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Biomedical subjects

M W Adler

Publications and source records attributed to M W Adler.

At least 55 records · Page 3Linked to original sources
PubMed1997

Morphine induces sepsis in mice.

Gram-negative sepsis and subsequent endotoxic shock remain major health problems in the United States. The present study examined the role of morphine in inducing sepsis. Mice administered morphine by the subcutaneous implantation of a slow-release pellet developed colonization of the liver, spleen, and peritoneal cavity with gram-negative and other enteric bacteria. In addition, the mice became hypersusceptible to sublethal endotoxin challenge. The effects were blocked by the simultaneous implantation of a pellet containing the opioid antagonist naltrexone. These findings show that morphine pellet implantation in mice results in the escape of gram-negative organisms from the gastrointestinal tract, leading to the hypothesis that morphine used postoperatively or chronically for analgesia may serve as a cofactor in the precipitation of sepsis and shock. In addition, morphine-induced sepsis may provide a physiologically relevant model of gram-negative sepsis and endotoxic shock.

Analgesics, Opioid↗
PubMed1997

HIV partner notification policy and practice within GUM clinics in England: where are we now?

OBJECTIVES: To evaluate the extent to which larger genitourinary medicine (GUM) clinics in England have established local clinic policies for HIV Partner Notification (PN) and to describe the process of HIV PN within this setting. DESIGN: A cross-sectional survey of HIV PN policies and practices within GUM clinics. SUBJECTS AND SETTING: Senior consultants in 59 GUM clinics in England. MAIN OUTCOME MEASURES: The presence of clinic policies for HIV PN, indicators of HIV PN activity (that is, its initiation, documentation, performance and evaluation) and factors hindering the acceptance of HIV PN into clinical practice. RESULTS: Only 18% (10/57) of respondents stated that their clinics had developed their own local policies for HIV PN. Fifteen percent (9/58) of clinics had audited HIV PN activity, 15% had provided specific HIV PN training for doctors and 47% (27/58) for health advisers. Within GUM clinics, health advisers play a key role in the HIV PN process, being responsible for initiating the discussion of partners, patient follow-up and documenting HIV PN activity in patients' notes. Notifying partners was primarily seen as the responsibility of the newly diagnosed HIV positive patient. Although 77% (43/56) of responding consultants believed that HIV PN had become an accepted part of their clinics' practice, the perceived unacceptability of HIV PN to patients and health care workers were seen as important limiting factors. CONCLUSION: In many GUM clinics, local policies on HIV PN have yet to be established and appropriate training for the health personnel provided. Nevertheless, there appears to be wide-spread acceptance of HIV PN in clinical practice with an acknowledgement of its limiting factors. Further research into the acceptability of HIV PN to health care workers and patients in this setting should be undertaken.

Attitude of Health Personnel↗
PubMed1997

Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain.

Opioids administered by i.c.v. injection produce body temperature (Tb) changes and analgesic responses in rats. The present study was undertaken to investigate the effects on Tb and analgesia of highly selective mu and kappa opioid receptor agonists and antagonists delivered directly into the preoptic anterior hypothalamus (POAH) and periaqueductal gray (PAG) by the intracerebral microdialysis method. Microdialyzed into the POAH, the mu receptor agonist Tyr-Pro-N-MePhe-D-Pro-NH2 induced dose-related hyperthermia that could be prevented or antagonized by the mu receptor antagonist cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 or by naloxone, but not by the kappa receptor antagonist nor-binaltorphimine. The kappa receptor agonist dynorphin A(1-17), microdialyzed into the POAH, induced dose-related hypothermia that was prevented or antagonized by nor-binaltorphimine but not cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2. Neither Tyr-Pro-N-MePhe-D-Pro-NH2 nor dynorphin A(1-17) microdialyzed into the PAG produced significant changes in Tb. However, these agonists microdialyzed into the PAG produced analgesic responses that did not occur after administration into the POAH. These results support the hypothesis that the hyperthermic response to opioids is mediated by the mu receptor and the hypothermic response is mediated by the kappa receptor in rats. The POAH is a primary functional area in Tb, but not in analgesic, responses to opioids, whereas the PAG is a sensitive area for analgesic, but not for Tb, responses to opioids.

Analgesics, Opioid↗
PubMed1997

Substance P release in the rat periaqueductal gray and preoptic anterior hypothalamus after noxious cold stimulation: effect of selective mu and kappa opioid agonists.

Intracerebral microdialysis was used to measure changes in the extracellular level of substance P (SP) released from the periaqueductal gray (PAG) and the preoptic anterior hypothalamus (POAH) of freely moving Sprague-Dawley rats after noxious cold stimulation. Artificial cerebrospinal fluid was perfused into the dialysis probe in the PAG or POAH and samples were collected every 30 min for 4 hr. SP-like immunoreactivity in the samples was measured by radioimmunoassay. In the PAG, SP base-line release was 0.43 +/- 0.08 fmol/fraction. SP release was increased to 1.3 +/- 0.4 fmol/fraction during the first collection period after noxious cold. Pretreatment with the selective mu opioid receptor agonist PL017 (0.8-3.4 nmol) or the kappa opioid receptor agonist dynorphin A1-17 (4.6-9.2 nmol), administered into the PAG by microinjection, produced dose-related inhibition of the cold-evoked SP release. Naloxone (10 mg/kg s.c.) administration 10 min before these opioid agonists reduced the inhibition of SP release. In the POAH, SP base-line release was 0.45 +/- 0.06 fmol/fraction and noxious cold did not cause any significant change in SP release. Microdialysis of SP (271 fmol-271 pmol/microl/min, for 30 min) into the PAG, but not the POAH, induced dose-related analgesia (35-68% MPA) in the cold-water tail-flick test. However, microdialysis of SP into the POAH or PAG failed to induce any significant change in body temperature. These data suggest that 1) SP released from the PAG acts as a neuromodulator to transmit nociceptive information; 2) opioid receptor agonists can suppress this information by inhibiting SP release; 3) SP evoked by noxious cold may have a role in triggering the antinociceptive function of the PAG; and 4) SP does not appear to act as a neuromodulator for thermoregulatory responses in the POAH.

Animals↗
PubMed1996

Antisense confirmation of mu- and kappa-opioid receptor mediation of morphine's effects on body temperature in rats.

Previous studies showed that parenterally administered morphine at 4-16 mg/kg markedly increased body temperature in the rat, but higher doses of morphine (> or = 30 mg/kg, subcutaneously, sc) caused a profound decrease in body temperature. Based on the use of selective opioid agonists and antagonists, we postulated that these effects were due to morphine's actions on mu and kappa receptors, respectively. In the present study, we sought to determine whether an antisense (AS) oligodeoxynucleotide (oligo) against cloned mu or kappa opioid receptors could affect morphine-induced body temperature changes. AS oligos were directed against nucleotides 1-18 of the coding region of the mu receptor and 4-21 of the coding region of the kappa receptor. Male SD rats were surgically implanted with intracerebroventricular (icv) cannulae. Rats received icv injections of vehicle or oligo in the animal colony room on days 1, 3 and 5. Either AS oligo or missense (MS) oligo was infused in a volume of 5 microliters over 30 s to freely moving animals. On day 6, the rats were tested. The results showed that icv treatment with an AS oligo against mu opioid receptors, but not an MS oligo against the mu opioid receptor or an AS oligo against the kappa opioid receptor, significantly attenuated the hyperthermia normally produced by a relatively low dose of morphine administered sc. In addition, treatment with an AS oligo against kappa receptors, but not an MS oligo against kappa opioid receptor or an AS oligo against the mu opioid receptor, significantly blocked the hypothermia induced by a high dose of morphine. This study confirms our earlier postulate that morphine at 4 mg/kg, sc, induces an increase in body temperature primarily via mu opioid receptors in the brain and a high dose (30 mg/kg) of morphine administered sc produces a decrease primarily through kappa opioid receptors in the brain.

Animals↗
PubMed1996

Use of a mu-antisense oligodeoxynucleotide as a mu opioid receptor noncompetitive antagonist in vivo.

We examined whether mu-antisense (AS) oligodeoxynucleotide (oligo) treatment can be used in a manner similar to the mu-selective irreversible antagonist beta-funaltrexamine (beta-FNA) for in vivo pharmacology. Rats were injected intracerebroventricularly (icv) with a mu-AS or a missense (MS) oligo on days 1, 3, 5, 7, and 9 and were tested for the antinociceptive effect of sc injection of morphine on days 2, 4, 6, 8, and 10 in the cold water tail-flick (CWT) test. In another set of experiments, rats were also tested for the antinociceptive action of morphine twenty-four hours after icv injection of beta-FNA. Both beta-FNA and mu-AS produced rightward shifts in the dose-effect curves of morphine. In addition, pretreatment with 2.5 micrograms or more of beta-FNA or the mu-AS oligo for 5-9 days (but not for 1-3 days) reduced the maximal analgesic effect of morphine. The approximate fraction of functional receptor remaining for morphine was determined with the method of Furchgott to be 49.5% following 2.5 micrograms of beta-FNA; that after 5 days of the mu-AS oligo treatment was 50.8%. The results suggest that the mu-AS oligo can be used in the same manner as highly selective, irreversible mu opioid receptor ligands. Thus, properly designed AS oligos against receptors are of particular benefit when irreversible antagonists are not available. AS oligos represent a new class of selective and powerful pharmacological antagonists.

Animals↗
PubMed1996

Inhibition of primary murine macrophage cytokine production in vitro following treatment with the kappa-opioid agonist U50,488H.

Previous work in our laboratory has shown that both mu- and kappa-opioid agonists exhibit immunosuppressive activity for antibody responses in vitro. Our earlier work has suggested that both accessory cells and T cells may be altered following treatment with the kappa-opioid agonist U50,488H. We intend to further determine the identity of the immune cell population(s) which are affected by opioid treatment, and to determine the nature of the opioid receptor type expressed on these cells. In this study, non- elicited peritoneal macrophages were treated simultaneously with the kappa-agonist U50,488H and lipopolysaccharide (LPS), and the levels of the cytokines interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha were determined. The results show that U50,488H had a suppressive effect on the production of TNF-alpha and IL-1 at concentrations as low as 1 nM, while IL-6 was suppressed at concentrations as low as 10 nM. Additional experiments utilizing the opiate antagonist naloxone and the kappa-selective antagonist norbinaltorphimine (norBNI) were performed in order to further characterize the opioid receptor involved in the cytokine suppression produced by treatment with U50,488H. Results showed that naloxone was able to partially block U50,488H suppression while norBNI was able to completely reverse the suppression of IL-6 production. These results suggest that macrophage/monocyte function is significantly modulated following activation of the kappa-opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Sexually transmitted diseases control in developing countries.

Sexually transmitted diseases (STDs) are a major public health problem now compounded by the advent of AIDS and HIV infection. The size of the problem represented by STDs and HIV is unknown however it is estimated that there are 333 million new cases of STD per annum and currently 15-20 million people infected worldwide with HIV. Control programmes for STDs must prevent the acquisition of STDs, their complications and sequelae and interrupt and reduce transmission. They can also reduce the incidence of HIV infection. Such programmes must place emphasis on health education, condom usage, altering health seeking behaviour and providing case management. The syndromic approach currently offers the most realistic, and cost effective, way in which to treat patients.

Adolescent↗
PubMed1996

Electrical stimulation at traditional acupuncture sites in periphery produces brain opioid-receptor-mediated antinociception in rats.

Previous studies in rats measuring latency to tail flick with radiant heat have shown that the antinociceptive effect induced by electrical stimulation of different frequencies at traditional acupuncture sites is mediated via different opioid receptors in the spinal cord. The present study was designed to observe (1) whether electrical stimulation at such sites could produce antinociceptive effects in the cold water tail-flick (CWT) test; (2) whether the antinociceptive effects could be blocked by s.c. injection of the opioid receptor antagonist naloxone and (3) whether i.c.v. injection of selective antagonists for mu (cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, CTAP), delta (naltrindole) or kappa (nor-binaltorphimine) opioid receptors would block the antinociceptive effect produced by electrical stimulation. Sprague-Dawley rats were stimulated at frequencies of 2, 30 or 100 Hz with acupuncture needles inserted into acupoints Zusanli and Sanyinjiao in the hind leg for 30 min. Antinociception was assayed in the CWT. The results showed that (1) a significant, frequency-related increase in threshold in the CWT was observed in all electrical stimulation groups as compared with the placebo group and the antinociceptive effect lasted about 30 min poststimulation; (2) naloxone (s.c.) antagonized the antinociceptive effect induced by 2 Hz, 30 Hz or 100 Hz electrical stimulation and (3) either CTAP or naltrindole (i.c.v.) almost completely blocked the antinociceptive effect induced by 2 Hz or 30 Hz electrical stimulation, but was less effective in blocking antinociception induced by 100 Hz electrical stimulation; nor-binaltorphimine (i.c.v.) greatly reduced antinociception induced by 30 Hz or 100 Hz electrical stimulation, but not by 2 Hz electrical stimulation. These results indicate that the antinociception induced by 2 Hz electrical stimulation is mediated by both mu and delta opioid receptors; the antinociception induced by 100 Hz electrical stimulation is mediated primarily by the kappa receptor; and the antinociception induced by 30 Hz electrical stimulation is mediated by all three opioid receptor types. Thus, the antinociceptive effect induced by peripheral electrical stimulation, as measured by the CWT, involves opioid receptors in the rat brain.

Acupuncture Therapy↗
PubMed1995

Antisense oligodeoxynucleotides against mu- or kappa-opioid receptors block agonist-induced body temperature changes in rats.

PL017 and dynorphin A1-17 were shown previously to cause a marked increase and a profound decrease in body temperature (Tb), respectively. In this study, we examined whether an antisense (AS) oligodeoxynucleotide (oligo) against cloned mu or kappa opioid receptors could block PL017- or dynorphin A-induced body temperature changes. Treatment with an AS oligo against mu receptors, but not sense (S) oligo, missense (MS) oligo or artificial cerebrospinal fluid (aCSF), abolished PL017-induced hyperthermia. In addition, treatment with an AS oligo against kappa receptors, but not S oligo, MS oligo or aCSF, greatly attenuated dynorphin A-induced hypothermia. This study further supports the notion that mu and kappa receptors mediate Tb regulation.

Animals↗
PubMed1995

An antisense oligodeoxynucleotide to mu-opioid receptors inhibits mu-opioid receptor agonist-induced analgesia in rats.

We examined effects of an antisense oligodeoxynucleotide against the mu-opioid receptor on mu-opioid receptor agonist-induced antinociception in the cold water (-3 degrees C) tail-flick test in rats. Rats were injected intracerebroventricularly (i.c.v.) with an antisense, sense or missense oligodeoxynucleotide or artificial cerebrospinal fluid on days 1, 3 and 5. On day 6, antinociceptive effects of opioid agonists were tested. Compared to the artificial cerebrospinal fluid treatment, the cumulative dose-effect curve for subcutaneous (s.c.) morphine was shifted to the right by the antisense oligodeoxynucleotide, but not by the missense oligodeoxynucleotide or the sense oligodeoxynucleotide treatment. Antisense oligodeoxynucleotide treatment reduced the analgesic effect of the mu-opioid receptor agonist PL017 ([N-MePhe3,D-Pro4]morphiceptin), but not the delta-opioid receptor agonist BW373U86 ((+/-)-4-((a-R*)-a-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethyl-benzamide) or the kappa-opioid receptor agonist spiradoline ((+/-)-(5a,7a,8b)-3,4-dichloro-N-methyl-N-[7-(1- pyrrolidinyl)-1-(oxaspiro-[4,5]dec-8-yl]benzeneacetamide monohydrochloride). The drugs were given by i.c.v. injection. These findings indicate that i.c.v. administration of a mu antisense oligodeoxynucleotide specifically blocks mu-, but not delta- or kappa-opioid receptor-mediated analgesia in the rat cold water tail-flick test.

Analgesia↗
PubMed1995

Detection of kappa-opioid receptor mRNA in immature T cells.

The R1.1 cell line has been shown to express kappa-opioid receptors on the cell surface. Our analysis shows that the R1.1 cell line exhibits a CD4NEG CD8NEG CD3LOW CD25LOW cell surface phenotype, characteristic of thymocytes in one of the early stages of differentiation. We have developed reverse transcriptase polymerase chain reaction (RT-PCR) conditions that permit the detection of mRNA coding for the kappa-receptor. Using cell fractionation techniques we have isolated CD4NEG CD8NEG thymocytes, and analysis by RT-PCR shows that these primary immature thymocytes also express the kappa-opioid receptor. We hypothesize that the expression of kappa-opioid receptor may be a marker which is characteristic of immature T development.

Animals↗
PubMed1995

Cholecystokinin potentiates morphine anticonvulsant action through both CCK-A and CCK-B receptors.

Recent studies have suggested that cholecystokinin may have a role in modulating the effects of the endogenous opioid system in physiological functions such as thermoregulation and pain control. However, the possible interaction of cholecystokinin and morphine in epileptogenesis is unknown. We studied the effect of subcutaneous morphine and intracerebroventricularly administered cholecystokinin octapeptide sulphate ester and receptor antagonists CCK-A (MK 329) and CCK-B (L 365,260) on seizures provoked by maximal electroshock in male Sprague-Dawley rats. Seizures were induced through electrode-gel-coated ear clip electrodes by a high voltage, high internal resistance constant current generator, 30 minutes after morphine administration and 10 minutes after cholecystokinin-8-SE, CCK-A and CCK-B infusion. Morphine decreased the length of the tonic component of the seizure and cholecystokinin potentiated this decrease. Cholecystokinin antagonists blocked the effects of both cholecystokinin and morphine. The results suggest that cholecystokinin acts as an endogenous agonist with opioids in the regulation of seizure susceptibility through both CCK-A and B receptors and may be responsible for part of the anticonvulsant action of morphine.

Animals↗
PubMed1995

Sequence of kappa-opioid receptor cDNA in the R1.1 thymoma cell line.

To our knowledge, this is the first demonstration of kappa-opioid receptor mRNA in cells of the immune system. While the presence of opioid receptors on cells of the immune system has been controversial, cell-binding analysis has indicated that the kappa-opioid receptor is expressed by the immature T cell line R1.1. We have developed a reverse transcriptase-polymerase chain reaction protocol to amplify the mRNA extracted from R1.1 cells with primers derived from the cDNA sequence of the mouse kappa-opioid receptor. Nucleotide sequences of the amplified products were examined and two populations of cDNA were detected which differ in the 5' region upstream of the ATG start codon. Comparison of these sequences to the previously published kappa-opioid receptor cDNA sequence suggests the presence of an intron-exon junction in the 5' non-coding region.

Animals↗