Biomedical subjects
Publications and source records attributed to J S Shaw.
There is considerable variation in the potency of opioids across different animal models of antinociceptive activity. In the less sensitive tests the partial agonist analgesics behave as antagonists. The activity of opioids in antinociceptive tests appears to be dependent on both the intensity of the noxious stimulus and the intrinsic activity of the drug.
Symmetrical and unsymmetrical dimeric pentapeptide opioid antagonists have been prepared and studied on the mouse vas deferens preparation. The findings do not support the hypothesis that such agents bind to dimeric delta-opioid receptors.
The inhibitory action of dynorphin-(1-9) on the electrically stimulated mouse vas deferens was seen to be antagonised by the delta-selective opioid antagonist ICI 174864. The observed delta-receptor mediated responses were partially, but not totally, prevented by peptidase inhibitors which protect the C- and N-termini of dynorphin-(1-9). [3H]Dynorphin-(1-9) is rapidly degraded by slices of vasa deferentia of the mouse. The major product of this metabolism co-elutes with [Leu5]enkephalin on reverse phase HPLC. It is concluded that a major component of the inhibitory effects of dynorphin-(1-9) on the mouse vas deferens is mediated by degradation to [Leu5]enkephalin which in turn acts through delta-receptors. It is possible that in other in vitro and in vivo systems, the effects produced by dynorphin-(1-9) might be similarly mediated by delta-receptor activation.
It has recently been reported that the hamster vas deferens contains only delta-opioid receptors. We have demonstrated that three delta-receptor agonists [D-Ala2, D-Leu5]enkephalin (DADLE), [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Thr2, Leu5, Thr6] enkephalin (DTLET) appear to mediate their effects via the delta-receptor since they are readily reversed by the selective delta-receptor antagonist ICI 174864. In addition, a number of classical mu and k receptor compounds were devoid of activity in this preparation. However it was observed that some compounds such as etorphine and MR 2034 reported to possess delta-receptor affinity in other assay systems were weak or inactive on the hamster vas deferens.
Explore the source record for details and available documents.
Attempts have been made to confirm reports that naloxonazine and Mr2034 are able to selectively antagonise morphine-induced analgesia and respiratory depression respectively. In the present studies these antagonists proved to be equi-effective against both the analgesic and respiratory depressant effects of morphine, suggesting that these two actions are mediated by a common receptor.
Mu-receptor affinities have been determined for a number of opioid drugs using a combination of isolated tissue and receptor binding techniques. The affinities of antagonists and partial agonists were determined by their ability to antagonise responses to [D-Ala2,MePhe4,Glyol5]enkephalin (GLYOL) on the rat vas deferens preparation. There was little correlation between these results and affinities measured by displacement of [3H]-GLYOL from guinea-pig brain membranes incubated in 50mM Tris buffer. By contrast, affinities measured by displacement of [3H]-naloxone from rat brain membranes incubated in a Krebs/HEPES buffer containing a non-hydrolysable analogue of GTP, agreed very closely with the isolated tissue data.
The C57 mouse vas deferens preparation has been shown to be insensitive to mu-opioids. The present study indicates that this tissue possesses mu, d and k-receptors with similar affinities to those found in other isolated tissue preparations, but has a small receptor reserve. Thus partial agonists such as morphine are detected as antagonists.
The agonist potencies of normorphine and [D-Ala2,D-Leu5]enkephalin (DADL) have been determined on the mouse vas deferens preparation under different conditions. Reducing the temperature at which the assay was performed had little effect on the response to DADL whilst the Emax of normorphine was greatly reduced. Tissues rendered tolerant to either agent exhibited little, if any, cross-tolerance to the other drug. The results suggest the presence of at least two types of opiate receptor in the mouse vas deferens.
Diallylation of the amino group of [Leu]enkephalin methyl ester yields a moderately potent, delta-selective opiate receptor antagonist. The diallyl congeners of a larger range of potent mu-and delta-selective enkephalin agonists have been prepared and were found to be weak, non-selective antagonists as assessed by their ability to antagonise the effects of normorphine and [Leu]enkephalin on the field-stimulated mouse vas deferens. Conversely, whereas [Gly3 psi (CH2S)Phe4,Leu5]enkephalin and [Gly3 psi(CH2S)-D-Phe4,Leu5]enkephalin are virtually inactive as opiate agonists the corresponding diallyl analogues are moderately potent, highly selective delta-antagonists. Analogues of diallyl[Leu]enkephalin in which the Gly2 and Gly3 residues have been replaced by D- and L- Ala have also been prepared and tested as delta-receptor antagonists. In addition, the empiric energy program ECEPP has been used to derive eighteen low energy conformations of diallyl[Leu]enkephalin and to estimate the effect of the D- and L-Ala substitutions on the conformer energies. Two conformers were identified for which there was a partial correlation between the variations in conformational energy and delta-antagonist potency.
Seventy-one college students completed the Bem Sex-Role Inventory, a stressful life-events questionnaire, and some general questions on adjustment. Subjects were also asked to rate the stressful life events they had experienced in the prior 12 months along the dimensions of desirability, amount of change, anticipation, control, and meaningfulness. As hypothesized, androgynous subjects rated their stressful life events as less undesirable than other subjects, but this result only held for females (p less than .01). Undifferentiated subjects rated their stressful life events as less meaningful than other subjects (p less than .01) and androgynous subjects rated themselves as happier than other subjects (p less than .05). No differences were found among androgynous, masculine, feminine, and undifferentiated persons for the dimensions of change, anticipation, or control. Of the five dimensions examined, only meaningfulness was significantly related to happiness (r = .34, p less than .01). One possible reason for the results of this study may be differential access to and/or use of social support systems by persons of different sex-types. Some findings of the present study are presented that support this contention.
The action of gamma-aminobutyric acid (GABA) and related compounds on rat isolated atria and mouse and guinea pig isolated vas deferens has been studied. GABA depressed the evoked but not basal release of [3H]noradrenaline from atria (IC50 4 micro M) and reduced the twitch responses of the vas deferens (IC50 3 micro M) in a dose-dependent manner. These depressant effects were not prevented by recognized GABA antagonists such as bicuculline and picrotoxin. Numerous GABA analogues, in particular 3-aminopropanesulphonic acid, failed to mimic the action of GABA. However, beta-p-chlorophenyl GABA (baclofen) was stereospecifically active. Other related beta-substituted derivatives were also active but to a lesser degree than GABA. Pretreatment of the vas deferens with the neuronal GABA uptake inhibitors 2,4-diaminobutyric acid or cis-3-aminocyclohexanecarboxylic acid potentiated the action of GABA. These data suggest the presence of a bicuculline-insensitive GABA receptor on autonomic nerve terminals. Preliminary observations indicate a lack of chloride ion dependence in the action of GABA at this site.
Explore the source record for details and available documents.
We have studied three patients with ataxia-telangiectasia (AT) and found two of them to have a normal mixed leucocyte culture stimulating and responding ability. However, all three patients and one parent had defective cell-mediated lympholysis (CML), even in the face of a potent proliferative response to allogeneic leucocytes. None of these patients showed significant proliferative responses to common microbial antigens (tetanus toxoid, Candida albicans, purified protein derivative (PPD), diphtheria toxoid, influenza). Our studies indicate tha the T cell defect in AT preferentially affects certain T cell functions associated with antigen recognition and the generation of allogeneic CML, while sparing the allogeneic proliferative response. The selective deficiency of specific lymphocyte functions in a thymic immunodeficiency with a known defect in DNA repair is consistent with the concept that DNA modulating enzymes are important for T cell function.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The Homestyle Delivery Program, an alternative birth service at the University of California Davis Medical Center, Sacramento, is presented. The program was developed jointly by the departments of family practice, obstetrics, and pediatrics, in response to the needs and desires of patients and physicians to participate in a more natural family centered birthing process. A brief description of the program and data from the first 1 1/2 years of operation is given. This program, in contrast to many other alternative birthing programs, involves physicians in training; that is, residents in family practice and obstetrics who are being taught during their obstetrical training how to create and facilitate an intimate family oriented home-like birthing. Satisfaction with the program on the part of the participating families as well as physicians and program staff has been very high. Today, more families in this society are demanding this kind of alternative birthing experience; the Homestyle Delivery Program meets their needs and to data has demonstrated no increased risk to mother or infant.