiomers induced the formation of mutant 6-thioguanine (human) or 8-azaguanine-(bacterial)resistant cells. Diol-epoxide-modified nucleosides from human and from bacterial DNA hydrolysates were characterized by HPLC and showed essentially the same adduct species for human and bacterial cells treated with the same enantiomers. There were substantial differences, however, in the efficiency with which structurally-different adduct species were converted to mutant genotypes. In human cells, the mutagenic efficiency (mutation frequency/unit modified DNA) of the respective adduct species (+ anti much greater than -anti = +/- syn) at the hprt locus was exactly the opposite of that seen at a similar gene locus (gpt) in TA100 (-anti = +/- syn greater than + anti). The results suggest that the structural configuration of adducts in genomic DNA is important in determining whether a mutant genotype will result, and likewise, that there are differences in specificity between the human and bacterial systems which process these adduct lesions.
Benzopyrenes↗
Mutation at separate gene loci in Salmonella typhimurium TA100 related to DNA nucleotide modification by stereoisomeric benzo(a)pyrene 7,8-diol-9,10-epoxides.
Suspensions of Salmonella typhimurium TA100 or TA1535 cells were exposed to pure enantiomeric forms or racemic mixtures of 3H-labeled benzo(a)pyrene anti- or syn-7,8-dihydrodiol-9,10-epoxide. Diol-epoxide-induced cytotoxicity and mutation frequencies at the hisG and gpt loci were determined. Hydrolysates of diol-epoxide-modified bacterial DNA were also examined by high-performance liquid chromatography and the primary structure and level of diol-epoxide-nucleoside adduct species were related to the observed frequencies of reverse mutations at the mutant hisG46 codon (histidine prototrophy) or forward mutations at the gpt locus (8-azaguanine resistance). Significant differences in mutagenic efficiency (i.e., mutation frequency per mol DNA adduct) were observed for the different enantiomeric diol-epoxides (-anti = +/- syn much greater than, + anti) and the mutagenic efficiencies were the same at both loci. The combined results of the mutation and adduct characterizations suggest that there are basic differences in the structural configuration of each adduct species which are recognized during errant DNA repair and as a result lead to base changes at a frequency which is relatable to the configuration of the original adduct lesion.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Naloxone blocks the analgesic action of levorphanol but not of dextrorphan in the leopard frog.
Intraspinal injection of levorphanol (3 micrograms) at the lumbar area of the leopard frog, Rana pipiens, induced analgesia which was completely blocked by co-injection of naloxone (3 micrograms), whereas dextrorphan (3 micrograms) induced analgesia which was unaffected by naloxone. Subcutaneous levorphanol (20 or 80 mg/kg) induced a dose-dependent analgesia which was blocked by concurrent naloxone (2 mg/kg), while only the higher dose of dextrorphan (80 mg/kg) induced analgesia which was unaffected by concurrent naloxone at 8 or 80 mg/kg. These data are the first to indicate naloxone-insensitive, dextrorphan-induced analgesia.
Animals↗
Behavioral effects of morphine, levorphanol, dextrorphan and naloxone in the frog Rana pipiens.
Systemic morphine induces explosive motor behavior and generalized muscular rigidity in frogs. Naloxone does not reverse either of these effects of morphine but at high doses causes muscular flaccidity and unresponsiveness to stimulation. Intraspinal morphine induces rigidity, but not explosive motor behavior, and this action is blocked by naloxone. Behavioral effects are seen rarely after intraspinal levorphanol (rigidity) and never after intraspinal dextrorphan or naloxone. In contrast to systemic morphine and naloxone, systemic levorphanol and dextrorphan are lethal to frogs at high doses.
Animals↗
A spinal site mediates opiate analgesia in frogs.
The application of acetic acid to the hind leg of a frog will induce a spinally mediated wiping reflex only if the acetic acid concentration is above a certain threshold. By using this reflex as the basis of a test for nociception, we show that morphine sulfate is a potent analgesic in the frog when injected into the lumbar area of the spinal cord. Significant analgesia is induced within 5 min after injection of as little as 0.0316 microgram of morphine sulfate. Low doses of morphine sulfate (0.0316 or 0.1 microgram) induce analgesia which dissipates within 1 h while for higher doses (0.316, 1.0 or 3.16 micrograms) the analgesia persists for at least 3 h. The analgesic effect of 0.316 micrograms of morphine sulfate is completely blocked by naloxone HCl at either 0.158 or 0.316 micrograms. Animals receiving naloxone alone (0.316 micrograms) appear to be slightly hyperalgesic compared to saline injected controls but this effect is not significant.
Analgesia↗
New Mayo Clinic X-ray scanner promises to add to medical knowledge--and costs.
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Minnesota↗