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PubMed1994

Effect of morphine and stadol on lipid content in liver of rat.

The effects of repeated accumulative increasing doses (5, 10, 20 and 40 mg/kg body weight) of morphine and stadol on lipid content have been studied in liver of rat. The results obtained indicate that significant increases were recorded in hepatic triglycerides (TG) content after 1 and 12 hrs of morphine treatment while non-significant increases were recorded after stadol administration. After 36 hrs of treatment with either of the two drugs, the liver TG content was decreased which may indicate that drug tolerance might have developed. The phospholipids content showed increases especially after 12 hrs of morphine or stadol administration. The results obtained suggest enhanced phospholipid synthesis under the action of both drugs. Highly significant increases occurred in cholesterol content after 1, 12 and 24 hrs of treatment of both drugs. This might reflect the occurrence of decreased catabolism and turnover of cholesterol during the experiment. Total lipids content of liver showed marked and highly significant increases after 12 hrs of morphine and after 12 and 24 hrs of stadol administration respectively. The data obtained suggest that morphine and stadol may be hepatotoxic to rats.

Animals↗
PubMed1985

Endorphins and food intake: kappa opioid receptor agonists and hyperphagia.

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2006

High throughput screening of sub-ppb levels of basic drugs in equine plasma by liquid chromatography-tandem mass spectrometry.

This paper describes a high throughput LC-MS-MS method for the screening of 75 basic drugs in equine plasma at sub-ppb levels. The test scope covers diversified classes of drugs including some alpha- and beta-blockers, alpha- and beta-agonists, antihypotensives, antihypertensives, analgesics, antiarrhythmics, antidepressants, antidiabetics, antipsychotics, antiulcers, anxiolytics, bronchodilators, CNS stimulants, decongestants, sedatives, tranquilizers and vasodilators. A plasma sample was first deproteinated by addition of trichloroacetic acid. Basic drugs were then extracted by solid-phase extraction (SPE) using a Bond Elut Certify cartridge, and analysed by LC-MS-MS in positive electrospray ionization (+ESI) and multiple reaction monitoring (MRM) mode. Liquid chromatography was performed using a short C(8) column (3.3 cm L x 2.1mm ID with 3 microm particles) to provide fast analysis time. The overall instrument turnaround time was 8 min, inclusive of post-run and equilibration time. No interference from the matrices at the expected retention times of the targeted masses was observed. Over 60% of the drugs studied gave limits of detection (LoD) at or below 25 pg/mL, with some LoDs reaching down to 0.5 pg/mL. The inter-day precision for the relative retention times ranged from 0.01 to 0.54%, and that for the relative peak area ratios (relative to the internal standard) ranged from 4 to 37%. The results indicated that the method has acceptable precision to be used on a day-to-day basis for qualitative identification.

Animals↗
PubMed2004

Transgenic mice ectopically expressing HOXA5 in the dorsal spinal cord show structural defects of the cervical spinal cord along with sensory and motor defects of the forelimb.

Mutation of murine Hoxa5 has shown that HOXA5 controls lung, gastrointestinal tract and vertebrae development. Hoxa5 is also expressed in the spinal cord, yet no central nervous system phenotype has been described in Hoxa5 knockouts. To identify the role of Hoxa5 in spinal cord development, we developed transgenic mice that express HOXA5 in the dorsal spinal cord in the brachial region. Using HOXA5-specific antibodies, we show this expression pattern is ectopic as the endogenous protein is expressed only in the ventral spinal cord at this anterio-posterior level. This transgenic line (Hoxa5SV2) also displays forelimb-specific motor and sensory defects. Hoxa5SV2 transgenic mice cannot support their body weight in a forelimb hang, and forelimb strength is decreased. However, Rotarod performance was not impaired in Hoxa5SV2 mice. Hoxa5SV2 mice also show a delayed forelimb response to noxious heat, although hindlimb response time was normal. Administration of an analgesic significantly reduced the hang test defect and decreased the transgene effect on forelimb strength, indicating that pain pathways may be affected. The morphology of transgenic cervical (but not lumbar) spinal cord is highly aberrant. Nissl staining indicates superficial laminae of the dorsal horn are severely disrupted. The distribution of cells and axons immunoreactive for substance P, neurokinin-B, and their primary receptors were aberrant only in transgenic cervical spinal cord. Further, we see increased levels of apoptosis in transgenic spinal cord at embryonic day 13.5. Our evidence suggests apoptosis due to HOXA5 misexpression is a major cause of loss of superficial lamina cells in Hoxa5SV2 mice.

Animals↗
PubMed1996

Influence of acute and chronic morphine or stadol on the secretion of adrenocorticotrophin and its hypothalamic releasing hormone in the rat.

The effects of acute and chronic treatment with morphine and stadol on the functional activity of the hypothalamo-pituitary-adrenocortical (HPA) system in the rat were studied by investigating their effects on the secretion of adrenocorticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing hormone (CRH) by the hypothalamus. The acute injection of morphine or stadol (3.5 mg/100 g body weight i.p.) caused a rise at 5 and 25 min followed by a fall at 90 and 120 min in the concentrations of ACTH in the plasma and adenohypophysis and in hypothalamic CRH content. It appears that, in the rat, the response of HPA system to acute morphine or stadol administration could change depending upon the time of courses. In addition, chronic morphine or stadol (0.5 mg/100 g body weight i.p. daily) administration for a period of 7 days have little effect on plasma and adenohypophysis ACTH concentrations and hypothalamic CRH content. This may indicate that drug tolerance might have developed. Conversely, repeated daily doses of morphine or stadol (2 mg/ 100 g body weight i.p.) for 7 days cause a significant lowering of plasma and pituitary ACTH concentrations and hypothalamic CRH content. These data suggest that the effect of both drugs is dose related. Overall, the present results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine or stadol treatment for a short-term, and with a decreased release of these peptides in chronic treatment. However, the results indicate that morphine and stadol change HPA activity by acting on specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRH.

Adrenal Cortex↗
PubMed1984

Kappa opioid agonists and antagonists: effects on drinking and urinary output.

Several opioid antagonists have previously been shown to decrease drinking. The data have suggested that this was due to an antagonist action at kappa opioid receptors rather than mu or delta opioid receptors. Kappa agonists have a marked diuretic effect through suppression of vasopressin release. Antagonism of this kappa receptor-mediated effect can be used as an in vivo test for determining kappa-receptor antagonist activity. The potencies of opioid antagonists for antagonizing the diuretic effects of the kappa agonist bremazocine do not correlate directly with the potencies for decreasing deprivation-induced drinking. Further work should investigate the receptor specificity for effects on drinking and kappa-mediated diuresis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

Effect of enterostatin and kappa-opioids on macronutrient selection and consumption.

Enterostatin, the activation peptide of pancreatic procolipase, suppresses consumption of high-fat diets and selectively suppresses fat consumption over carbohydrate consumption. Kappa-opioid subtype agonists stimulate feeding whereas antagonists suppress feeding. We investigated the effects of enterostatin, the kappa-opioid agonist U50488, and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) on macronutrient selection and food consumption in rats adapted to choose between a high-fat (HF) diet or a low-fat-high-carbohydrate (LF) diet. In fasted rats, lateral cerebro-ventricular injection (LV) of enterostatin selectively suppressed consumption of the HF diet, with no effect on LF diet consumption. Nor-BNI also selectively suppressed consumption of the HF diet without affecting LF diet consumption. Additionally, U50488 prevented the suppression of consumption of the HF diet in response to enterostatin. In food-sated rates, U50488 preferentially increased consumption of the HF diet and had no effect on consumption of the LF diet. Combined infusions of subthreshold doses of enterostatin and nor-BNI also inhibited consumption of the HF but not the LF diet, whereas combined infusions of maximal doses of enterostatin and nor-BNI had no additive effects. Collectively, these data suggest that a kappa-opioid pathway modulates selection and consumption of diets high in fat and that enterostatin modulates consumption of dietary fat by interacting with this pathway.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

[Use of epidural and intrathecal opiates in obstetrics].

The discovery of opiate receptors and naturally occurring opiate-like substances in the central nervous system started a new era in pain control. Epidural and spinal opiates have been increasingly used since 1979. However, applying these analgesic techniques in obstetrics has been criticized because of possible side-effects on the mother and foetus. In this literature survey, their advantages and disadvantages are analyzed. Maternal side-effects include pruritus, nausea, urinary retention, and, most of all, respiratory depression. As a general rule, these side-effects are greater with the intrathecal route, high doses, and the use of morphine. The effects on the course of labour are small, and neonatal status is not altered. Spinal and epidural opiates are efficient analgesic techniques for labour and caesarean section. They provide a dose-related, but not surgical, analgesia. Currently, there is a great deal of interest in mixtures of a diluted local anaesthetic agent and a lipophilic drug for use during labour or caesarean section. An opiate alone may not consistently provide satisfactory analgesia during labour, and it cannot be recommended for routine use, except for patients in whom the cardiovascular effects of routine regional anaesthesia are to be avoided. The choice of a lipid-soluble opiate like fentanyl is safe. However, when considering new drugs, great care must be taken to avoid unforeseen problems. A good knowledge of the problem and a cautious approach combined with careful monitoring of the respiratory rate and adequacy of ventilation are the keys to the safe use of spinal and epidural opiates.

Adult↗
PubMed1985

Reassessment of verbal and visual analog ratings in analgesic studies.

The relative performance of three analgesic rating scales--visual pain analog, verbal pain intensity, and verbal pain relief--was assessed in clinical trials with 1,497 patients and a variety of pain models. The scales correlated strongly with one another, with inconsistent and generally minimal differences in sensitivity. Overall, the verbal relief scale tended to be slightly more sensitive than the pain analog rating, which in turn showed a small advantage over the verbal pain intensity assessment. When the scores derived from the categorized ratings 1 hour after drug dosing (generally the time of peak effect) were analyzed, there was little difference whether a parametric or nonparametric approach was taken. When the cumulative measures of overall effect over 6 hours were considered, however, the nonparametric approach was decidedly more powerful. There was a similar pattern when the analog scores were analyzed. This unanticipated finding appears to be due to the cumulative measures (from all three scales) being more skewed toward the lower end of their respective ranges than are the 1-hour scores. A composite efficacy variable was defined, incorporating data from the three primary scales; this measure was found to be generally comparable in sensitivity to the individual scales and may be useful as a global summary of response. While our investigation provides evidence that any of the ratings considered will accurately reflect analgesic response, the verbal relief scale was the most sensitive and might be the best choice if a single measure is desired.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1992

Apnea and cardiopulmonary arrest during and after endoscopy.

Ten patients developed apnea or cardiopulmonary arrest during or following endoscopy in more than 10,000 consecutive endoscopies. These complications occurred in patients over the age of 60 years with many associated diseases. Four of the reactions occurred close to the time of giving intravenous medication, the majority after the stimulation of the procedure had ended, usually more than 30 min after the last dose of medication. The initial 7,500 procedures were conducted without automated monitoring, but the most recent 2,500 procedures employed finger pulse oximetry. Monitoring has not prevented apnea and cardiopulmonary arrest, but it provides earlier recognition.

Aged↗