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Sample records for acute morphine administration

  1. Antinatriuretic effect of acute morphine administration in conscious rats.

    PubMed

    Walker, L A; Murphy, J C

    1984-05-01

    The renal response to the acute administration of morphine was examined in conscious, chronically catheterized, nonhydrated rats. After control clearance periods, morphine sulfate was injected i.v. at 4 mg/kg followed by an infusion of 2 mg/kg X hr. Morphine caused an increase in urine flow which was variable in magnitude and duration. The initial diuresis was not maintained despite continued morphine administration and replacement of lost fluid. Compared to vehicle treatment morphine also induced marked sodium and chloride retention which was sustained throughout the 2-hr infusion period. There were no changes in blood pressure or heart during the clearance periods, although an initial transient hypotension and bradycardia were observed with morphine injection. There were no changes in glomerular filtration rate which could account for the antinatriuresis. Naloxone pretreatment blocked all of the observed renal responses. The results indicate that morphine exerts its effects on electrolyte excretion by enhancing renal tubular sodium or chloride reabsorption rather than changes in systemic hemodynamics or glomerular filtration rate. In a separate series of experiments, urine osmolality, osmolar clearance and free water clearance were estimated. All rats receiving morphine transiently excreted a hypotonic urine (minimum 183 +/- 23 mOsmol/kg of H2O) with a reduction in osmolar clearance and a sharp increase in free water clearance. These findings are consistent with a temporary inhibition of vasopressin release by morphine. PMID:6716265

  2. Gene expression following acute morphine administration.

    PubMed

    Loguinov, A V; Anderson, L M; Crosby, G J; Yukhananov, R Y

    2001-08-28

    The long-term response to neurotropic drugs depends on drug-induced neuroplasticity and underlying changes in gene expression. However, alterations in neuronal gene expression can be observed even following single injection. To investigate the extent of these changes, gene expression in the medial striatum and lumbar part of the spinal cord was monitored by cDNA microarray following single injection of morphine. Using robust and resistant linear regression (MM-estimator) with simultaneous prediction confidence intervals, we detected differentially expressed genes. By combining the results with cluster analysis, we have found that a single morphine injection alters expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. RNAs for these proteins were mostly downregulated both in the medial striatum and in lumbar part of the spinal cord. These transitory changes were prevented by coadministration of the opioid antagonist naloxone. Data indicate that microarray analysis by itself is useful in describing the effect of well-known substances on the nervous system and provides sufficient information to propose a potentially novel pathway mediating its activity. PMID:11526201

  3. Increases of CCK mRNA and peptide in different brain areas following acute and chronic administration of morphine.

    PubMed

    Ding, X Z; Bayer, B M

    1993-10-15

    The present study examined whether either acute or chronic administration of morphine resulted in changes in the content of CCK mRNA and CCK immunoactive peptide in selective areas of the rat brain and spinal cord. Two hours after a single injection of morphine (10 mg/kg, s.c.), CCK mRNA significantly increased in the hypothalamus (0.8-fold) and spinal cord (2-fold) relative to the CCK mRNA content in saline-injected controls. No significant differences in CCK mRNA were observed in the frontal cortex, hippocampus, midbrain or brainstem. There were no significant alterations in CCK immunoreactivity in any brain regions and spinal cord after the acute treatment with morphine. Upon repeated morphine administration, the content of CCK mRNA in both the hypothalamus and the spinal cord was further elevated by at least 3-fold. A significant increase of CCK mRNA content in brain stem (2.8-fold) was also observed following chronic morphine administration. In contrast to the acute exposure to morphine, chronic administration resulted in significant increases in CCK immunoactive peptide in hypothalamus (2.6-fold), spinal cord (2.1-fold) and brainstem (1.6-fold), but not in the other brain areas. These results demonstrate that morphine, especially following repeated administrations, stimulates endogenous CCK biosynthesis in selective brain regions. PMID:8242392

  4. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    PubMed Central

    Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

  5. Effect of interaction between acute administration of morphine and cannabinoid compounds on spontaneous excitatory and inhibitory postsynaptic currents of magnocellular neurons of supraoptic nucleus

    PubMed Central

    Yousefpour, Mitra; Naderi, Nima; Motamedi, Fereshteh

    2016-01-01

    Objective(s): Opioids and cannabinoids are two important compounds that have been shown to influence the activity of magnocellular neurons (MCNs) of supraoptic nucleus (SON). The interaction between opioidergic and cannabinoidergic systems in various structures of the brain and spinal cord is now well established, but not in the MCNs of SON. Materials and methods: In this study, whole cell patch clamp recording of neurons in rat brain slice was used to investigate the effect of acute morphine and cannabinoid administration on spontaneous inhibitory and excitatory spostsynaptic currents (sIPSCs and sEPSCs) in MCNs. Results: Bath application of morphine produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency. In contrast, bath application of URB597 (fatty acid amide hydrolase (FAAH) inhibitor) produced a decrease in sEPSCs frequency but an increase in sIPSCs frequency. WIN55212-2 (cannabinoid receptor agonist) decreased both sIPSCs and sEPSCs frequencies of MCNs. Co-application of morphine and URB597 attenuated the effect of morphine on MCNs. Conclusion: Taken together, these data indicated that at the cellular level, pharmacological augmentation of endocannabinoids could attenuate morphine effects on MCNs. PMID:27482350

  6. The effects of acute and chronic nicotine hydrogen (+)-tartrate administration and subsequent withdrawal on rat liver tryptophan pyrrolase activity and their comparison with those of morphine, phenobarbitone and ethanol.

    PubMed Central

    Badawy, A A; Evans, M

    1975-01-01

    Acute administration of nicotine hydrogen (+)-tartrate enhances the activity of rat liver tryptophan pyrrolase by a hormonal mechanism. Chronic nicotine treatment inhibits, and subsequent withdrawal enhances, the pyrrolase activity. The inhibition during chronic treatment is not due to a defective apoenzyme synthesis nor a decreased cofactor availability. Regeneration of liver NADP+ in vitro and in vivo reverses the inhibition. Chronic nicotine administration increases the liver NADPH concentration. The above effects of nicotine resemble to a remarkable degree those previously shown for morphine, phenobarbitone and ethanol. All effects are compared, and their possible significance in relation to drug dependence is discussed. PMID:989

  7. Morphine-augmented cholescintigraphy in the diagnosis of acute cholecystitis

    SciTech Connect

    Kim, E.E.; Pjura, G.; Lowry, P.; Nguyen, M.; Pollack, M.

    1986-12-01

    Cholescintigraphy is a sensitive procedure for diagnosing or excluding acute cholecystitis. However, when rapid diagnosis is critical, the requirement for delayed images (4 hr or more after injection) to minimize the false-positive rate diminishes its utility. We prospectively evaluated 40 cholescintigraphic examinations that did not visualize the gallbladder 1 hr after injection of 99mTc diisopropyliminodiacetic acid. These examinations were then augmented by administration of IV morphine, followed by an additional 30 min of imaging. After the morphine, 18 of these examinations demonstrated visualization of the gallbladder; none subsequently required surgical exploration. Of the remaining 22, who demonstrated persistent nonvisualization of the gallbladder post-morphine, 11 were explored surgically and found to be abnormal. The 11 others were treated medically. Low-dose morphine administered when the gallbladder fails to visualize after 1 hr is a useful adjunct to conventional cholescintigraphy because it reduces the time required to obtain a diagnostic result and decreases the number of false-positive results.

  8. Effects of Acute and Chronic Morphine on Delay Discounting in Pigeons

    PubMed Central

    Eppolito, Amy K.; France, Charles P.; Gerak, Lisa R.

    2015-01-01

    When reinforcers of different magnitudes are concurrently available, choice is greater for a large reinforcer; that choice can be reduced by delaying its delivery, a phenomenon called delay discounting and represented graphically by a delay curve in which choice is plotted as a function of delay to the large reinforcer. Morphine, administered acutely, can alter responding for large, delayed reinforcers. In this study, the impact of morphine tolerance, dependence and withdrawal on choice of delayed reinforcers was examined in 6 pigeons responding to receive a small amount of food delivered immediately or a larger amount delivered immediately or after delays that increased within sessions. Acutely, morphine decreased responding for the large reinforcer, and the effect was greater when morphine was administered immediately, rather than 6 hr, before sessions. During 8 weeks of daily administration, morphine produced differential effects across pigeons, shifting the delay curve downward in some and upward in others. In all pigeons, tolerance developed to the response rate-decreasing effects of morphine but not to its effects on delay discounting. When chronic morphine treatment was discontinued, rate of responding decreased in 4 pigeons, indicating the emergence of withdrawal; choice of the large reinforcer increased, regardless of delay, in all pigeons, an effect that persisted for weeks. These data suggest that chronic morphine administration has long-lasting effects on choice behavior, which might impact vulnerability to relapse in opioid abusers. PMID:23553726

  9. Efficacy of Intravenous Paracetamol Versus Intravenous Morphine in Acute Limb Trauma

    PubMed Central

    Jalili, Mohammad; Mozaffarpour Noori, Ali; Sedaghat, Mojtaba; Safaie, Arash

    2016-01-01

    Background: Efficient pain management is one of the most important components of care in the field of emergency medicine. Objectives: This study was conducted to compare intravenous paracetamol and intravenous morphine sulfate for acute pain reduction in patients with limb trauma. Patients and Methods: In a randomized double-blinded clinical trial, all patients (aged 18 years and older) with acute limb trauma and a pain score of greater than 3/10 in the emergency department were recruited; they received either 1 g intravenous paracetamol or 0.1 mg/kg intravenous morphine sulfate over 15 minutes. The primary outcome was the pain score measured on a numerical rating scale at 0, 15 and 30 minutes after commencing drug administration. The requirement for rescue analgesia and the frequency of adverse reactions were also recorded. Results: Sixty patients randomly received either IV paracetamol (n = 30) or IV morphine (n = 30). The mean reduction in numerical rating scale pain intensity scores at 30 minutes was 3.86 (± 1.61) for paracetamol, and 2.16 (± 1.39) for morphine. However, pain relief was significantly higher in the paracetamol group compared to the morphine group (P < 0.001). Four patients in the paracetamol group and 15 patients in the morphine group needed rescue analgesia and the difference was significant (P = 0.05). Conclusions: Intravenous paracetamol appears to provide better analgesia than intravenous morphine in acute limb trauma. Further larger studies are required. PMID:27218042

  10. Impact of the Timing of Morphine Administration on Lipopolysaccharide-Mediated Lethal Endotoxic Shock in Mice.

    PubMed

    Fukada, Tomoko; Kato, Hidehito; Ozaki, Makoto; Yagi, Junji

    2016-05-01

    Sepsis is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of the cytokine storm caused by dysregulation of cytokine production. Morphine influences the severity of infection in vivo and in vitro because it regulates cytokine production. We investigated the immunological function of morphine using a mouse model of septic shock. We treated mice with α-galactosylceramide (2 μg/mouse) to induce lethal endotoxic shock following a challenge with lipopolysaccharide (LPS, 1.5 μg/mouse). This model represents acute lung injury and respiratory failure, and reflects the clinical features of severe septic shock. We evaluated the effect of the timing of morphine (0.8 mg/mouse) administration on the survival rate, cytokine production in vivo, and histological changes of mice with LPS-mediated lethal endotoxic shock. Morphine treatment before LPS challenge suppressed lethal endotoxic shock. In contrast, when we administered after LPS, morphine exacerbated lethal endotoxic shock; hematoxylin and eosin staining revealed a marked increase in the accumulation of infiltrates comprising polymorphonuclear leukocytes and mononuclear cells in the lung; and Elastica van Gieson staining revealed the destruction of alveoli. The plasma levels of tumor necrosis factor-α, interferon-γ, monocyte-chemotactic protein-1, and interleukin-12 in the group treated with morphine after LPS challenge were higher than those treated with morphine before LPS challenge. In conclusion, one of the factors that determine whether morphine exacerbates or inhibits infection is the timing of its administration. Morphine treatment before shock improved the survival rate, and morphine treatment after shock decreased the rate of survival. PMID:26682949

  11. Cholescintigraphy in acute cholecystitis: use of intravenous morphine

    SciTech Connect

    Choy, D.; Shi, E.C.; McLean, R.G.; Hoschl, R.; Murray, I.P.C.; Ham, J.M.

    1984-04-01

    Conventional cholescintigraphy (60 patients) and a modified protocol (59 patients) were compared in 74 females and 45 males with acute cholecystitis. In the modified protocol, intravenous morphine was administered whenever the gallbladder was not seen 40 minutes after injection of Tc-99m-pyroxylidene-glutamate. Accuracy was 98% with morphine, compared with 88% for the conventional protocol; specificity improved from 83% to 100% with no loss of sensitivity. Low doses of morphine are well tolerated and can result in a highly accurate diagnosis of acute cholecystitis without the need for delayed imaging.

  12. [Acute respiratory distress subordinate to a morphine overdose during a frail elderly patient controlled analgesia].

    PubMed

    Ades, A; Compère, V; Abriou, C; Baert, O; Fourdrinier, V; Dureuil, B

    2009-04-01

    We describe a case-report of an 85-year-male patient with a patient-controlled analgesia (PCA) after a total hip arthroplasty. Four hours after surgery, acute respiratory distress secondary to a morphine overdose occurred, requiring an antagonisation with naloxone. Morphine overdose during a PCA was always caused by a wrong use of the pump. In this case-report, no mistake of programming or administration's use was found. Too important morphine's doses managed in comparison with the patient's age and his renal failure could explain this morphine's accumulation and the respiratory distress. This observation reminds us the obligation to determine the optimal posology in accordance with the rate of glomerular filtration estimated by Cockcroft and Gault formula for patients using a PCA. PMID:19361945

  13. The role of gaseous neurotransmitters in the antinociceptive effects of morphine during acute thermal pain.

    PubMed

    Gou, Gemma; Leánez, Sergi; Pol, Olga

    2014-08-15

    Treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer, CORM-2) or a classical inducible heme oxygenase (HO-1) inducer (cobalt protoporphyrin IX, CoPP) enhanced the antinociceptive effects of morphine during chronic pain but the role played by these compounds in acute thermal nociception was not evaluated. The effects of CORM-2 and CoPP treatments on the local antinociceptive actions of morphine and their interactions with nitric oxide during acute pain were evaluated by using wild type (WT), neuronal (nNOS-KO) or inducible (iNOS-KO) nitric oxide synthase knockout mice and assessing their thermal nociception to a hot stimulus with the hot plate test. Our results showed that the absence of nNOS or iNOS genes did not alter licking and jumping responses nor the antinociceptive effects produced by morphine indicating that the local thermal inhibitory effects produced by this drug in the absence of inflammation or injury are not mediated by the nitric oxide pathway triggered by nNOS or iNOS enzymes. Moreover, while the systemic administration of CORM-2 or CoPP inhibited licking and jumping latencies in all genotypes, these treatments only enhanced the local inhibition of jumping latencies produced by morphine in WT and nNOS-KO mice which effects were reversed by the peripheral administration of an HO-1 inhibitor. These data indicate that the co-administration of morphine with CORM-2 or CoPP produced remarkable local antinociceptive effects in WT and nNOS-KO mice and reveal that a significant interaction between carbon monoxide and nitric oxide systems occurs on the local antinociceptive effects produced by morphine during acute thermal nociception. PMID:24846012

  14. The on- and off-target effects of morphine in acute coronary syndrome: A narrative review.

    PubMed

    McCarthy, Cian P; Mullins, Kieran V; Sidhu, Sunjeet S; Schulman, Steven P; McEvoy, John W

    2016-06-01

    With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest pain due to acute Myocardial Infarction (MI). However, observational data suggest that morphine administration during MI may have negative consequences. While vomiting, hypotension and respiratory depression are established side effects, recent reports have demonstrated attenuated and delayed oral anti-platelet agent absorption, as well as suboptimal reperfusion after MI, all of which may translate into adverse cardiovascular outcomes. These data have resulted in reduced support for morphine in recent European and U.S. clinical practice guidelines for MI; despite the absence of any prospective randomized outcomes trials addressing this question. As such, randomized trials are now necessary to confirm whether or not morphine, which is administered in up to 30% of MI cases, causes adverse clinical outcomes in these patients. However, given that placebo-controlled randomized trial designs evaluating morphine in MI are limited by an ethical requirement for appropriate analgesia, alternative investigational approaches may be necessary. In this article we review the updated evidence for morphine in MI and outline novel strategies that may facilitate future investigation of this clinical dilemma. PMID:27264228

  15. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients

    PubMed Central

    Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman

    2016-01-01

    The present study aimed to evaluate the effectiveness of morphine and meperidine (pethidine) as pain relief in opioid-dependent patients with acute pain. A total of 122 opioid-dependent patients with acute pain were included in the study. Their pain severity was assessed, using visual analog scale (VAS) scores ranging from 0 to 10. The patients randomly received intravenous morphine (up to 0.15 mg/kg) or meperidine (up to 1.5 mg/kg) for pain control by patient control analgesia (PCA) pump. The clinical opioid withdrawal scale (COWS) was employed for the assessment of withdrawal symptoms. The pain relief and the emergence of withdrawal symptoms were measured at 15, 30, and 60 minutes after drug administration. The patients who received morphine reported a better pain control compared to those who received meperidine (mean ± standard deviation [SD] VAS scores 4.11±1.90 vs 5.85±2.08 at the end of the study; P<0.001). On the other hand, the patients who received meperidine indicated prominent withdrawal symptoms (mean ± SD COWS scores 4.80±2.18 vs. 1.98±0.82 at the end of the study; P<0.001). Our findings revealed that morphine can be recommended in acute pain management of opioid-dependent patients. In addition, emergency physicians should ask their patients about any drug dependence before selecting the appropriate drug for their acute pain management.

  16. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients.

    PubMed

    Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman

    2016-01-01

    The present study aimed to evaluate the effectiveness of morphine and meperidine (pethidine) as pain relief in opioid-dependent patients with acute pain. A total of 122 opioid-dependent patients with acute pain were included in the study. Their pain severity was assessed, using visual analog scale (VAS) scores ranging from 0 to 10. The patients randomly received intravenous morphine (up to 0.15 mg/kg) or meperidine (up to 1.5 mg/kg) for pain control by patient control analgesia (PCA) pump. The clinical opioid withdrawal scale (COWS) was employed for the assessment of withdrawal symptoms. The pain relief and the emergence of withdrawal symptoms were measured at 15, 30, and 60 minutes after drug administration. The patients who received morphine reported a better pain control compared to those who received meperidine (mean ± standard deviation [SD] VAS scores 4.11±1.90 vs 5.85±2.08 at the end of the study; P<0.001). On the other hand, the patients who received meperidine indicated prominent withdrawal symptoms (mean ± SD COWS scores 4.80±2.18 vs. 1.98±0.82 at the end of the study; P<0.001). Our findings revealed that morphine can be recommended in acute pain management of opioid-dependent patients. In addition, emergency physicians should ask their patients about any drug dependence before selecting the appropriate drug for their acute pain management. PMID:27621675

  17. Intra-administration associations and withdrawal symptoms: morphine-elicited morphine withdrawal.

    PubMed

    McDonald, Robert V; Siegel, Shepard

    2004-02-01

    On the basis of a conditioning analysis, some drug "withdrawal symptoms" are conditional responses elicited by stimuli paired with the drug effect. Prior demonstrations of conditional elicitation of withdrawal symptoms evaluated the role of environmental cues; however, pharmacological cues also typically signal a drug effect. Within each administration, early drug onset cues (DOCs) may become associated with the later, larger drug effect (intra-administration associations). This experiment evaluated the contribution of intra-administration associations to withdrawal symptoms. The results indicated that (a). 5 mg/kg morphine elicited behavioral and thermic withdrawal symptoms in rats previously injected on a number of occasions with 50 mg/kg morphine and that (b). DOC-elicited withdrawal symptoms are not a sensitized response to the opiate but rather an associative phenomenon. PMID:14769091

  18. Effect of chronic morphine administration on circulating dendritic cells in SIV-infected rhesus macaques.

    PubMed

    Cornwell, William D; Wagner, Wendeline; Lewis, Mark G; Fan, Xiaoxuan; Rappaport, Jay; Rogers, Thomas J

    2016-06-15

    We studied the effect of chronic morphine administration on the circulating dendritic cell population dynamics associated with SIV infection using rhesus macaques. Animals were either first infected with SIV and then given chronic morphine, or visa versa. SIV infection increased the numbers of myeloid DCs (mDCs), but morphine treatment attenuated this mDC expansion. In contrast, morphine increased the numbers of plasmacytoid DCs (pDCs) in SIV-infected animals. Finally, chronic morphine administration (no SIV) transiently increased the numbers of circulating pDCs. These results show that chronic morphine induces a significant alteration in the available circulating levels of critical antigen-presenting cells. PMID:27235346

  19. The Effect of Acute and Chronic Morphine on Some Blood Biochemical Parameters in an Inflammatory Condition in Gonadectomized Male Rats

    PubMed Central

    Chahkandi, Mohadeseh; Askari, Nayerreh; Asadikaram, Gholamreza

    2015-01-01

    Background Opiates affect blood factors as well as pain and inflammation in a gender-dependent manner. The aim of the present study was to evaluate the effects of morphine on serum glucose, cholesterol, triglycerides, and urea in gonadectomized and inflammation conditions. Methods Animals were divided as follows: control group, carrageenan and chronic morphine recipients, acute morphine recipients, chronic morphine recipients, carrageenan recipients, acute morphine and carrageenan recipients, gonadectomized group, gonadectomized recipients of carrageenan, gonadectomized recipients of morphine, gonadectomized recipients of chronic morphine, gonadectomized recipients of carrageenan and chronic morphine, gonadectomized recipients of acute morphine and carrageenan. Findings Our results have shown that acute and chronic morphine elevates blood glucose level in the acute and chronic morphine group. Cholesterol level has shown to be increasing in the morphine and carrageenan recipient group compared with a group which merely received morphine. Triglyceride has shown to be decreasing in acute and chronic morphine recipient group compared with control group. A significant increase in serum urea was observed in acute and chronic morphine recipients compared with the carrageenan recipient group. Conclusion Morphine alters the serum glucose, cholesterol, triglyceride, and urea in the normal and inflammatory conditions differently, hence, this finding should be considered in the patients who use morphine as a relief of pain, especially in an inflammatory condition. PMID:26885349

  20. Extended-release morphine sulfate in treatment of severe acute and chronic pain

    PubMed Central

    Balch, Robert J; Trescot, Andrea

    2010-01-01

    Morphine is the archetypal opioid analgesic. Because it is a short-acting opioid, its use has been limited to the management of acute pain. The development of extended-release formulations have resulted in the increased utilization of morphine in chronic pain conditions. This review documents the history of morphine use in pain treatment, and describes the metabolism, pharmacodynamics, formulations, and efficacy of the currently available extended-release morphine medications. PMID:21197323

  1. Intrathecal Administration of Morphine Decreases Persistent Pain after Cesarean Section: A Prospective Observational Study

    PubMed Central

    Moriyama, Kumi; Ohashi, Yuki; Motoyasu, Akira; Ando, Tadao; Moriyama, Kiyoshi; Yorozu, Tomoko

    2016-01-01

    Purpose Chronic pain after cesarean section (CS) is a serious concern, as it can result in functional disability. We evaluated the prevalence of chronic pain after CS prospectively at a single institution in Japan. We also analyzed perioperative risk factors associated with chronic pain using logistic regression analyses with a backward-stepwise procedure. Materials and Methods Patients who underwent elective or emergency CS between May 2012 and May 2014 were recruited. Maternal demographics as well as details of surgery and anesthesia were recorded. An anesthesiologist visited the patients on postoperative day (POD) 1 and 2, and assessed their pain with the Prince Henry Pain Scale. To evaluate the prevalence of chronic pain, we contacted patients by sending a questionnaire 3 months post-CS. Results Among 225 patients who questionnaires, 69 (30.7%) of patients complained of persistent pain, although no patient required pain medication. Multivariate analyses identified lighter weight (p = 0.011) and non-intrathecal administration of morphine (p = 0.023) as determinant factors associated with persistent pain at 3 months. The adjusted odds ratio of intrathecal administration of morphine to reduce persistent pain was 0.424, suggesting that intrathecal administration of morphine could decrease chronic pain by 50%. In addition, 51.6% of patients had abnormal wound sensation, suggesting the development of neuropathic pain. Also, 6% of patients with abnormal wound sensation required medication, yet no patients with persistent pain required medication. Conclusion Although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased chronic pain after CS. PMID:27163790

  2. Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats

    SciTech Connect

    Fuhrman-Lane, C.; Fujimoto, J.M.

    1982-09-01

    The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of (/sup 14/C)morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate (morphine-3-glucuronide (MG)). However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of (/sup 14/C)MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

  3. Memory Impairment and Reduced Exploratory Behavior in Mice after Administration of Systemic Morphine

    PubMed Central

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Fujii, Mei; Goto, Akiko; Kanda, Yusuke; Koizumi, Akira; Kuroiwa, Hirotoshi; Mibayashi, Satoko; Muranishi, Yumi; Otaki, Soichiro; Sumikawa, Minako; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Uhl, George R; Takemura, Motohiko

    2015-01-01

    In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by μ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety. PMID:25987850

  4. Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys.

    PubMed

    Maguire, David R; Gerak, Lisa R; France, Charles P

    2016-04-01

    Opioid abusers discount delayed reinforcers more rapidly than nonusers; however, it is unclear whether chronic drug administration or its discontinuation impacts discounting. This study examined the impact of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Responding on one lever delivered one food pellet immediately; responding on another lever delivered two food pellets either immediately or after a delay (30-120 s) that increased within the session. Monkeys (n=3) responded for the large reinforcer when both reinforcers were delivered immediately and more for the smaller, immediately available reinforcer as the delay to delivery of the large reinforcer increased. When administered acutely, morphine (0.032-5.6 mg/kg) increased trial omissions and had variable effects on choice, with small doses decreasing and large doses increasing choice of the large delayed reinforcer. Chronic morphine administration (0.1 mg/kg/day to 3.2 mg/kg twice daily) reduced choice of the large delayed reinforcer in two monkeys, while increasing choice in a third monkey. Despite the development of tolerance to some effects (i.e. rightward shifts in dose-effect curves for the number of trials omitted) and evidence of mild opioid dependence (e.g. decrease in the number of trials completed, as well as body weight), discontinuation of treatment did not appear to systematically impact discounting. Overall, these results suggest that repeated opioid administration causes persistent effects on choice under a delay discounting procedure; however, differences in the direction of effect among individuals suggest that factors other than, or in addition to, changes in discounting might play a role. PMID:26397762

  5. Effects of central administration of morphine on renal function in conscious rats.

    PubMed

    Danesh, S; Walker, L A

    1988-02-01

    Systemic administration of morphine in rats produces an anti-natriuretic effect that is at least partially dependent on renal nerves. The present studies were carried out in order to assess the renal response to central administration of morphine. Male Sprague-Dawley rats were surgically prepared with arterial, venous and bladder cannulas. In addition, a guide cannula was placed into the lateral ventrical and secured to the surface of the skull. Experiments were carried out at least 3 days after surgery. Renal clearance measurements were 30 min each. After a basal period, morphine sulfate (4 micrograms/4 microliters) or vehicle was injected into the lateral cerebral ventricle. Two clearance measurements were obtained, followed by central administration of naloxone HCl (4 micrograms/4 microliters) or vehicle and two more clearance periods. Morphine administration had no effect on blood pressure or heart rate but caused a sharp reduction in sodium excretion (3200 +/- 958 vs 970 +/- 158 nEq/100 g/min in period 5; P less than .05). This response was reversed by the addition of naloxone (3280 +/- 583 nEq/100 g/min in period 5; P less than .05). Furthermore, morphine had no effect on renal plasma flow and glomerular filtration rate. Naloxone increased the renal plasma flow and glomerular filtration rate in morphine-treated rats, whereas it had no effect in controls. It is concluded that central administration of morphine in conscious rats enhances renal tubular sodium reabsorption by an opiate receptor-dependent mechanism. PMID:3346840

  6. Treadmill exercise reduces self-administration of morphine in male rats.

    PubMed

    Hosseini, Mahmoud; Alaei, Hojjat Allah; Naderi, Asieh; Sharifi, Mohammad Reza; Zahed, Reza

    2009-06-01

    Exercise can activate the same pathways as morphine. The aim of the present study was to clarify the effect of short-term and mid-term exercises on the self-administration of morphine in rats. Male Wistar rats were initially trained to receive small pellets of food by pressing the active lever in self-administration apparatus. Rats were divided into 4 groups: Saline, Morphine, Exercise 1 (11 days) and Exercise 2 (30 days). Their jugular vein was cannulated. The animals were placed in self-administration apparatus and allowed to self-administer morphine (0.5mg per infusion all test groups) or saline (Saline group) during consecutive days, for 2h/sessions. In the group 1 the rats were running before each session of self-administration and of group Exercise 2, 30 days before surgery as well as before each session. The pressing numbers of active and passive levers in each group and among different groups were compared. The number of active lever pressing of Morphine group was significantly higher than Saline group (p<0.001). In Exercise 1 and Exercise 2 groups, the number of active lever pressing was significantly lower than Morphine group (p<0.001). As exercise can activate many neurotransmitter systems involved in the addiction process and increase the release of endorphins, it is likely that could decrease the morphine self-administration in this experimental setup. PMID:19131225

  7. Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis

    PubMed Central

    Ding, Xibing; Jin, Shuqing; Niu, Xiaoyin; Wang, Tingting; Zhao, Xiang; Ren, Hao; Tong, Yao; Li, Quan

    2014-01-01

    Purpose: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. Methods: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. Results: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. Conclusion: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness. PMID:25356103

  8. Time Dependent Antinociceptive Effects of Morphine and Tramadol in the Hot Plate Test: Using Different Methods of Drug Administration in Female Rats

    PubMed Central

    Gholami, Morteza; Saboory, Ehsan; Mehraban, Sogol; Niakani, Afsaneh; Banihabib, Nafiseh; Azad, Mohamad-Reza; Fereidoni, Javid

    2015-01-01

    Morphine and tramadol which have analgesic effects can be administered acutely or chronically. This study tried to investigate the effect of these drugs at various times by using different methods of administration (intraperitoneal, oral, acute and chronic). Sixty adult female rats were divided into six groups. They received saline, morphine or tramadol (20 to 125 mg/Kg) daily for 15 days. A hot plate test was performed for the rats at the 1st, 8th and 15th days. After drug withdrawal, the hot plate test was repeated at the 17th, 19th, and 22nd days. There was a significant correlation between the day, drug, group, and their interaction (P<0.001). At 1st day (d1), both morphine, and tramadol caused an increase in the hot plate time comparing to the saline groups (P<0.001), while there was no correlation between drug administration methods of morphine and/or tramadol. At the 8th day (d8), morphine and tramadol led to the most powerful analgesic effect comparing to the other experimental days (P<0.001). At the 15th day (d15), their effects diminished comparing to the d8. After drug withdrawal, analgesic effect of morphine, and tramadol disappeared. It can be concluded that the analgesic effect of morphine and tramadol increases with the repeated use of them. Thereafter, it may gradually decrease and reach to a level compatible to d1. The present data also indicated that although the analgesic effect of morphine and tramadol is dose-and-time dependent, but chronic exposure to them may not lead to altered nociceptive responses later in life. PMID:25561936

  9. Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

    PubMed Central

    Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619

  10. Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration

    PubMed Central

    Piepponen, T Petteri; Mikkola, Janne A V; Ruotsalainen, Minna; Jonker, Daniël; Ahtee, Liisa

    1999-01-01

    The effect of intrastriatally-administered morphine on striatal dopamine (DA) release was studied in freely moving rats. Morphine (1, 10 or 100 μM) was given into the striatum by reversed microdialysis, and concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously measured from the striatal dialysates.Intrastriatally-administered morphine significantly and dose-dependently decreased the extracellular concentration of DA, the concentrations of the acidic DA metabolites were only slightly decreased. The effect of morphine was antagonized by naltrexone (2.25 mg kg−1, s.c.). Pretreatment with a preferential κ-opioid receptor antagonist, MR2266 [(−)-5,9 alpha-diethyl-2-(3-furylmethyl)-2′-hydroxy-6,7-benzomorphane; 1 mg kg−1, s.c.], had no effect on the decrease of extracellular DA evoked by intrastriatal morphine (100 μM).Intrastriatal administration of the selective μ-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO; 1 μM), significantly decreased the extracellular concentration of DA in the striatum.When the rats were given morphine repeatedly in increasing doses (10–25 mg kg−1, s.c.) twice daily for 7 days and withdrawn for 48 h, the decrease of extracellular DA induced by morphine (100 μM) was significantly less than that seen in saline-treated controls.Our results show that besides the well-known stimulatory effect there is a local inhibitory component in the action of morphine on striatal DA release in the terminal regions of nigrostriatal DA neurones. Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the μ-opioid receptors. PMID:10369482

  11. Evaluation of analgesic effect of local administration of morphine after iliac crest bone graft harvesting: A double blind study

    PubMed Central

    Singh, Devinder; Gombar, K K; Bhatia, Nidhi; Gombar, Satinder; Garg, Sudhir

    2013-01-01

    Background and Objective: Pain is a complex process influenced by both physiological and psychological factors. In spite of an armamentarium of analgesic drugs and techniques available to combat post-operative pain, appropriate selection, and effective management for relief of post-operative pain still poses unique challenges. The discovery of peripheral opioid receptors has led to growing interest in the use of locally applied opioids (intra-articular, intra-pleural, intra-peritoneal, and perineural) for managing acute pain. As bone graft harvesting is associated with significant post-operative pain and there is a paucity of literature on the use of peripheral opioids at the iliac crest bone harvesting site, the present study was planned to evaluate the analgesic efficacy of local administration of morphine after iliac crest bone graft harvesting. Materials and Methods: A total of 60 patients, 20-50 years of age scheduled to undergo elective surgery for delayed and non-union fracture both bone leg with bone grafting under general anaesthesia (GA) were randomly assigned to one of the four groups of 15 patients each: group 1: 2.5 ml normal saline (NS) +2.5 ml NS infiltrated into the harvest site at 2 sites + 1 ml NS intramuscularly (i/m); Group 2: 2.5 ml NS + 2.5 ml NS infiltrated into the harvest site at 2 sites + 5 mg morphine in 1 ml i/m.; Group 3: 2.5 mg (2.5 ml) morphine + 2.5 mg (2.5 ml) morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m; Group 4: 0.5 mg naloxone (2.5 ml) +5 mg (2.5 ml) morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m. Pain from the bone graft site and operative site was assessed for 24 h post-operatively. Results: The patients who had received morphine infiltration (Group 3) had significantly less pain scores at the graft site at 4, 6, and 10 post-operative hours. They also had significantly less morphine consumption and overall better pain relief as compared to the other groups. Conclusions: Morphine

  12. Involvement of neuropeptide Y in the acute, chronic and withdrawal responses of morphine in nociception in neuropathic rats: behavioral and neuroanatomical correlates.

    PubMed

    Upadhya, Manoj A; Dandekar, Manoj P; Kokare, Dadasaheb M; Singru, Praful S; Subhedar, Nishikant K

    2009-08-01

    Although morphine is a potent antinociceptive agent, its chronic use developed tolerance in neuropathic pain (NP). Furthermore, opioid antagonist naloxone attenuated the antinociceptive effect of neuropeptide Y (NPY). The present study investigated the role of NPY and NPY Y1/Y5 receptors in acute and chronic actions of morphine in neuropathic rats using thermal paw withdrawal test and immunocytochemistry. In acute study, intracerebroventricular (icv) administration of morphine, NPY or NPY Y1/Y5 receptors agonist [Leu(31),Pro(34)]-NPY produced antinociception, whereas selective NPY Y1 receptors antagonist BIBP3226 caused hyperalgesia. While NPY or [Leu(31),Pro(34)]-NPY potentiated, BIBP3226 attenuated morphine induced antinociception. Chronic icv infusion of morphine via osmotic minipumps developed tolerance to its antinociceptive effect, and produced hyperalgesia following withdrawal. However, co-administration of NPY or [Leu(31),Pro(34)]-NPY prevented the development of tolerance and withdrawal hyperalgesia. Sciatic nerve ligation resulted in significant increase in the NPY-immunoreactive (NPY-ir) fibers in ventrolateral periaqueductal gray (VLPAG) and locus coeruleus (LC); fibers in the dorsal part of dorsal raphe nucleus (DRD) did not respond. While chronic morphine treatment significantly reduced NPY-ir fibers in VLPAG and DRD, morphine withdrawal triggered significant augmentation in NPY-immunoreactivity in the VLPAG. NPY-immunoreactivity profile of LC remained unchanged in all the morphine treatment conditions. Furthermore, removal of sciatic nerve ligation reversed the effects of NP, increased pain threshold and restored NPY-ir fiber population in VLPAG. NPY, perhaps acting via Y1/Y5 receptors, might profoundly influence the processing of NP information and interact with the endogenous opioid system primarily within the framework of the VLPAG. PMID:19556004

  13. ANDROGENS AND OPIATES: TESTOSTERONE INTERACTION WITH MORPHINE SELF-ADMINISTRATION IN MALE RATS

    PubMed Central

    Cooper, Sarah E.; Wood, Ruth I.

    2016-01-01

    Abuse of anabolic-androgenic steroids (AAS) and opioids intersect in athletics. Evidence from humans and animals suggests that AAS may act in the brain via opioidergic mechanisms, and may potentiate effects of opioids. To determine if AAS enhance motivation for opioid intake, this study treated male rats chronically for 6 weeks with high levels of testosterone (7.5 mg/kg) or vehicle s.c. and tested them for morphine self-administration under fixed (FR) and progressive ratio (PR) schedules. Initially, rats received chronic morphine infusion (16.8–50 mg/kg/day) over 7 days. Subsequently, rats were tested for morphine self-administration (3.2 mg/kg) 6h/day for 3 days under an FR1 schedule, and for 7 days under a PR 9-4 schedule. With FR1, controls self-administered more morphine (95.9±8.5 mg/kg), compared with testosterone-treated rats (63.2±7.2 mg/kg, p<0.05). Under PR, there was no effect of testosterone on morphine intake or operant responding (26.7±5.7 responses vs 30.9±5.9 responses for vehicle; n.s.). To determine if testosterone enhances morphine sedation, additional rats were treated with testosterone or vehicle and evaluated for locomotor behavior and rearing activity over 30 min in response to saline or 10 mg/kg morphine. Morphine inhibited locomotor activity and rearing; testosterone selectively reduced rearing behavior, but did not alter locomotor behavior. These results suggest that testosterone does not increase motivation for morphine. PMID:24488032

  14. Intrathecal morphine attenuates acute opioid tolerance secondary to remifentanil infusions during spinal surgery in adolescents

    PubMed Central

    Tripi, Paul A; Kuestner, Matthew E; Poe-Kochert, Connie S; Rubin, Kasia; Son-Hing, Jochen P; Thompson, George H; Tobias, Joseph D

    2015-01-01

    Introduction The unique pharmacokinetic properties of remifentanil with a context-sensitive half-life unaffected by length of infusion contribute to its frequent use during anesthetic management during posterior spinal fusion in children and adolescents. However, its intraoperative administration can lead to increased postoperative analgesic requirements, which is postulated to be the result of acute opioid tolerance with enhancement of spinal N-methyl-D-aspartate receptor function. Although strategies to prevent or reduce tolerance have included the coadministration of longer acting opioids or ketamine, the majority of these studies have demonstrated little to no benefit. The current study retrospectively evaluates the efficacy of intrathecal morphine (ITM) in preventing hyperalgesia following a remifentanil infusion. Methods We retrospectively analyzed 54 patients undergoing posterior spinal fusion with segmental spinal instrumentation, to evaluate the effects of ITM on hyperalgesia from remifentanil. Patients were divided into two groups based on whether they did or did not receive remifentanil during the surgery: no remifentanil (control group) (n=27) and remifentanil (study group) (n=27). Data included demographics, remifentanil dose and duration, Wong–Baker visual analog scale postoperative pain scores, and postoperative intravenous morphine consumption in the first 48 postoperative hours. Results The demographics of the two study groups were similar. There were no differences in the Wong–Baker visual analog scale pain scores in the postanesthesia care unit and on postoperative days 1 and 3. Pain scores were higher in the remifentanil group on postoperative day 2 (2.9 vs 3.8). Postoperative morphine requirements were similar between the two groups (0.029 vs 0.017 mg/kg/48 h for the control group and the study group, respectively). Conclusion In patients receiving preincisional ITM during spinal surgery, intraoperative remifentanil does not increase

  15. RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

    PubMed Central

    Darcq, Emmanuel; Befort, Katia; Koebel, Pascale; Pannetier, Solange; Mahoney, Megan K; Gaveriaux-Ruff, Claire; Hanauer, André; Kieffer, Brigitte L

    2012-01-01

    It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor–RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex. PMID:22218090

  16. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration.

    PubMed

    Tzvetkov, Mladen V; dos Santos Pereira, Joao N; Meineke, Ingolf; Saadatmand, Ali R; Stingl, Julia C; Brockmöller, Jürgen

    2013-09-01

    We investigated whether morphine and its pro-drug codeine are substrates of the highly genetically polymorphic organic cation transporter OCT1 and whether OCT1 polymorphisms may affect morphine and codeine pharmacokinetics in humans. Morphine showed low transporter-independent membrane permeability (0.5 × 10⁻⁶ cm/s). Morphine uptake was increased up to 4-fold in HEK293 cells overexpressing human OCT1. The increase was concentration-dependent and followed Michaelis-Menten kinetics (KM = 3.4 μM, VMAX = 27 pmol/min/mg protein). OCT1-mediated morphine uptake was abolished by common loss-of-function polymorphisms in the OCT1 gene and was strongly inhibited by drug-drug interactions with irinotecan, verapamil and ondansetron. Morphine uptake in primary human hepatocytes was strongly reduced by MPP⁺, an inhibitor of organic cation transporters, and morphine was not a substrate of OCT3, the other organic cation transporter expressed in human hepatocytes. In concordance with the in vitro data, morphine plasma concentrations in healthy volunteers were significantly dependent on OCT1 polymorphisms. After codeine administration, the mean AUC of morphine was 56% higher in carriers of loss-of-function OCT1 polymorphisms compared to non-carriers (P = 0.005). The difference remained significant after adjustment for CYP2D6 genotype (P = 0.03). Codeine itself had high transporter-independent membrane permeability (8.2 × 10⁻⁶ cm/s). Codeine uptake in HEK293 cells was not affected by OCT1 overexpression and OCT1 polymorphisms did not affect codeine AUCs. In conclusion, OCT1 plays an important role in the hepatocellular uptake of morphine. Carriers of loss-of-function OCT1 polymorphisms may be at higher risk of adverse effects after codeine administration, especially if they are also ultra-rapid CYP2D6 metabolizers. PMID:23835420

  17. Comparison of Clinical Efficacy of Intravenous Acetaminophen with Intravenous Morphine in Acute Renal Colic: A Randomized, Double-Blind, Controlled Trial

    PubMed Central

    Forouzan, Arash; Asgari Darian, Ali; Feli, Maryam; Barzegari, Hassan; Khavanin, Ali

    2014-01-01

    The aim of this study was to compare the clinical efficacy of intravenous acetaminophen with intravenous morphine in acute renal colic pain management. In this double-blind controlled trial, patients aged 18–55 years, diagnosed with acute renal colic, who met the inclusion and exclusion criteria, were randomized into two groups. First, using the visual analogue scale (VAS), intensity of pain was assessed in both groups. Then, one gram of intravenous acetaminophen or 0.1 mg/kg morphine was infused in 100 mL normal saline to either acetaminophen or morphine group. Intensity of pain was reassessed in 15, 30, 45, and 60 minutes according to VAS criteria. Finally, data from 108 patients were analyzed, 54 patients in each group. No significant difference was observed between the two groups in regard to sex (P = 0.13), mean age (P = 0.54), and baseline visual analogue score (P = 0.21). A repeated measure analysis of variance revealed that the difference between the two treatments was significant (P = 0.0001). The VAS reduction at primary endpoint (30 min after drug administration) was significantly higher in the acetaminophen group than in the morphine group (P = 0.0001). This study demonstrated that intravenous acetaminophen could be more effective than intravenous morphine in acute renal colic patients' pain relief. PMID:25197573

  18. Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut derived sepsis in mice during chronic morphine administration

    PubMed Central

    Babrowski, Trissa; Holbrook, Christopher; Moss, Jonathan; Gottlieb, Lawrence; Valuckaite, Vesta; Zaborin, Alexander; Poroyko, Valeriy; Liu, Donald C.; Zaborina, Olga; Alverdy, John C.

    2011-01-01

    OBJECTIVE This study was designed to examine the effect of morphine administration on the intestinal mucus barrier and determine its direct effect on the virulence and lethality of Pseudomonas aeruginosa, one of the most frequent pathogens to colonize the gut of critically ill patients. SUMMARY BACKGROUND DATA Surgical injury is associated with significant exposure of host tissues to morphine from both endogenous release as well as its use as a potent analgesic agent. Morphine use in surgical patients exposed to extreme physiologic stress is well established to result in increased infection risk. Although morphine is a known immunosuppressant, whether it directly induces virulence expression and lethality in microbes that colonize the human gut remains unknown. METHODS Mice were implanted with a slow release morphine or placebo pellet with and without intestinal inoculation of P. aeruginosa created by direct cecal injection. Mucus production and epithelial integrity was assessed in cecal tissue via Alcian Blue staining and histological analysis. In vivo and in vitro P. aeruginosa virulence expression was examined using reporter strains tagged to the epithelial barrier disrupting protein PA-I lectin. P. aeruginosa chemotaxis toward morphine was also assayed in vitro. Finally the direct effect of morphine to induce PA-I lectin expression was determined in the absence and presence of methylnaltrexone, a mu opioid receptor antagonist. RESULTS Mice intestinally inoculated with P. aeruginosa and implanted with a morphine pellet demonstrated significant suppression of intestinal mucus, disrupted intestinal epithelium and enhanced mortality whereas exposure of mice to either systemic morphine or intestinal P. aeruginosa alone enhanced intestinal mucus without mortality suggesting a shift in P. aeruginosa during morphine exposure to a mucus suppressing, barrier disrupting, and lethal phenotype. Direct exposure of P. aeruginosa to morphine in vitro confirmed that morphine

  19. Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys.

    PubMed

    Wade-Galuska, Tammy; Galuska, Chad M; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self-administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs. PMID:21541117

  20. Effect of the co-administration of glucose with morphine on glucoregulatory hormones and causing of diabetes mellitus in rats

    PubMed Central

    Radahmadi, Maryam; Sharifi, Mohammad Reza; Amini, Masoud; Fesharaki, Mehrafarin

    2016-01-01

    Background: Morphine is related to dysregulation of serum hormone levels. In addition, addict subjects interest to sugar intake. Therefore, this study investigated the effect of co-administration of glucose with Mo on the glucoregulatory hormones and causing of diabetes mellitus in rats. Materials and Methods: Male rats were randomly divided into four groups including, control, morphine, Morphine-Glucose and diabetes groups. Morphine was undergone through doses of 10, 20, 30, 40, 50, and 60 mg/kg, respectively on days 1, 2, 3, 4, 5, and 6. Then, dose of 60 mg/kg was used repeated for 20 extra days. The Morphine-Glucose group received the same doses of morphine plus 1 g/kg glucose per day. Diabetes was induced by intraperitoneal injection of 65 mg/kg streptozotocin. At the end of experiment, the serum insulin, glucagon, growth hormone (GH), cortisol, and glucose levels were measured. The homeostasis model assessment (HOMA) indexes concluding the HOMA-insulin resistance (HOMA-IR) and HOMA-β were evaluated. Results: Morphine insignificantly induced a hyperglycemia condition and insulin resistance. Whereas, the beta-cell functions significantly (P < 0.05) decreased only in morphine group. The co-administration of glucose slightly increased the GH, and increased insulin and cortisol levels significantly (P < 0.05 and P < 0.01; respectively) in the Morphine-Glucose group. Furthermore, the co-administration of glucose with morphine could nearly modulate the morphine effects on body weight, glucose, and glucagon levels. Conclusion: It is probable that the co-administration of glucose with morphine modulate the serum glucose levels by stimulating the beta-cell functions and to increase insulin secretion. PMID:26962523

  1. Morphine and codeine in oral fluid after controlled poppy seed administration.

    PubMed

    Concheiro, Marta; Newmeyer, Matthew N; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A; Huestis, Marilyn A

    2015-07-01

    Opiates are an important drug class in drug testing programmes. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only two addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45 g raw poppy seed doses, each containing 15.7 mg morphine and 3.1 mg codeine, 8 h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography-tandem mass spectrometry (1 µg/L morphine and codeine limits of quantification). Specimens (n = 459) were collected before and up to 32 h after the first dose. All specimens screened positive 0.5 h after dosing and remained positive for 0.5-13 h at Draeger 20 µg/L morphine cut-off. Maximum OF morphine and codeine concentrations (Cmax ) were 177 and 32.6 µg/L, with times to Cmax (Tmax ) of 0.5-1 h and 0.5-2.5 h post-dose, respectively. Windows of detection after the second dose extended at least 24 h for morphine and to 18 h for codeine. After both doses, the last morphine positive OF result was 1 h with 40 µg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cut-off, and 0.5 h with 95 µg/L cut-off, recently recommended by the Driving under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1 h after ingestion of 15.7 mg of morphine in raw poppy seeds, depending on the cut-off employed. PMID:25345619

  2. Stability of morphine sulfate in infusion devices and containers for intravenous administration.

    PubMed

    Duafala, M E; Kleinberg, M L; Nacov, C; Flora, K P; Hines, J; Davis, K; McDaniel, A; Scott, D

    1990-01-01

    The stability of morphine sulfate in one brand of polyvinyl chloride (PVC) container, one brand of glass syringe, and two brands of disposable infusion devices was determined. Solutions of morphine sulfate 2 and 15 mg/mL were used to fill the PVC containers and drug administration devices. Stability was determined for both concentrations of morphine sulfate at room temperature (23-25 degrees C) and 4 degrees C in the PVC containers, glass syringes, and disposable infusion devices; stability was also determined at 31 degrees C in the disposable infusion devices. At 0, 1, 2, 4, 7, 12, and 15 days, portions of the solutions were removed and assayed in triplicate by a stability-indicating high-performance liquid chromatographic method. At each time point the drug-infusion fluid combinations were inspected visually for color changes and the presence of particulate matter, and pH was measured. Morphine sulfate 2 and 15 mg/mL remained stable for at least 12 days in all the containers and devices at each temperature tested. No substantial changes in the pH or physical appearance of the solutions were observed. Morphine sulfate can be repackaged in the disposable glass syringe, PVC container, and both disposable infusion devices for routine clinical use. PMID:2301422

  3. Characterization of scratching behavior induced by intradermal administration of morphine and fentanyl in mice.

    PubMed

    Yamamoto, Atsuki; Kuyama, Shoji; Kamei, Chiaki; Sugimoto, Yukio

    2010-02-10

    Itching is known as a commonly side effect of opioid administration. However, the relationship of opioid receptors to itching is unclear. In this study, we examined the effect of intradermal injection of morphine and fentanyl on the itching sensation. When injected intradermally into the rostral back of mice, morphine and fentanyl elicited scratching behavior. In addition, an opioid receptor antagonist, naloxone, and a peripherally restricted opioid receptor antagonist, naloxone methiodide, significantly suppressed morphine- and fentanyl-induced scratching behavior. Moreover, the morphine-induced scratching behavior was suppressed by histamine H(1) receptor antagonists, such as diphenhydramine, chlorpheniramine, epinastine and cetirizine. On the other hand, fentanyl-induced scratching behavior was not suppressed by histamine H(1) receptor antagonists. Additionally, scratching behavior induced by morphine and fentanyl were not suppressed by glucocorticoids (predonisolone and dexamethasone). In conclusion, opioid-induced itching may involve in peripheral opioid receptors. Moreover, histamine and arachidonic acid metabolites played no main role in opioid-induced scratching behavior. PMID:19900440

  4. 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats.

    PubMed

    Glick, S D; Kuehne, M E; Maisonneuve, I M; Bandarage, U K; Molinari, H H

    1996-05-01

    Ibogaine, a naturally occurring iboga alkaloid, has been claimed to be effective in treating addiction to opioids and stimulants, and has been reported to inhibit morphine and cocaine self-administration in rats. However, ibogaine also has acute nonspecific side effects (e.g. tremors, decreased motivated behavior in general) as well as neurotoxic effects (Purkinje cell loss) manifested in the vermis of the cerebellum. 18-Methoxycoronaridine (MC) is a novel, synthetic iboga alkaloid congener that mimics ibogaine's effects on drug self-administration without appearing to have ibogaine's other adverse effects. Acutely, in rats, MC decreased morphine and cocaine self-administration but did not affect bar-press responding for water. In some rats, treatment with MC (40 mg/kg) induced prolonged decreases in morphine or cocaine intake lasting several days or weeks. MC had no apparent tremorigenic effect, and there was no evidence of cerebellar toxicity after a high dose (100 mg/kg) of MC. Similar to the effects of ibogaine and other iboga alkaloids that inhibit drug self-administration, MC (40 mg/kg) decreased extracellular levels of dopamine in the nucleus accumbens. MC therefore appears to be a safer, ibogaine-like agent that might be useful in the treatment of addictive disorders. PMID:8782860

  5. Morphine effects on gentamicin disposition and toxicity in mice.

    PubMed

    Hurwitz, A; Garty, M; Ben-Zvi, Z

    1988-05-01

    Morphine has been shown to reduce renal and hepatic clearance of several xenobiotics in rodents. After iv administration of gentamicin, 10 to 30 mg/kg, its plasma levels were elevated in mice given morphine, 20 mg/kg sc. Plasma clearance of gentamicin was nearly halved by morphine, due primarily to lowering of the elimination constant of gentamicin from 0.03 to 0.02 min-1 (p less than 0.01). Morphine also significantly reduced urine levels of gentamicin and urine volume. In mice given naloxone, 2 mg/kg sc, morphine did not significantly raise plasma levels of gentamicin nor reduce its elimination into urine. Mice were made tolerant by morphine administration for 9 days at ascending doses to 100 mg/kg twice daily. An acute challenge with morphine, 20 mg/kg, was less effective in raising plasma levels of gentamicin or lowering its urinary elimination in tolerant mice than after chronic saline treatment. Partial tolerance to acutely administered morphine and reversal of morphine effects by naloxone suggest opioid receptor-mediated reduction of glomerular filtration by morphine in mice. Despite marked elevation of plasma gentamicin levels in morphine-treated mice, narcotic administration did not significantly increase the acute toxicity of a single dose of gentamicin. LD50 of acutely administered iv gentamicin was 51.6 mg/kg after saline and 45.3 mg/kg after treatment with morphine, 20 mg/kg sc. However, this dose of morphine enhanced the lethality of intravenously infused gentamicin. Morphine administration significantly reduced the dose of infused gentamicin needed to achieve the critical lethal plasma level. PMID:3368920

  6. Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content.

    PubMed

    Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; LoDico, Charles; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

    2014-08-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45 g oral poppy seed doses 8 h apart, each containing 15.7 mg morphine and 3mg codeine. Urine was collected ad libitum up to 32 h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2000 and 300 μg/L cutoffs, and the ThermoFisher CEDIA(®) heroin metabolite (6-acetylmorphine, 6-AM) and Lin-Zhi 6-AM immunoassays with 10 μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32 h following dosing; 26.6% and 83.4% were positive for morphine at 2000 and 300 μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7522 μg/L with a median peak concentration of 5239 μg/L. The median first morphine-positive urine sample at 2000 μg/L cutoff concentration occurred at 6.6 h (1.2-12.1), with the last positive from 2.6 to 18 h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2000 μg/L, but 20.2% exceeded 300 μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300 μg/L cutoffs. The CEDIA 6-AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. PMID

  7. Morphine administration by Paramedics: an application of the Theory of Planned Behaviour.

    PubMed

    Weber, Anthony; Dwyer, Trudy; Mummery, Kerry

    2012-09-01

    Timely and appropriate pain management in the pre-hospital environment is paramount to effective patient care. Experts agree that there are many factors that hinder the delivery of adequate pain management to patients with pain. The purpose of this study was to use the Theory of Planned Behaviour (TPB) model to identify the factors influencing Ambulance Paramedics' intention to administer morphine to patients with pain. Participants of this study were Advanced Care and Intensive Care Paramedics who were deemed competent in morphine administration. Data were collected by means of a questionnaire that used the constructs of the TPB, including subjective norm, perceived behavioural control and attitude. Whilst participants reported strong intentions to administer morphine they also reported negative attitudes towards the behaviour. The constructs of the TPB explained 26% of the variance in intention to administer morphine with subjective norm being the strongest significant predictor. The findings related to specific attitudes and normative pressures provide an understanding into Paramedic's pain management behaviour. PMID:21215396

  8. Hypothalamic-pituitary-adrenal activity and pro-opiomelanocortin mRNA levels in the hypothalamus and pituitary of the rat are differentially modulated by acute intermittent morphine with or without water restriction stress.

    PubMed

    Zhou, Y; Spangler, R; Maggos, C E; Wang, X M; Han, J S; Ho, A; Kreek, M J

    1999-11-01

    Acute administration of morphine stimulates the secretion of hypothalamic-pituitary-adrenal (HPA) hormones, ACTH, beta-endorphin and corticosterone in the rat. In this study we investigated the effects of repeated multiple-dose morphine on HPA activity under two different conditions: without or with water restriction stress. Rats received six intermittent injections of morphine (6.25 mg/kg per injection, s.c.) every 2 h and were killed 30 min after the last injection. The results were as follows. (1) Morphine significantly elevated plasma ACTH and corticosterone levels; water restriction also significantly increased ACTH secretion, but with no significant increase of plasma corticosterone levels. In contrast, rats treated with morphine under the water restriction condition failed to show any increases of either ACTH or corticosterone levels. (2) Morphine did not change pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary; whereas water restriction significantly increased the POMC mRNA levels. The water restriction-induced increases of POMC mRNA in the anterior pituitary were absent in the rats which received morphine. (3) Morphine significantly increased POMC mRNA levels in the hypothalamus; water restriction had no effect. The morphine-induced increases in POMC mRNA in the hypothalamus were absent in the rat under the water restriction condition. These findings, that the effects of morphine on HPA activation or POMC mRNA expression depend on the presence of stress, suggest a counter-regulatory role of opiates on a stress response and opioid gene expression. PMID:10556776

  9. Managing acute withdrawal syndrome on patients with heroin and morphine addiction by acupuncture therapy.

    PubMed

    Lu, Po-kuang; Lu, Gabriel P; Lu, Dominic P; Lu, D P; Lu, Winston I

    2004-01-01

    Though there are articles and case reports about using acupuncture to detoxify and to break the narcotic addiction, few articles describe in the West about using acupuncture therapy to treat the emergence of acute withdrawal symptom due to heroin, opium, or morphine. Most often the method of treatment are using the methadone or benzodiazepine and phenoziazine drugs this article describes many years of clinical experience with non-drug approach to treat the acute withdrawal symptoms with acupuncture therapy. Unlike the drug approach, which usually has side effects, there is no adverse effect with acupuncture therapy. PMID:15807100

  10. Effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazol-induced epileptic behaviors in infant and prepubertal rats.

    PubMed

    Ebrahimi, Loghman; Saboory, Ehsan; Roshan-Milani, Shiva; Hashemi, Paria

    2014-09-01

    Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. Many reports have shown an interaction between morphine- and stress-induced behavioral changes in adult rats. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazole (PTZ)-induced epileptic behaviors was investigated in rat offspring to address effect of the interaction between morphine and stress. Pregnant rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, the rats were placed in 25 °C water on 17-19 days of pregnancy. In the morphine/saline group, the rats received morphine/saline on the same days. In the morphine/saline-stressed group, they were exposed to stress and received morphine/saline simultaneously. On postnatal day 15 (P15), blood samples were collected to determine corticosterone (COS) level. On P15 and P25, PTZ was injected to the rest of pups to induce seizure. Then, epileptic behaviors of each rat were individually observed. Latency of tonic-colonic seizures decreased in control-morphine and stressed-saline groups while increasing in stressed-morphine rats compared to control-saline group on P15. Duration of tonic-colonic seizures significantly increased in control-morphine and stressed-saline rats compared to stressed-morphine and control-saline rats on P15, but not P25. COS levels increased in stressed-saline group but decreased in control-morphine group compared to control-saline rats. Body weight was significantly higher in morphine groups than saline treated rats. Prenatal exposure to forced-swim stress potentiated PTZ-induced seizure in the offspring rats. Co-administration of morphine attenuated effect of stress on body weight, COS levels, and epileptic behaviors. PMID:24464467

  11. The Comparison of Apotel plus Low Dose of Morphine and Full Dose of Morphine in Pain Relief in Patients with Acute Renal Colic

    PubMed Central

    Morteza-Bagi, Hamid Reza; Amjadi, Mohsen; Mirzaii-Sousefidi, Reyhaneh

    2015-01-01

    Background Renal colic is an acute flank pain which may radiate to the groin, lower abdomen, or external genitalia due to the passage of a urinary stones. Pain management is the most important task in emergency wards when a patient with renal colic attends. This study aims to compare intravenous acetaminophen plus a low dose of morphine with a full dose of morphine in renal colic. Methods In present randomized clinical trial, 100 patients with confirmed renal colic were recruited from the Emergency Ward of Imam Reza Teaching Hospital affiliated to Tabriz University of Medical Sciences, Iran, during a one-year period. These patients randomly received either intravenous acetaminophen (Apotel, 1 g) plus a low dose of morphine (n = 50), or a high dose of morphine (5 mg) (n = 50). Visual analogue scale (VAS) was used for reporting pain during 35 minutes. Side effects and rescue analgesic demand were recorded after 30 minutes. Findings The two groups were matched for the patients' age and gender. Intra-group analysis showed significant gradual decreases in pain intensity after 35 minutes for both groups. Inter-group analysis, however, did not show a significant difference between the two groups in this regard. There was no significant difference between the two groups in terms of side effects. The rate of rescue analgesic demand was 36% in the first and 40% in the second group (P = 0.68). Conclusion According to the results study, Apotel plus a low dose of morphine is at least as effective and safe as a full dose of morphine in patients with renal colic. PMID:26322213

  12. Spinal cord distribution of sup 3 H-morphine after intrathecal administration: Relationship to analgesia

    SciTech Connect

    Nishio, Y.; Sinatra, R.S.; Kitahata, L.M.; Collins, J.G. )

    1989-09-01

    The distribution of intrathecally administered {sup 3}H-morphine was examined by light microscopic autoradiography in rat spinal cord and temporal changes in silver grain localization were compared with results obtained from simultaneous measurements of analgesia. After tissue processing, radio-activity was found to have penetrated in superficial as well as in deeper layers (Rexed lamina V, VII, and X) of rat spinal cord within minutes after application. Silver grain density reached maximal values at 30 min in every region of cord studied. Radioactivity decreased rapidly between 30 min and 2 hr and then more slowly over the next 24 hr. In rats tested for responses to a thermal stimulus (tail flick test), intrathecal administration of morphine (5 and 15 micrograms) resulted in significant dose dependent analgesia that peaked at 30 min and lasted up to 5 hr (P less than 0.5). There was a close relationship between analgesia and spinal cord silver grain density during the first 4 hr of the study. It is postulated that the onset of spinal morphine analgesia depends on appearance of molecules at sites of action followed by the activation of anti-nociceptive mechanisms.

  13. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster

    PubMed Central

    Garcia-Concejo, Adrian; Jimenez-Gonzalez, Ada; Rodríguez, Raquel E.

    2016-01-01

    Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1). The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3’ UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes. PMID:27380026

  14. Haemodynamic effects of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure.

    PubMed Central

    Timmis, A D; Rothman, M T; Henderson, M A; Geal, P W; Chamberlain, D A

    1980-01-01

    The haemodynamic effects of intravenous morphine sulphate (0.2 mg/kg body weight) were measured in 10 patients with acute myocardial infarction complicated by severe left ventricular failure. Fifteen minutes after morphine injection there was a significant fall in mean heart rate (from 109 to 101 beats/min) and mean systemic arterial pressure (from 80 to 65 mm HG), and a small fall in mean cardiac index (from 2.4 to 2.21/min/m2). Haemodynamic changes at 45 minutes were similar. Neither stroke index nor indirect left ventricular filling pressure (measured as pulmonary artery end-diastolic pressure) were consistently improved 15 or 45 minutes after injection. The useful action of morphine in relieving distressing cardiac dyspnoea is not adequately explained by systemic venous blood pooling. These results suggest that the effects of morphine on the central nervous system are more important. Images p982-a PMID:7417767

  15. Role of prolactin in the modulation of NK and LAK cell activity after short- or long-term morphine administration in neoplastic patients.

    PubMed

    Provinciali, M; Di Stefano, G; Stronati, S; Raffaeli, W; Pari, G; Fabris, N

    1996-10-01

    In a previous work we demonstrated that chronic in vivo antalgic therapy of cancer patients with morphine reduced the endogenous cytotoxic activity of natural killer (NK) cells, while increasing the development of lymphokine activated killer (LAK) cell cytotoxicity. In order to investigate the mechanisms by which morphine affects NK and LAK cell function further, we evaluated the modulation exerted by short- or long-term morphine administration on either NK/LAK cell cytotoxicities or plasma levels of prolactin (PRL) and other immunomodulating neurohormones. An intravenous morphine injection (10 mg) significantly increased the plasma levels of PRL, reduced the cytotoxic activity of NK cells, and increased the development of LAK cell activity 30 min after drug injection in neoplastic patients. The administration of bromocriptine before the injection of morphine prevented both PRL augmentation and the increase in LAK cell activation, although it did not prevent the inhibition of NK cytotoxicity. The chronic oral administration of morphine (90 +/- 30 mg/day for 1 month) also resulted in higher PRL levels; the NK and LAK cell activities were, respectively, lower than or higher than those found in neoplastic patients untreated with morphine. The plasma levels of thyrotropin (TSH), adrenocorticotropic hormone (ACTH) and cortisol were not significantly modified in either short- or long-term experiments. The absolute number and the percentages of lymphocyte populations, as well as the percentage of IL-2 receptors, were not modified after short-term morphine administration whereas little changes of T lymphocyte populations and NK cell number were observed after oral treatment with morphine. In vitro morphine did not affect the development of LAK cell activity. In conclusion, our findings indicate that morphine reduces NK cytotoxicity and increases the development of LAK cell cytotoxicity after short- and long-term administration. The effect of morphine on LAK cell activation

  16. Plasma malondialdehyde levels and opiate withdrawal signs observed in rats treated with morphine plus naloxone: effects of alpha-lipoic acid administration.

    PubMed

    Pinelli, Arnaldo; Cighetti, Giuliana; Trivulzio, Silvio

    2008-08-01

    A number of experimental studies have found that reactive oxygen species are involved during morphine treatment or withdrawal. The aims of this study were to analyse whether morphine administration and/or removal are related to peroxide generation and/or signs of withdrawal in rats, and whether the changes in antioxidant status induced by the administration of an antioxidant may modify peroxide levels and behavioural signs. We injected morphine or morphine and naloxone into rats and evaluated the plasma levels of peroxide malondialdehyde (MDA) and the appearance of withdrawal signs. We also investigated the effects on these parameters induced by the administration of the antioxidant alpha-lipoic acid (LA). Morphine treatment increased MDA levels. Abrupt naloxone-induced morphine withdrawal caused a further and significant increase in MDA, and the appearance of withdrawal signs such as abnormal fecal excretion, shortened latency times and jumping. The administration of LA lowered MDA levels in the rats treated with morphine or morphine plus naloxone, and also decreased MDA values and abstinence signs in the animals treated with morphine plus naloxone. The effects of LA were attributed to its capacity to scavenge peroxides and interfere with the biogenesis of the arachidonic acid metabolites involved in the expression of abstinence symptoms. PMID:18705754

  17. CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats

    PubMed Central

    Wills, Kiri L.; Vemuri, Kiran; Kalmar, Alana; Lee, Alan; Limebeer, Cheryl L.; Makriyannis, Alexandros

    2014-01-01

    Rationale Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm. Objective CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB1 antagonist/inverse agonist, AM251, and the neutral CB1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated. Materials and methods Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), and AM6527 (5 mg/kg, oral) were administered prior to conditioning. Results AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA. Conclusions Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal. PMID:24770676

  18. Temporal and anatomic patterns of immediate-early gene expression in the forebrain of C57BL/6 and DBA/2 mice after morphine administration.

    PubMed

    Ziółkowska, B; Gieryk, A; Solecki, W; Przewłocki, R

    2015-01-22

    Although morphine was previously reported to produce an instant induction of c-fos in the striatum, our recent studies have demonstrated that the expression of numerous immediate early genes (IEGs) is significantly elevated at delayed time-points (several hours) after morphine administration. To better dissect the time-course of opioid-produced IEG induction, we used in situ hybridization to examine the expression of the IEGs c-fos, zif268 and arc in the mouse forebrain at several time-points after acute morphine injection. To link drug-produced behavioral changes with the activity of specific neuronal complexes, this study was performed comparatively in the C57BL/6 and DBA/2 mouse strains, which differ markedly in their locomotor responses to opioids and opioid reward. Our study demonstrates that morphine produces two episodes of IEG induction, which are separate in time (30 min vs. 4-6 h) and which have different neuroanatomic distribution. At 30 min, one or more IEGs were induced in circumscribed subregions of the dorsal striatum (dStr) and of the nucleus accumbens (NAc) shell, as well as in the lateral septum. The observed inter-strain differences in IEG expression at 30 min support earlier proposals that activation of the dorsomedial striatum may mediate morphine-elicited locomotor stimulation (both effects were present only in the C57BL/6 strain). In contrast, NAc shell activation does not appear to be linked to morphine-elicited changes in locomotor behavior. The second IEG induction (of arc and of zif268) was more widespread, involving most of the dStr and the cortex. The second IEG induction peaked earlier in the DBA/2 mice than in the C57BL/6 mice (4 h compared with 6 h) and displayed no apparent relation to locomotor behavior. This delayed episode of IEG activation, which has largely been overlooked thus far, may contribute to the development of long-term effects of opioids such as tolerance, dependence and/or addiction. PMID:25290009

  19. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain

    PubMed Central

    Van Bockstaele, Elisabeth J.; Qian, Yaping; Sterling, Robert C.; Page, Michelle E.

    2009-01-01

    The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pretreatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional four hours. At the end of the

  20. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

    PubMed

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie; Kreilgaard, Mads; Lund, Trine Meldgaard

    2016-01-20

    Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients. PMID:26610393

  1. Preventive Effect of Central Administration of Venlafaxine on Morphine Physical Dependence, Nociception, and Blood Cortisol Level in Rat

    PubMed Central

    Motaghinejad, Majid; Ebrahimzadeh, Andia; Shabab, Behnaz

    2014-01-01

    Background: Chronic abuse of opiates induces dependency, but the neurobiological mechanisms of this event remain unclear. The aim of this study was to evaluate the effects of intracerebroventricular of venlafaxine on the morphine dependence and pain perception. Methods: A total of 80 adult male rats were divided into two major groups: (1) 40 of them was divided into groups of positive control (morphine dependent) negative control (received saline) and morphine dependent groups under treatment by central administration of venlafaxine at various dosages (25, 50, or 100 μg), after drug treatment total withdrawal index (TWI), latency time of withdrawal syndrome expression and blood cortisol as marker of anxiety were measured and compared with positive control and negative control. (2) Forty rats were grouped in control; indometacin treated (5 mg/kg) and grouped which received central administration of venlafaxine at three doses (25, 50, or 100 μg) and then pain perception and expression was assessed in the writhing test (acetic acid induced abdominal constriction), tail flick, and hot plate test. Results: Central administration of three doses (25, 50, or 100 μg,) of venlafaxine attenuates TWI to 47 ± 1.2, 38 ± 1.5, and 23 ± 1.1 and decrease blood cortisol level to 14 ± 1, 13.75 ± 0.5, and 12.5 ± 0.8, this decreases was significant in comparison with the positive control group (P < 0.05). Central administration of venlafaxine at mentioned doses significantly attenuates pain response with 37%, 24%, and 20% inhibition in writhing test, 69%, 34%, and 23% inhibition in hot plate test, and 29%, 23%, and 15% inhibition in tail flick test in comparison with control group (P < 0.05). Conclusions: This study suggested that central administration of venlafaxine attenuated morphine withdrawal index and can be effective in modulation of pain that was induced by morphine dependency. PMID:25538838

  2. Effect of morphine on synaptosomal Ca++ uptake.

    PubMed

    Guerrero-Munoz, F; Cerreta, K V; Guerrero, M L; Way, E L

    1979-04-01

    The effect of morphine on the uptake of 45Ca++ was studied in synaptosomes from mouse brain using two procedures, centrifugation and filtration. The addition of morphine (1.7 x 10(-7) or 3.4 x 10(-7) M) reduced 45CA++ uptake by either technique, although the basal 45Ca++ uptake by the filtration method was approximately 7-fold higher than that by the centrifugation procedure. Similar effects were obtained after acute morphine treatment with 10 mg/kg s.c. Previous naloxone in vitro treatment (1.9 x 10(-8) M) or in vivo administration (2 mg/kg s.c.) reversed the morphine inhibition of the 45Ca++ uptake. On the other hand, after the animal was rendered tolerant and dependent by morphine pellet implantation, an enhancement of the synaptosomal 45Ca++ uptake was observed. It is concluded that changes in Ca++ fluxes in synaptosomes observed after acute and chronic morphine treatment may be involved with morphine pharmacological action related with analgesia, tolerance and physical dependence. PMID:571016

  3. Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats.

    PubMed

    Biegler, Jessica M; Freet, Christopher S; Horvath, Nelli; Rogers, Ann M; Hajnal, Andras

    2016-05-01

    Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss. Opioid analgesics are primarily used to manage postoperative pain as fewer alternative medication options are available for bariatric surgery patients than for the general population. Recent clinical studies support a greater risk for substance use following bariatric surgery, including an increased use of opioid medications. The present study is the first to study morphine self-administration in a rat model of RYGB. High fat diet-induced obese (HFD-DIO) rats underwent RYGB (n=14) or sham-surgery with ad libitum HFD (SHAM, n=14) or a restricted amount that resulted in weight matched to the RYGB cohort (SHAM-WM, n=8). An additional normal-diet (ND, n=7), intact (no surgery) group of rats was included. Two months after the surgeries, rats were fitted with jugular catheters and trained on a fixed ratio-2 lick task to obtain morphine intravenously. Both morphine-seeking (number of licks on an empty spout to obtain morphine infusion) and consumption (number of infusion) were significantly greater in RYGB than any control group beginning on day 3 and reached a two-fold increase over a period of two weeks. These findings demonstrate that RYGB increases motivation for taking morphine and that this effect is independent of weight loss. Further research is warranted to reveal the underlying mechanisms and to determine whether increased morphine use represents a risk for opioid addiction following RYGB. Identifying risk factors preoperatively could help with personalized postoperative care to prevent opioid abuse and addiction. PMID:26304761

  4. Nasal administration of morphine-6-glucuronide in sheep--a pharmacokinetic study.

    PubMed

    Illum, L; Davis, S S; Pawula, M; Fisher, A N; Barrett, D A; Farraj, N F; Shaw, P N

    1996-11-01

    The pharmacokinetics of morphine-6-glucuronide (M6G) after both intravenous dosing and nasal administration were studied in sheep. The nasal formulation consisted of M6G in combination with an absorption promoting delivery system in the form of chitosan. The mean half-life of M6G after intravenous administration was 51.0 +/- 8.2 min and that after intranasal dosing was 45.0 +/- 5.5 min. M6G clearance and volume of distribution were 5.4 +/- 1.5 mL min-1 kg-1 and 0.4 +/- 0.1 L kg-1 respectively. The plasma profile after nasal administration demonstrated rapid absorption of M6G. The bioavailability of M6G in the chitosan formulation was found to be 31.4%. These results suggest that M6G administered in combination with the chitosan delivery system may be considered as a suitable non-parenteral means of administering this analgesic. PMID:8950049

  5. Morphine or capsaicin administration alters the secretion of beta-endorphin into the hypophysial portal vasculature of the rat.

    PubMed

    Koenig, J I; Meltzer, H Y; Gudelsky, G A

    1986-01-01

    Immunoreactive beta-endorphin (ir-beta-END) concentrations were measured in the hypophysial portal plasma of the male rat under urethane anesthesia. On the basis of immunochemical studies and gel filtration chromatography it appears that ir-beta-END in rat hypophysial portal plasma is primarily beta-endorphin (beta-END) and not beta-lipotropin (beta-LPH). In addition, much of the ir-beta-END in portal plasma may be of pituitary origin since acute hypophysectomy resulted in approximately an 80% decrease in the portal plasma concentration of ir-beta-END. Nevertheless, in anesthetized animals that had been hypophysectomized acutely, portal plasma concentrations of ir-beta-END were still 5 times those in systemic plasma, indicative of hypothalamic secretion of the peptide. The administration of morphine sulfate (3 mg/kg, i.v.) resulted in a decrease of ir-beta-END concentrations from 3,157 +/- 547 pg/ml to 1,044 +/- 250 pg/ml. This effect was blocked by naltrexone (1 mg/kg, s.c.) pretreatment. Capsaicin (10 micrograms), which, when infused into the lateral cerebral ventricle of the rat, has been shown to decrease the amount of beta-END in the hypothalamus, but not elsewhere in the central nervous system, selectively decreased the concentration of ir-beta-END in portal plasma without changing systemic ir-beta-END concentrations. These studies indicate that ir-beta-END in portal plasma is probably beta-END which is derived from neurons in the hypothalamus. Moreover, it is concluded that the regulation of the release of ir-beta-END from these neurons involves opiate receptor mechanisms. The inhibitory influence of opiates on ir-beta-END secretion may be indicative of a classical feedback regulation of ir-beta-END-containing neurons. PMID:2944026

  6. Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice.

    PubMed

    Eriksen, Guro Søe; Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C; Huestis, Marilyn A; Mørland, Jørg

    2016-08-01

    Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (-)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (-)-naloxone in the blood and brain. We found that (-)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (-)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

  7. Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

    PubMed

    Liu, Tao; Lewis, Tamorah; Gauda, Estelle; Gobburu, Jogarao; Ivaturi, Vijay

    2016-08-01

    Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population. PMID:26712409

  8. Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial

    PubMed Central

    Poonai, Naveen; Bhullar, Gina; Lin, Kangrui; Papini, Adam; Mainprize, David; Howard, Jocelyn; Teefy, John; Bale, Michelle; Langford, Cindy; Lim, Rodrick; Stitt, Larry; Rieder, Michael J.; Ali, Samina

    2014-01-01

    Background: Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain. Methods: We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale — Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose. Results: We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre–post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) −0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI −0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ −0.1 [95% CI −0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI −0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points (p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p < 0.01). Interpretation: We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective

  9. Epidural Co-Administration of Dexmedetomidine and Levobupivacaine Improves the Gastrointestinal Motility Function after Colonic Resection in Comparison to Co-Administration of Morphine and Levobupivacaine

    PubMed Central

    Zeng, Xian-Zhang; Lu, Zhi-Fang; Lv, Xiang-Qi; Guo, Yue-Ping; Cui, Xiao-Guang

    2016-01-01

    Gastrointestinal motility may be impaired after intestinal surgery. Epidural morphine is effective in controlling postoperative pain, but can further reduce gastrointestinal motility. Here, we aimed to investigate the effects of epidural dexmedetomidine on gastrointestinal motility in patients undergoing colonic resection. Seventy-four patients undergoing colonic resection were enrolled in this clinical trial and allocated randomly to treatment with dexmedetomidine (D group) or morphine (M group). The D group received a loading dose epidural administration of 3 ml dexmedetomidine (0.5 μg kg-1) and then a continuous epidural administration of 80 μg dexmedetomidine in 150 ml levobupivacaine (0.125%) at 3 ml h-1 for two days. The M group received a loading dose epidural administration of 3 ml morphine (0.03 mg kg-1) and then a continuous epidural administration of 4.5 mg morphine in 150 ml levobupivacaine at 3 ml h-1 for two days. Verbal rating score (VRS), postoperative analgesic requirements, side effects related to analgesia, the time to postoperative first flatus (FFL) and first feces (FFE) were recorded. VRS and postoperative analgesic requirements were not significantly different between treatment groups. In contrast, the time to FFL and time to FFE were significant longer in M group in comparison to D group (P < 0.05). Moreover, patients in M group had a significantly higher incidence of nausea, vomiting, and pruritus (P < 0.05). No patients showed neurologic deficits in either group. In comparison to morphine, epidural dexmedetomidine is safe and beneficial for the recovery of gastrointestinal motility after colonic resection when used as an adjunct with levobupivacaine for postoperative pain control. Trial Registration Chinese Clinical Trial Registry ChiCTR-TRC-14004644 PMID:26751791

  10. Effect of renal denervation on the antinatriuretic response to morphine administration in conscious rats.

    PubMed

    Walker, L A; Murphy, J C

    1986-06-01

    The effect of surgical denervation on the antinatriuretic response to morphine was assessed in conscious rats prepared with arterial and venous catheters and bladder cannulas. In sham-operated animals, morphine sulfate (4 mg/kg i.v. plus 2 mg/kg X hr) caused a marked reduction in sodium excretion (650 +/- 218 vs. 2394 +/- 265 nEq/100 g X min in vehicle-treated animals; P less than .05). Although glomerular filtration rate was reduced, fractional excretion of sodium, expressed as a percentage of the filtered load, was also markedly decreased by morphine (0.62 +/- 0.18 vs. 1.51 +/- 0.15% in the vehicle group; P less than .05). The changes in sodium excretion were readily reversed by naloxone. In rats subjected to the renal denervation procedure, morphine had no effect on sodium excretion (1614 +/- 261 vs. 1926 +/- 520 nEq/100 g X min) or on fractional sodium excretion (1.92 +/- 0.50 vs. 1.41 +/- 0.37%). However, glomerular filtration rate was reduced by morphine as in the sham-denervated rats. Blood pressure and heart rate were not significantly affected by morphine in either group. The results suggest that morphine enhances renal tubular sodium reabsorption, at least in part, by a mechanism dependent on intact renal nerves. Because there was no evidence of generalized sympathetic activation (as judged by blood pressure and heart rate changes), the effect may be selective for the renal innervation. PMID:3712279

  11. Influence of morphine on the activity of low-threshold visceral mechanoreceptors in cats with acute pericarditis.

    PubMed

    Bałkowiec, A; Kukuła, K; Szulczyk, P

    1994-11-01

    The purpose of this investigation was to test whether morphine (morphinum hydrochloricum) applied to the receptive field of the thoracic visceral afferent fibres modifies their activity. Experiments were performed on chloralose-anaesthetised cats, paralysed and artificially ventilated, in a state of pericarditis that was induced by intrapericardial injection of lambda-carrageenan and kaolin. Resulting acute inflammation was proven histopathologically and documented electrocardiographically. Single afferent fibres with receptive fields in thoracic viscera were dissected from thoracic sympathetic chain (19 fibres), as well as the vagus nerve (9 fibres). All tested fibres transmitted sensory information from the low-threshold mechanoreceptors. As a final result, it was found that morphine (0.001-1.0 mg/ml) when applied locally activates, depending on the dose, afferent fibres as follows: 12 sympathetic afferents (out of 12 tested), and 7 vagal afferents (out of 9 tested). In examining the specificity of morphine action, the preliminary local application of naloxone (1.0 mg/ml) just before morphine, blocked all excitatory responses. The excitatory response was present whether the receptive field was located in the inflammatory area, or outside it, in group III or IV fibres. PMID:7892023

  12. Effect of postoperative extradural morphine on lower urinary tract function.

    PubMed

    Husted, S; Djurhuus, J C; Husegaard, H C; Jepsen, J; Mortensen, J

    1985-02-01

    The effect of postoperative extradurally administered morphine on lower urinary tract function was studied in female patients undergoing uterine surgery. Urodynamic measurements were made on the day before and on the day after the operation, using a DISA 2-channel carbon dioxide (CO2) cystomictrograph. In ten patients without postoperative urinary retention no changes in cystometry were found during morphine administration, while two patients who developed acute urinary retention had a marked increase in bladder capacity and of detrusor pressure. In contrast, the urethral pressure profile was unchanged in both groups of patients. Intravenously administered naloxone tended to normalize the bladder capacity in the patients with urinary retention. These findings seem to indicate a marked effect in some patients of extradurally administered morphine and the acute urinary retention, following morphine administration, may be treated with naloxone. PMID:3976331

  13. Chemical Stability of Admixtures Combining Ziconotide with Morphine or Hydromorphone During Simul ated Intrathecal Administration.

    PubMed

    Shields, David; Montenegro, Rick; Ragusa, Matthew

    2005-10-01

    Objective.  To determine the stability of admixtures combining ziconotide with morphine or hydromorphone under simulated intrathecal infusions. Materials and Methods.  Admixtures of ziconotide (25 µg/mL) with morphine or hydromorphone (both at 35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°C, and in control vials at 37°C and 5°C. Drug concentrations were determined using high-performance liquid chromatography. Results.  The ziconotide pump concentration with morphine declined to 79% of initial in 17 days, and to 88% of initial after 25 days with hydromorphone. Ziconotide concentrations in control vials stored at 37°C displayed similar rates of decay, but vials stored at 5°C exhibited no ziconotide loss. A statistical evaluation of the two combinations shows ziconotide-hydromorphone retaining 80% stability for 40 days (extrapolated), compared to 15 days for ziconotide-morphine. Morphine and hydromorphone were stable in the presence of ziconotide under all conditions. Conclusions.  Ziconotide-hydromorphone admixtures were more stable than ziconotide-morphine admixtures. PMID:22151554

  14. Post-training and post-reactivation administration of amphetamine enhances morphine conditioned place preference

    PubMed Central

    Blaiss, Cory A.; Janak, Patricia H.

    2006-01-01

    Amphetamine has been shown to enhance consolidation in a variety of memory paradigms. However, it is not known if amphetamine can modulate the consolidation of the types of context-reward associations involved in drug addiction, such as those formed in the conditioned place preference (CPP) task. Also, some types of memory exhibit a second period of lability following memory reactivation, and it is not known whether amphetamine administered during this period can modulate CPP. Our study investigated whether amphetamine can enhance morphine CPP when administered during the consolidation period or the post-reactivation period. Subjects were trained in the CPP task and injected with amphetamine or vehicle immediately or six hours after each training session. The day after the completion of training, they were tested. Amphetamine injected immediately but not six hours after training enhanced morphine CPP. In separate experiments, subjects were first trained in the CPP task. The day following the completion of training, subjects were given a memory reactivation session and injected with amphetamine or vehicle immediately or six hours after reactivation. Subjects were tested the next day. Amphetamine injected immediately but not six hours after memory reactivation enhanced morphine CPP. However, amphetamine injected without memory reactivation had no effect on the expression of morphine CPP. Our results suggest that amphetamine enhances the consolidation of morphine CPP and that morphine CPP exhibits a temporally limited period of post-reactivation lability during which the memory can be modulated. PMID:16698095

  15. Glutamate receptors in the dorsal hippocampus mediate the acquisition, but not the expression, of conditioned place aversion induced by acute morphine withdrawal in rats

    PubMed Central

    Hou, Yuan-yuan; Liu, Yao; Kang, Shuo; Yu, Chuan; Chi, Zhi-qiang; Liu, Jing-gen

    2009-01-01

    Aim: To evaluate the role of glutamate receptors in the dorsal hippocampus (DH) in the motivational component of morphine withdrawal. Methods: NMDA receptor antagonist D-AP5 (5 μg/0.5 μL per side) or AMPA receptor antagonist NBQX (2 μg/0.5 μL per side) was microinjected into DH of rats. Conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal were assessed. Results: Preconditioning microinjection of D-AP5 or NBQX into the DH impaired the acquisition of CPA in acute morphine-dependent rats. However, intra-DH microinjection of D-AP5 or NBQX after conditioning but before the testing session had no effect on the expression of CPA. Conclusion: Our results suggest that NMDA and AMPA receptors in the dorsal hippocampus are involved in the acquisition, but not in the expression, of the negative motivational components of acute morphine withdrawal in rats. PMID:19767765

  16. Physical compatibility of binary and ternary mixtures of morphine and methadone with other drugs for parenteral administration in palliative care.

    PubMed

    Destro, Massimo; Ottolini, Luca; Vicentini, Lorenza; Boschetti, Silvia

    2012-10-01

    The parenteral administration of combinations of drugs is often necessary in palliative medicine, particularly in the terminal stage of life, when patients are no longer able to take medication orally. The use of infusers to administer continuous subcutaneous infusions is a well-established practice in the palliative care setting and enables several drugs to be given simultaneously, avoiding the need for repeated administrations and the effects of peaks and troughs in the doses of medication. The method is also appreciated by patients and caregivers in the home care setting because the devices and infusion sites are easy to manage. Despite their frequent use, however, the mixtures of drugs adopted in clinical practice are sometimes not supported by reliable data concerning their chemical and physical compatibility. The present study investigates the chemical compatibility of binary mixtures (morphine with ketorolac) and the physical compatibility of binary (morphine or methadone with ketorolac) or ternary mixtures (morphine with ketorolac and/or haloperidol, and/or dexamethasone, and/or metoclopramide, and/or hyoscine butylbromide) with a view to reducing the aleatory nature of the empirical use of such combinations, thereby increasing their safety and clinical appropriateness. PMID:22252547

  17. Blockade of tolerance to morphine analgesia by cocaine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  18. Endogenous Cholinergic Neurotransmission Contributes to Behavioral Sensitization to Morphine

    PubMed Central

    Bajic, Dusica; Soiza-Reilly, Mariano; Spalding, Allegra L.; Berde, Charles B.; Commons, Kathryn G.

    2015-01-01

    Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg), a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter) in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg) dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg. PMID:25647082

  19. Morphine Rectal

    MedlinePlus

    Rectal morphine is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Rectal morphine comes as a suppository to insert in the rectum. It is usually inserted every 4 hours. Use ...

  20. Acute kidney injury in a preterm infant homozygous for the C3435T polymorphism in the ABCB1 gene given oral morphine

    PubMed Central

    Pogliani, Laura; Mameli, Chiara; Cattaneo, Dario; Clementi, Emilio; Meneghin, Fabio; Radice, Sonia; Bruno, Simona; Zuccotti, Gian Vincenzo

    2012-01-01

    A 34-week infant born from a mother with a history of drug abuse developed neonatal abstinence syndrome (NAS) in the first hours of life. Urine drug screening was positive for cocaine and heroin. The infant developed acute kidney injury and bilateral hydronephrosis while receiving oral morphine for control of NAS. Cessation of morphine therapy and urinary catheterization resulted in a rapid and complete resolution of the symptoms. Our patient was homozygous for the C3435T polymorphism in the ABCB1 gene, a polymorphism previously associated with impaired P-glycoprotein activity. We hypothesize that acute renal toxicity was related to accumulation of morphine within urothelial cells due to genetically determined impaired P-glycoprotein activity. PMID:26019822

  1. Compatibility of esmolol hydrochloride with morphine sulfate and fentanyl citrate during simulated Y-site administration.

    PubMed

    Karnatz, N N; Wong, J; Kesler, H; Baaske, D M; Speicher, E R

    1988-02-01

    The compatibility and stability of esmolol hydrochloride in admixtures during simulated Y-site injection of morphine sulfate or fentanyl citrate was studied. One milliliter of either morphine sulfate (15 mg/mL) or fentanyl citrate (0.05 mg/mL) was injected into a running infusion of esmolol hydrochloride (10 mg/mL) in 5% dextrose and 0.9% sodium chloride injection, and the solution was visually observed for changes. To determine the stability of the drugs during Y-site injection, esmolol hydrochloride 4 mL (1000 mg) in 5% dextrose and 0.9% sodium chloride injection was combined with 100 mL of either morphine sulfate 15 mg/mL or fentanyl citrate 0.05 mg/mL to simulate concentrations of the drugs that might be expected during Y-site injection. The admixtures were stored at ambient room temperature under normal light, and drug concentrations were determined using high-performance liquid chromatography at time zero and at two, four, and eight hours. Admixtures were also tested for pH and observed for visual changes. No immediate changes were observed in any of the admixtures, and the concentrations of the drugs varied by less than 4% throughout the study period. No precipitate or color changes were noted during Y-site injection of either drug into the running esmolol infusion. Under all of the conditions studied, esmolol hydrochloride in 5% dextrose and 0.9% sodium chloride injection is compatible with morphine sulfate or fentanyl citrate. PMID:2896460

  2. The effects of morphine and morphine conditioned context on 50 kHz ultrasonic vocalisation in rats.

    PubMed

    Hamed, Adam; Taracha, Ewa; Szyndler, Janusz; Krząścik, Paweł; Lehner, Małgorzata; Maciejak, Piotr; Skórzewska, Anna; Płaźnik, Adam

    2012-04-15

    The 50 kHz ultrasonic vocalisations (USVs) that are emitted by rats are dependent on activity of dopaminergic neurons projecting from the ventral tegmental area to the limbic and cortical structures. According to many experimental data, emission of the 50 kHz USV reflects a positive emotional state. The appetitive calls are also emitted in response to the administration of drugs of abuse, e.g., cocaine or amphetamine (AMPH), or in a reply to a positively conditioned context. However, there is no strong evidence in the literature that morphine can also modulate 50 kHz USVs. The aim of this paper is to study the effects of morphine and morphine-conditioned context on 50 kHz USVs, using spontaneously or drug-modulated 50 kHz USVs. Our results showed that acute administration of morphine to rats after withdrawal period inhibited the emission of 50 kHz USVs. The stimulating effect of morphine-conditioned context on 50 kHz USVs appeared on the post-withdrawal challenge day immediately before drug injection, 14 days after the last episode of morphine-induced context conditioning. The context-induced 50 kHz USVs can be used as a sensitive test for drug dependency. The current study also shows that 50 kHz USVs can be useful tool for studying the mechanisms of long lasting central effects of morphine. PMID:22326697

  3. Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats

    PubMed Central

    Pravetoni, M; Raleigh, MD; Le Naour, M; Tucker, AM; Harmon, TM; Jones, JM; Birnbaum, AK; Portoghese, PS; Pentel, PR

    2012-01-01

    Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)4 linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components. PMID:22583811

  4. Effects of acute caffeine administration on adolescents.

    PubMed

    Temple, Jennifer L; Dewey, Amber M; Briatico, Laura N

    2010-12-01

    Acute caffeine administration has physiological, behavioral, and subjective effects. Despite its widespread use, few studies have described the impact of caffeine consumption in children and adolescents. The purpose of this study was to investigate the effects of acute caffeine administration in adolescents. We measured cardiovascular responses and snack food intake after acute administration of 0 mg, 50 mg, 100 mg, and 200 mg of caffeine. We also compared usual food intake and subjective effects of caffeine between high- and low-caffeine consumers. Finally, we conducted a detailed analysis of caffeine sources and consumption levels. We found main effects of caffeine dose on heart rate (HR) and diastolic blood pressure (DBP), with HR decreasing and DBP increasing with increasing caffeine dose. There were significant interactions among gender, caffeine use, and time on DBP. High caffeine consumers (>50 mg/day) reported using caffeine to stay awake and drinking coffee, tea, soda, and energy drinks more than low consumers (<50 mg/day). Boys were more likely than girls to report using getting a rush, more energy, or improved athletic performance from caffeine. Finally, when we examined energy and macronutrient intake, we found that caffeine consumption was positively associated with laboratory energy intake, specifically from high-sugar, low-fat foods and also positively associated with protein and fat consumption outside of the laboratory. When taken together, these data suggest that acute caffeine administration has a broad range of effects in adolescents and that the magnitude of these effects is moderated by gender and chronic caffeine consumption. PMID:21186925

  5. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts

    PubMed Central

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2014-01-01

    This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  6. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

    PubMed

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2013-09-01

    This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  7. Dopamine-dependent responses to morphine depend on glucocorticoid receptors

    PubMed Central

    Marinelli, Michela; Aouizerate, Bruno; Barrot, Michel; Le Moal, Michel; Piazza, Pier Vincenzo

    1998-01-01

    Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 μg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction. PMID:9636221

  8. Tolerance to hyperthermia produced by morphine in rat.

    PubMed

    Mucha, R F; Kalant, H; Kim, C

    1987-01-01

    The present study addressed the prevailing notion that the rat develops tolerance only to the hypothermic effect of morphine and not to its hyperthermic effect. Rectal temperatures were measured at different intervals after various test doses of morphine in rats that had been rendered tolerant to morphine antinociception, by daily intraperitoneal injections of 0, 20, or 200 mg/kg morphine, and dependent, as seen by naloxone-produced loss of body weight. The well-known tolerance to the hypothermic effect was confirmed by changes in the dose-response curves for latency to peak hyperthermic response. In the falling arm of the test dose time/effect curve, consistent, clear decreases in morphine hyperthermia were seen. These decreases were proportional to the chronic treatment dose, and occurred in a normal test environment, where acute hypothermic effects were produced by morphine at short test intervals, and in a warm test environment, where no hypothermia was seen. Similar effects were noted when the data were analyzed in terms of area under the time/effect curve for hyperthermia. In the morphine-treated animals, decreased hyperthermia was seen despite serum morphine levels at the time of testing being up to twice as high as those in control rats. It was concluded that substantial tolerance develops to hyperthermia produced by opiates in rats. The previous difficulty in seeing this effect is discussed in regard to the probability that, in naive rats, the effect of morphine shortly after administration of a test dose reflects a summation of two opposing, acute thermic effects. The findings challenge the view that tolerance develops only to the depressant, and not to the excitatory, effects of opiates. PMID:3114798

  9. Antinociceptive effect of palm date spathe hydroalcoholic extract on acute and chronic pain in mice as compared with analgesic effect of morphine and diclofenac

    PubMed Central

    Peyghambari, Fatemeh; Dashti-Rahmatabadi, Mohammad Hossein; Rozabadi, Mansooreh Dehghanfi; Rozabadi, Razieh Dehghanfi; Rozabadi, Fatemeh Dehghanfi; Pangalizadeh, Mohammadesmaeil; Dehghanimohammadabadi, Narges

    2015-01-01

    Backgrounds: In Persian traditional medicine, palm date spathe (PDS) is introduced as an analgesic. Therefore, this study was designed to investigate the analgesic effect of hydroalcoholic extract of PDS on acute and chronic pain in mice in comparison with diclofenac and morphine. Materials and Methods: In this study, which was conducted in summer 2014, 220 male mice (20–30 g) were randomly divided into two categories, each consists of 11 groups as follows: A normal control group, a solvent (Tween 80) control group, 3 morphine positive control groups (2, 4 and 8 mg/kg), 3 diclofenac positive control groups (10, 20 and 30 mg/kg), and 3 main experimental PDS groups (2, 20, and 200 mg/kg). Hot plate was applied on animals in one category and writing test on the other category to assess acute and chronic pain, respectively. Results: In the writing test, the average writing time and number of animals receiving a maximum dosage of morphine, diclofenac, and PDS were significantly less than the control group. In the hot plate test, only groups receiving different doses of morphine at different time points and those received 30 mg/kg diclofenac at 15 min after the intervention showed significant difference with the control group. Conclusion: 200 mg/kg extract of PDS, revealed a significant analgesic effect on chronic pain, but it did not show any analgesic effect on acute pain. PMID:26693469

  10. Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats.

    PubMed

    Wills, Kiri L; Petrie, Gavin N; Millett, Geneva; Limebeer, Cheryl L; Rock, Erin M; Niphakis, Micah J; Cravatt, Benjamin F; Parker, Linda A

    2016-06-01

    Both CB1 receptor antagonism and agonism, in particular by 2-arachidonyl glycerol (2-AG), have been shown to reduce somatic symptoms of morphine withdrawal (MWD). Here we evaluated the effects of both systemic pretreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG) and central administration of both MJN110 and the CB1 antagonist (AM251) on the affective properties of MWD. Acute MWD induced place aversion occurs when naloxone is administered 24 h following a single exposure to a high dose of morphine. Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects of acute MWD by a CB1 receptor-dependent mechanism. Furthermore, in a double dissociation, AM251 infusions into the central amygdala, but MJN110 infusions into the basolateral amygdala, interfered with the naloxone-precipitated MWD induced place aversion. As well, MJN110, but not AM251, infusions into the interoceptive insular cortex (a region known to be activated in acute MWD) also prevented the establishment of the place aversion by a CB1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD. PMID:26647976

  11. Effective management of intractable neuropathic pain using an intrathecal morphine pump in a patient with acute transverse myelitis

    PubMed Central

    Wu, Wei-Ting; Huang, Yu-Hui; Chen, Der-Cherng; Huang, Yu-Hsuan; Chou, Li-Wei

    2013-01-01

    Transverse myelitis is a rare inflammatory myelopathy characterized by loss of motor and sensory function below the affected level of the spinal cord, and causes neurogenic bowel and bladder. Occasionally, it also causes neuropathic pain with spasticity. Traditional therapies for neuropathic pain are multiple, including multimodal analgesic regimens, antiepileptic or antidepressant medications, opioids, sympathetic blocks, and spinal cord stimulation. Persistent neuropathic pain can cause emotional distress by affecting sleep, work, recreation, and emotional well-being. Here we report the case of a patient suffering from intractable neuropathic pain following acute transverse myelitis that was not relieved by combinations of nonsteroidal anti-inflammatory, anti-epileptic, antidepressant, and opioid medications, or by acupuncture. Implantation of an intrathecal morphine pump controlled the pain successfully without side effects, and enabled the patient to embark on intensive rehabilitation. The patient’s muscle strength has improved significantly and the patient may soon be able to use a walker with minimal assistance. PMID:23935366

  12. Formation of aversive memories associated with conditioned drug withdrawal requires BDNF expression in the amygdala in acute morphine-dependent rats

    PubMed Central

    Ju, Yun-yue; Long, Jian-dong; Liu, Yao; Liu, Jing-gen

    2015-01-01

    Aim: Brain-derived neurotrophic factor (BDNF) plays an important role in learning and memory in multiple brain areas. In the present study, we investigated the roles of BDNF in aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats. Methods: Conditioned place aversion (CPA) was induced in male SD rats exposed to a single dose of morphine (10 mg/kg, sc) followed by naloxone (0.3 mg/kg, sc). In some rats, BDNF receptor antagonist K252a (8.5 ng per side) or BDNF scavenger TrkB-FC (0.65 μg per side) was bilaterally microinjected into amygdala before naloxone injection. BDNF mRNA and protein expression levels in amygdala were detected after the behavior testing. Results: CPA behavior was induced in rats by the naloxone-precipitated morphine withdrawal, which was accompanied by significantly increased levels of BDNF mRNA and protein in the amygdala. Bilateral microinjection of TrkB-FC or K252a into the amygdala completely blocked CPA behavior in the rats. Conclusion: Formation of aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats requires BDNF expression in the amygdala. PMID:26567727

  13. Morphine Oral

    MedlinePlus

    ... relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used to relieve severe ( ... use of other pain medications. Morphine extended-release tablets and capsules should not be used to treat ...

  14. Evidence of slow-release morphine sulfate abuse and diversion: epidemiological approaches in a French administrative area.

    PubMed

    Peyriere, Hélène; Nogue, Erika; Eiden, Céline; Frauger, Elisabeth; Charra, Maryline; Picot, Marie-Christine

    2016-10-01

    Slow-release oral morphine sulfate (SM) is one of the most abused prescription opioids in France. However, the regional feature of the abuse of morphine is poorly documented. To investigate the abuse of SM in a French administrative region, a multisource approach was applied. The first approach was based on SM exposition at national and regional level using the OPPIDUM survey. In a second approach, we analyzed a drug reimbursement database to assess the magnitude of SM abuse in Languedoc-Roussillon (LR) region. A clustering method was applied to classify patients and to describe the profile of deviant patients. The third approach was based on a self-administered anonymous questionnaire, proposed to patients seen in addiction care centers in the LR region and consuming oral SM. The OPPIDUM study showed that in most regions, where the prevalence of heroin use is higher than the national average of 9.1%, SM consumers were fewer. With the clustering method, three subgroups were identified. One of them gathered 35 users (3.2%) with a deviant behavior characterized by significantly more dispensations, dispensing pharmacies, and prescribers. These subjects were mainly men, younger, and more consumers of benzodiazepines and opioid maintenance therapy than the others. The third study allowed specifying that SM was mainly injected (93.7%), bought in the street (80%), and used because of unavailability and the poor quality of heroin (33.9%). The three proposed approaches are complementary and help to clarify the abuse of oral SM, while assessing the motivations of this abuse. PMID:27315486

  15. Comparison of (+)- and (−)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

    PubMed Central

    Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C.; Huestis, Marilyn A.; Mørland, Jørg

    2016-01-01

    Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (−)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (−)-naloxone in the blood and brain. We found that (−)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (−)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers’ ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

  16. Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum.

    PubMed

    Glick, S D; Kuehne, M E; Raucci, J; Wilson, T E; Larson, D; Keller, R W; Carlson, J N

    1994-09-19

    Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7820611

  17. Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation- and drug priming-induced reinstatement of morphine seeking in rats.

    PubMed

    Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas

    2015-01-01

    Dopamine is a predominant neurotransmitter in the nervous system, which plays an important role in both drug priming- and cue-induced reinstatement of cocaine and heroin seeking. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to evaluate the effects of intra-accumbal administration of SCH23390 as a dopamine D1-like receptor antagonist on food deprivation (FD) and drug priming-induced reinstatement. Sixty-eight adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannulae into the nucleus accumbens (NAc). For induction of the CPP, subcutaneous (sc) administration of morphine (5mg/kg) was used daily during a three-day conditioning phase. The conditioning score and locomotor activity were recorded by using the Ethovision software. Under extinction conditions, rats were given an 'off' period and were tested for FD-induced reinstatement following the 24-h or 48-h FD condition, and for drug priming-induced reinstatement under the sated condition following an injection of 0.5 and 1mg/kg (sc) morphine. In the next experiments, animals received different doses of intra-accumbal SCH23390 (0.25, 1 and 4 μg/0.5 μl saline) bilaterally and were subsequently tested for FD- and morphine priming-induced reinstatement. Our findings indicated that only a dose of 1mg/kg and not 0.5mg/kg of morphine induced the reinstatement of morphine. 24-h FD similar to 48-h FD induced the reinstatement of seeking behaviors facilitated by an ineffective dose of morphine (0.5mg/kg). Furthermore, the D1-like receptor antagonist attenuated FD- and drug priming-induced reinstatement dose-dependently. It is concluded that FD- and drug priming-induced reinstatement may be mediated, at least in some way, by activation of dopamine D1-like receptors in the NAc. PMID:25835321

  18. The interaction of adenosine and morphine on pentylenetetrazole-induced seizure threshold in mice.

    PubMed

    Moezi, Leila; Akbarian, Reyhane; Niknahad, Hossein; Shafaroodi, Hamed

    2013-09-01

    Adenosine agonists or low doses of morphine exert anti-convulsant effects in different models of seizures. On the other hand, a tight interaction has been reported between morphine and adenosine in various paradigms. This study investigated the effect of the interaction of adenosine and morphine on seizure susceptibility in the intravenous mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. The researchers used acute systemic administration of morphine, N(6)-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), naltrexone (an opioid receptor antagonist) and 8-Cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist). Acute administration of morphine (0.25, 0.5 and 1 mg/kg) or CHA (0.25, 0.5, 1, 2 and 4 mg/kg) raised the threshold of seizures induced by PTZ. Non-effective dose of 8-CPT (2 mg/kg) inhibited the anticonvulsant effects of CHA (0.5 and 1 mg/kg). Combination of sub-effective doses of morphine (0.125 mg/kg) and CHA (0.125 mg/kg) increased clonic seizure latency showing the additive effect of morphine and CHA. The enhanced latency induced by combination of low doses of morphine and CHA completely reversed by 8-CPT (2 mg/kg) or naltrexone (1 mg/kg). Moreover, 8-CPT (2 mg/kg) inhibited anticonvulsant effects of morphine (0.25 and 0.5 mg/kg) and naltrexone (1 mg/kg) inhibited anticonvulsant effects of CHA (0.25, 0.5 and 1 mg/kg). Combination of low doses of 8-CPT (1 mg/kg) and naltrexone (0.5 mg/kg) inhibited the anticonvulsant effect of CHA (0.5 and 1 mg/kg). In conclusion, adenosine and morphine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, probably through A1 or μ receptors. PMID:23624288

  19. Administration of the Glial Condition Medium in the Nucleus Accumbens Prolong Maintenance and Intensify Reinstatement of Morphine-Seeking Behavior.

    PubMed

    Arezoomandan, Reza; Khodagholi, Fariba; Haghparast, Abbas

    2016-04-01

    Accumulating evidence suggested that glial cells are involved in synaptic plasticity and behavioral changes induced by drugs abuse. The role of these cells in maintenance and reinstatement of morphine (MRP) conditioned place preference (CPP) remains poorly characterized. The aim of present study was to investigate the direct role of glial cells in nucleus accumbens (NAc) in the maintenance and reinstatement of MRP-seeking behavior. CPP induced with injection of MRP (5 mg/kg, s.c. for 3 days), lasted for 7 days after cessation of MRP treatment and priming dose of MRP (1 mg/kg, s.c.) reinstated the extinguished MRP-induced CPP. The astrocyte-conditioned medium (ACM) and neuroglia conditioned medium (NCM) exposed to MRP (10 and 100 µM) have been microinjected into the NAc. Intra-NAc administration of ACM during extinction period failed to change the maintenance of MRP-CPP, but MRP 100-treated ACM could slightly increase the magnitude of reinstatement. In contrast to ACM, intra-NAc administration of MRP 100-treated NCM caused slower extinction by 3 days and significantly increased the magnitude of reinstatement. Our findings suggest the involvement of glial cells activation in the maintenance and reinstatement of MRP-seeking behaviors, and provides new evidence that these cells might be a potential target for the treatment of MRP addiction. PMID:26547198

  20. Persistent Pain Model Reveals Sex Difference in Morphine Potency

    PubMed Central

    Wang, Xiaoya; Traub, Richard J.; Murphy, Anne Z.

    2010-01-01

    Central or systemic administration of agonists directed at the mu or delta opiate receptors generally produce a greater degree of analgesia in males than in females. To date, the majority of studies examining sex based differences in opioid analgesia have employed acute noxious stimuli (i.e. tail-flick and hot plate test); thus, the potential dimorphic response of centrally acting opiates in the alleviation of persistent inflammatory pain is not well established. In the present study, right hindpaw withdrawal latency (PWL) to radiant thermal stimuli was measured in intact male and cycling female Sprague-Dawley rats before and after unilateral hindpaw injection of the inflammatory agent complete Freund’s adjuvant (CFA). Control animals received intraplantar injection of saline. Twenty four hours after CFA or saline injection, animals received either saline or morphine bisulfate (0.5 – 15 mg/kg; s.c.). Separate groups of control or inflamed animals were tested on their responsiveness to morphine at 7, 14 and 21 days post-CFA or saline. No sex differences were noted for baseline PWLs, and females displayed slightly less thermal hyperalgesia at 24 hrs post-CFA. At all morphine doses administered, both the antihyperalgesic effects of morphine in the inflamed animals, and the antinociceptive effects of morphine in control animals, were significantly greater in males in comparison to females. Similarly, in males, the antihyperalgesic effects of morphine increased significantly at 7–21 days post-CFA; no significant shift in morphine potency was noted for females. These studies demonstrate sex-based differences in the effects of morphine on thermal hyperalgesia in a model of persistent inflammatory pain. PMID:16497818

  1. Chemical stability of ziconotide-clonidine hydrochloride admixtures with and without morphine sulfate during simulated intrathecal administration.

    PubMed

    Shields, David; Montenegro, Rick

    2007-10-01

    Objective.  To determine the stability of ziconotide-clonidine hydrochloride admixtures with and without morphine sulfate during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods.  Admixtures of ziconotide (25 µg/mL) and clonidine hydrochloride (2 mg/mL) with and without morphine sulfate (35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°. Pumps were sampled immediately after filling and at four additional time points over the course of 28 (ziconotide-clonidine hydrochloride admixture) or 20 (ziconotide-clonidine hydrochloride-morphine sulfate admixture) days. Drug concentrations were determined using high-performance liquid chromatography. Results.  Ziconotide concentration exceeded 97% of initial at all time points when combined with clonidine alone; statistical evaluation indicated that both ziconotide and clonidine concentrations would remain above 90% of initial for more than 60 days. When compounded with both clonidine and morphine, ziconotide and clonidine concentrations declined; statistical evaluation indicated that the ziconotide concentration was 70% of initial after 20 days, and that clonidine would remain 90% stable for 42 days. Morphine was stable in the presence of ziconotide and clonidine. Conclusions.  A ziconotide-clonidine admixture was 90% stable for 60 days (extrapolated), and a ziconotide-clonidine-morphine admixture was 70% stable for 20 days. PMID:22150946

  2. AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY

    PubMed Central

    Hook, Michelle A.; Washburn, Stephanie N.; Moreno, Georgina; Woller, Sarah A.; Puga, Denise; Lee, Kuan H.; Grau, James W.

    2010-01-01

    Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 hrs later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 hrs after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function. PMID:20974246

  3. Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain.

    PubMed

    Wang, X M; Zhou, Y; Spangler, R; Ho, A; Han, J S; Kreek, M J

    1999-03-20

    We determined the effects of morphine on mRNA levels for the opioid ligands preprodynorphin (PPD) and preproenkephalin (PPE) and the kappa opioid receptor (KOR). Rats received six injections of morphine (6.25 mg/kg/injection) every 2 h, and were sacrificed 30 min later. mRNA levels were measured in brain tissue after removal of the cortex, cerebellum and brainstem. There were increases in PPD and KOR mRNA levels (P<0.05 and P<0.005, respectively), with no alteration of PPE. These alterations in the kappa/dynorphin system may counter morphine-induced effects on the brain. PMID:10095091

  4. Effects of a Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice.

    PubMed

    Mattioli, Laura; Perfumi, Marina

    2011-03-01

    This study investigated the effect of Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice. Therefore animals were injected with repeated administration of morphine (10 mg/kg, subcutaneous) twice daily for five or six days, in order to make them tolerant or dependent. Rhodiola rosea L. extract (0, 10, 15 and 20 mg/kg) was administered by the intragastric route 60 min prior to each morphine injection (for acquisition) or prior the last injection of morphine or naloxone on test day (for tolerance or dependence expression, respectively). Morphine tolerance was evaluated by testing its analgesic effect in the tail flick test at the 1st and 5th days. Morphine dependence was evaluated by counting the number of withdrawal signs (jumping, rearing, forepaw tremor, teeth chatter) after naloxone injection (5 mg/kg; intraperitoneal) on the test day (day 6). Results showed that Rhodiola rosea L. extract significantly reduced the expression of morphine tolerance, while it was ineffective in modulating its acquisition. Conversely, Rhodiola rosea L. extract significantly and dose-dependently attenuated both development and expression of morphine dependence after chronic or acute administration. These data suggest that Rhodiola rosea L. may have human therapeutic potential for treatment of opioid addiction. PMID:20142299

  5. Nociceptin levels in the cerebrospinal fluid of chronic pain patients with or without intrathecal administration of morphine.

    PubMed

    Raffaeli, William; Samolsky Dekel, Boaz Gedaliahu; Landuzzi, Daniela; Caminiti, Alessandro; Righetti, Donatella; Balestri, Marco; Montanari, Francesco; Romualdi, Patrizia; Candeletti, Sanzio

    2006-10-01

    The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid-like receptor ORL-1 and is thought to be involved in pain transmission and modulation. Human studies have not yet defined its role in pain patients. The aims of this study were 1) to verify the presence of N/OFQ in the cerebrospinal fluid (CSF) of human controls and patients with chronic noncancer pain, including those treated with intrathecally administered morphine, and 2) to determine whether pain or treatment with long-term intrathecal morphine influences its levels. The CSF of 27 patients (nine controls and 18 with chronic noncancer pain, of whom 12 were treated chronically with intrathecally administered morphine and six were opioid naïve) was analyzed, blindly, with radioimmunoassay methods. N/OFQ was detected in all patients. Mean CSF concentrations were lowest in the morphine-treated group and highest in the untreated chronic pain patients (12.06+/-1.19 and 57.41+/-10.06 fmol/ml, respectively), and the difference between the morphine-treated group and controls was statistically significant (44.72+/-13.56 fmol/ml, P<0.05). The presence of N/OFQ peptide in human CSF may correlate with biological activities that are influenced by different pain states and long-term intrathecal-morphine treatment. Further studies should verify whether the determination of this peptide CSF level may provide information on opioid treatment efficacy and on the presence of opioid tolerance. PMID:17000354

  6. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

    PubMed Central

    Hutchinson, Mark R.; Northcutt, Alexis L.; Chao, Lindsey W.; Kearney, Jeffrey J.; Zhang, Yingning; Berkelhammer, Debra L.; Loram, Lisa C.; Rozeske, Robert R.; Bland, Sondra T.; Maier, Steven F.; Gleeson, Todd T.; Watkins, Linda R.

    2008-01-01

    Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation. PMID:18706994

  7. Effects of Brugmansia arborea Extract and Its Secondary Metabolites on Morphine Tolerance and Dependence in Mice.

    PubMed

    Mattioli, Laura; Bracci, Antonio; Titomanlio, Federica; Perfumi, Marina; De Feo, Vincenzo

    2012-01-01

    The aim of the present study was to investigate, in vivo, the effect of a Brugmansia arborea extract (BRU), chromatographic fractions (FA and FNA), and isolated alkaloids on the expression and the acquisition of morphine tolerance and dependence. Substances were acutely (for expression) or repeatedly (for acquisition) administered in mice treated with morphine twice daily for 5 or 6 days, in order to make them tolerant or dependent. Morphine tolerance was assessed using the tail-flick test at 1st and 5th days. Morphine dependence was evaluated through the manifestation of withdrawal symptoms induced by naloxone injection at 6th day. Results showed that BRU significantly reduced the expression of morphine tolerance, while it was ineffective to modulate its acquisition. Chromatographic fractions and pure alkaloids failed to reduce morphine tolerance. Conversely BRU, FA, and pure alkaloids administrations significantly attenuated both development and expression of morphine dependence. These data suggest that Brugmansia arborea Lagerh might have human therapeutic potential for treatment of opioid addiction. PMID:22454681

  8. Effects of Brugmansia arborea Extract and Its Secondary Metabolites on Morphine Tolerance and Dependence in Mice

    PubMed Central

    Mattioli, Laura; Bracci, Antonio; Titomanlio, Federica; Perfumi, Marina; De Feo, Vincenzo

    2012-01-01

    The aim of the present study was to investigate, in vivo, the effect of a Brugmansia arborea extract (BRU), chromatographic fractions (FA and FNA), and isolated alkaloids on the expression and the acquisition of morphine tolerance and dependence. Substances were acutely (for expression) or repeatedly (for acquisition) administered in mice treated with morphine twice daily for 5 or 6 days, in order to make them tolerant or dependent. Morphine tolerance was assessed using the tail-flick test at 1st and 5th days. Morphine dependence was evaluated through the manifestation of withdrawal symptoms induced by naloxone injection at 6th day. Results showed that BRU significantly reduced the expression of morphine tolerance, while it was ineffective to modulate its acquisition. Chromatographic fractions and pure alkaloids failed to reduce morphine tolerance. Conversely BRU, FA, and pure alkaloids administrations significantly attenuated both development and expression of morphine dependence. These data suggest that Brugmansia arborea Lagerh might have human therapeutic potential for treatment of opioid addiction. PMID:22454681

  9. Morphine Tolerance as a Function of Ratio Schedule: Response Requirement or Unit Price?

    ERIC Educational Resources Information Center

    Hughes, Christine; Sigmon, Stacey C.; Pitts, Raymond C.; Dykstra, Linda A.

    2005-01-01

    Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, "l"-methadone, and cocaine dose-dependently decreased…

  10. Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Wade-Galuska, Tammy; Galuska, Chad M.; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or…

  11. The effects of intraperitoneal administration of antagonists and development of morphine tolerance on the antinociception induced by stimulating the anterior pretectal nucleus of the rat.

    PubMed Central

    Rees, H.; Prado, W. A.; Rawlings, S.; Roberts, M. H.

    1987-01-01

    1 The effects of intraperitoneal administration of antagonists to morphine, 5-hydroxytryptamine (5-HT), noradrenaline and dopamine have been studied on the antinociceptive effects of electrical stimulation of the anterior pretectal nucleus (APtN) of the rat. 2 A 15 s period of 35 microA sine wave stimulation of APtN significantly increased the latency of the tail flick reflex to noxious heat for periods up to 1 h. 3 Naloxone (0.25-1.0 mg kg-1) attenuated the effects of APtN stimulation in a dose-dependent manner. In rats made tolerant to morphine by daily administration of morphine, the antinociceptive effects of APtN stimulation were significantly reduced. 4 The 5-HT receptor antagonists methysergide (5 mg kg-1) and ketanserin (1 mg kg-1), the dopamine receptor antagonist haloperidol (1 mg kg-1) and the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had little effect on the antinociceptive effects of stimulating the APtN. 5 alpha-Adrenoceptor antagonists caused a dose-dependent antagonism of the response. The order of potency was; idazoxan greater than prazosin greater than phenoxybenzamine, the respective ED50 for each drug being 0.08: 0.45: 1.5 mg kg-1. 6 It is concluded that antagonism at opioid receptors and alpha-adrenoceptors but not beta-adrenoceptors, dopamine or 5-HT receptors reduces the antinociceptive effects of APtN stimulation. This differs from the reported effects of these antagonists on the antinociception caused by stimulating other sites in the brain. PMID:2892554

  12. Assessment of Intraoperative Intra-articular Morphine and Clonidine Injection in the Acute Postoperative Period After Hip Arthroscopy

    PubMed Central

    Cogan, Charles J.; Knesek, Michael; Tjong, Vehniah K.; Nair, Rueben; Kahlenberg, Cynthia; Dunne, Kevin F.; Kendall, Mark C.; Terry, Michael A.

    2016-01-01

    Background: Previous authors have suggested that intra-articular morphine and clonidine injections after knee arthroscopy have demonstrated equivocal analgesic effect in comparison with bupivacaine while circumventing the issue of chondrotoxicity. There have been no studies evaluating the effect of intra-articular morphine after hip arthroscopy. Purpose: To evaluate the efficacy of intra-articular morphine in combination with clonidine on postoperative pain and narcotic consumption after hip arthroscopy surgery for femoroacetabular impingement. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective chart review was performed on 43 patients that underwent hip arthroscopy for femoroacetabular impingement at a single institution between September 2014 and May 2015. All patients received preoperative celecoxib and acetaminophen, and 22 patients received an additional intra-articular injection of 10 mg morphine and 100 μg of clonidine at the conclusion of the procedure. Narcotic consumption, duration of anesthesia recovery, and perioperative pain scores were compared between the 2 groups. Results: Patients who received intra-articular morphine and clonidine used significantly less opioid analgesic (mEq) in the postanesthesia recovery (median difference, 17 mEq [95% CI, –32 to –2 mEq]; P = .02) compared with the control group. There were no differences in time spent in recovery before hospital discharge or in visual analog pain scores recorded immediately postoperatively and at 1 hour after surgery. Conclusion: Intraoperative intra-articular injection of morphine and clonidine significantly reduced the narcotic requirement during the postsurgical recovery period after hip arthroscopy. The reduction in postsurgical opioids may decrease adverse effects, improve overall pain management, and lead to better quality of recovery and improved patient satisfaction. PMID:26977421

  13. Naloxone pro-drug rescues morphine induced respiratory depression in Sprague-Dawley rats.

    PubMed

    Wallisch, Michael; El Rody, Nehad M; Huang, Baohua; Koop, Dennis R; Baker, James R; Olsen, George D

    2012-01-15

    Respiratory depression is the main obstacle for the safe administration of morphine for acute pain after injury. Due to this complication, new delivery methods are needed to insure that safe and effective doses of opioid analgesics are administered during emergencies. A depot formulation containing a naloxone pro-drug was designed to release the antidote when morphine causes dangerous hypoxic conditions in the blood. The aim of this work was to test the naloxone release in vivo in response to a severe overdose of morphine in the Sprague-Dawley rat model. Non-invasive two-chamber plethysmography was used to monitor and record respiration and to test the capability of the naloxone pro-drug to respond to and rescue morphine-induced respiratory depression in the animal. We show that the pro-drug formulation can both prevent and reverse severe morphine induced respiratory depression. The animal model demonstrates that co-administration of the naloxone pro-drug reliably antagonizes profound respiratory depressive effects of morphine. PMID:22027217

  14. Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

    PubMed Central

    Klepstad, Pål; Hilton, Priscilla; Moen, Jorunn; Kaasa, Stein; Borchgrevink, Petter C; Zahlsen, Kolbjørn; Dale, Ola

    2004-01-01

    Background The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. Methods We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). Results The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). Conclusion These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine. PMID:15461818

  15. Effects of prior cocaine versus morphine or heroin self-administration on extinction learning driven by over-expectation versus omission of reward

    PubMed Central

    Lucantonio, Federica; Kambhampati, S; Haney, Richard Z; Atalayer, Deniz; Rowland, Neil E; Shaham, Yavin; Schoenbaum, Geoffrey

    2014-01-01

    Background Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward over-expectation. Methods In Experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hr/day (limited access). In Experiment 2, we trained rats to self-administer heroin or sucrose for 12 hr/day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the over-expectation procedure and later by omitting the food reward. Results Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both over-expectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to over-expectation. Conclusions The specific long-lasting effects of cocaine and heroin show that drug exposure induces long-lasting deficits in the ability to extinguish reward seeking after changes in expected outcomes. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of over-expectation. PMID:25641634

  16. Regulation of brain anandamide by acute administration of ethanol

    PubMed Central

    Ferrer, Belen; Bermúdez-Silva, Francisco Javier; Bilbao, Ainhoa; Alvarez-Jaimes, Lily; Sanchez-Vera, Irene; Giuffrida, Andrea; Serrano, Antonia; Baixeras, Elena; Khaturia, Satishe; Navarro, Miguel; Parsons, Loren H.; Piomelli, Daniele; Rodríguez de Fonseca, Fernando

    2007-01-01

    The endogenous cannabinoid acylethanolamide AEA (arachidonoylethanolamide; also known as anandamide) participates in the neuroadaptations associated with chronic ethanol exposure. However, no studies have described the acute actions of ethanol on AEA production and degradation. In the present study, we investigated the time course of the effects of the intraperitoneal administration of ethanol (4 g/kg of body mass) on the endogenous levels of AEA in central and peripheral tissues. Acute ethanol administration decreased AEA in the cerebellum, the hippocampus and the nucleus accumbens of the ventral striatum, as well as in plasma and adipose tissue. Parallel decreases of a second acylethanolamide, PEA (palmitoylethanolamide), were observed in the brain. Effects were observed 45–90 min after ethanol administration. In vivo studies revealed that AEA decreases were associated with a remarkable inhibition of the release of both anandamide and glutamate in the nucleus accumbens. There were no changes in the expression and enzymatic activity of the main enzyme that degrades AEA, the fatty acid amidohydrolase. Acute ethanol administration did not change either the activity of N-acyltransferase, the enzyme that catalyses the synthesis of the AEA precursor, or the expression of NAPE-PLD (N-acylphosphatidylethanolamine-hydrolysing phospholipase D), the enzyme that releases AEA from membrane phospholipid precursors. These results suggest that receptor-mediated release of acylethanolamide is inhibited by the acute administration of ethanol, and that this effect is not derived from increased fatty acid ethanolamide degradation. PMID:17302558

  17. Progesterone receptors activation after acute cocaine administration.

    PubMed

    Wu, Hui-Bing K; Fabian, Sosimo; Jenab, Shirzad; Quiñones-Jenab, Vanya

    2006-12-18

    Cocaine modulates serum levels of progesterone in intact female and male rats, as well as in pregnant dams, and progesterone decreases or attenuates cocaine-induced behavioral and reward responses. It has been postulated that cocaine's modulation of serum progesterone levels may in turn alter progesterone receptor activity, thereby contributing to cocaine-induced alterations of neuronal functions and genomic regulations. To test this hypothesis, intact male rats received acute injections of saline or cocaine (15 or 30 mg/kg, dissolved in 0.9% saline, intraperitoneal). Progesterone serum levels, progesterone receptor (PR) protein levels, and PR-DNA binding complexes were measured in the striatum by radioimmunoassay, Western blot, and gel shift analyses, respectively. After injection of 15 mg/kg of cocaine, induction of progesterone serum levels was closely followed by an increase in receptor protein levels and DNA binding complexes. After injection of 30 mg/kg of cocaine, similar effects were observed along with an attenuation of receptor protein levels and DNA binding complexes at 60 min. Our results suggest that activation of progesterone receptors may be a mechanism by which cocaine mediates behavior through molecular alterations in the central nervous system. PMID:17109827

  18. Effects of oxytocin-related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists.

    PubMed

    Kovács, G L; Sarnyai, Z; Izbéki, F; Szabó, G; Telegdy, G; Barth, T; Jost, K; Brtnik, F

    1987-05-01

    The hormonally and behaviorally active nonapeptide oxytocin (OXT), its behaviorally active N-terminal octapeptide desglycinamide9-OXT and Z-prolyl-D-leucine, a synthetic analog of the C-terminal prolyl7-leucine8 sequence, inhibited the development both of a moderate and of a strong tolerance to morphine. N-alpha-Acetyl-(2-0-methyltyrosine)-OXT and (penicillamine1-2-0-methyltyrosine)- lysine8-vasopressin, both OXT receptor antagonists, facilitated the development of a moderate morphine tolerance. The i.c.v. injection of either antagonist prevented the effects of i.c.v. and s.c. OXT treatment on the development of tolerance. The effect of desglycinamide9-OXT, but not that of Z-prolyl-D-leucine was also prevented by N-alpha-acetyl-(2-0-methyltyrosine)-OXT. It is concluded that OXT and desglycinamide9-OXT, but not Z-prolyl-D-leucine, attenuate morphine tolerance by affecting putative oxytocinergic binding sites in the mouse brain. The fact that i.c.v. injection of the receptor antagonist also blocked the effect of s.c. OXT treatment argues in favor of the possibility that a minor proportion of s.c. OXT (or behaviorally active fragments thereof) may reach central nervous system target sites. PMID:3033220

  19. Electroencephalographic changes associated with antinociceptive actions of lidocaine, ketamine, meloxicam, and morphine administration in minimally anaesthetized dogs.

    PubMed

    Kaka, Ubedullah; Hui Cheng, Chen; Meng, Goh Yong; Fakurazi, Sharida; Kaka, Asmatullah; Behan, Atique Ahmed; Ebrahimi, Mahdi

    2015-01-01

    Effects of ketamine and lidocaine on electroencephalographic (EEG) changes were evaluated in minimally anaesthetized dogs, subjected to electric stimulus. Six dogs were subjected to six treatments in a crossover design with a washout period of one week. Dogs were subjected to intravenous boluses of lidocaine 2 mg/kg, ketamine 3 mg/kg, meloxicam 0.2 mg/kg, morphine 0.2 mg/kg and loading doses of lidocaine 2 mg/kg followed by continuous rate infusion (CRI) of 50 and 100 mcg/kg/min, and ketamine 3 mg/kg followed by CRI of 10 and 50 mcg/kg/min. Electroencephalogram was recorded during electrical stimulation prior to any drug treatment (before treatment) and during electrical stimulation following treatment with the drugs (after treatment) under anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pretreatment median frequency was evidently increased (P < 0.05) for all treatment groups. Lidocaine, ketamine, and morphine depressed the median frequency resulting from the posttreatment stimulation. The depression of median frequency suggested evident antinociceptive effects of these treatments in dogs. It is therefore concluded that lidocaine and ketamine can be used in the analgesic protocol for the postoperative pain management in dogs. PMID:25695060

  20. Electroencephalographic Changes Associated with Antinociceptive Actions of Lidocaine, Ketamine, Meloxicam, and Morphine Administration in Minimally Anaesthetized Dogs

    PubMed Central

    Hui Cheng, Chen; Meng, Goh Yong; Fakurazi, Sharida; Kaka, Asmatullah; Behan, Atique Ahmed

    2015-01-01

    Effects of ketamine and lidocaine on electroencephalographic (EEG) changes were evaluated in minimally anaesthetized dogs, subjected to electric stimulus. Six dogs were subjected to six treatments in a crossover design with a washout period of one week. Dogs were subjected to intravenous boluses of lidocaine 2 mg/kg, ketamine 3 mg/kg, meloxicam 0.2 mg/kg, morphine 0.2 mg/kg and loading doses of lidocaine 2 mg/kg followed by continuous rate infusion (CRI) of 50 and 100 mcg/kg/min, and ketamine 3 mg/kg followed by CRI of 10 and 50 mcg/kg/min. Electroencephalogram was recorded during electrical stimulation prior to any drug treatment (before treatment) and during electrical stimulation following treatment with the drugs (after treatment) under anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pretreatment median frequency was evidently increased (P < 0.05) for all treatment groups. Lidocaine, ketamine, and morphine depressed the median frequency resulting from the posttreatment stimulation. The depression of median frequency suggested evident antinociceptive effects of these treatments in dogs. It is therefore concluded that lidocaine and ketamine can be used in the analgesic protocol for the postoperative pain management in dogs. PMID:25695060

  1. Editor's Choice-Chest pain relief in patients with acute myocardial infarction.

    PubMed

    Parodi, Guido

    2016-06-01

    Chest pain is the prevalent symptom at presentation in patients with acute myocardial infarction (AMI). Despite the complete absence of rigorous studies designed to assess the impact of morphine administration in patients with AMI, clinical practice guidelines strongly recommend morphine for analgesia. However, when using morphine to relieve chest pain in AMI patients, physicians must be aware that hypotension, respiratory depression, vomiting, and delayed onset of action of antiplatelet agents are potential unwanted side effects of the drug. The purpose of this report is to review morphine's clinical and side effects and to propose strategies able to reduce chest pain in AMI patients. PMID:25904757

  2. Analgesia or Addiction?: Implications for Morphine Use after Spinal Cord Injury

    PubMed Central

    Moreno, Georgina L.; Hart, Nigel; Wellman, Paul J.; Grau, James W.; Hook, Michelle A.

    2012-01-01

    Abstract Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery. PMID:22214368

  3. Differential pharmacokinetics and the brain distribution of morphine and ephedrine constitutional isomers in rats after oral administration with Keke capsule using rapid-resolution LC-MS/MS.

    PubMed

    Song, Yonggui; Su, Dan; Lu, Tulin; Mao, Chunqin; Ji, De; Liu, Yali; Wei, Binbin; Fan, Ronghua

    2014-02-01

    Opioid and ephedra alkaloids known as the active ingredients for Keke capsule, which is used to treat coughs and bronchial asthma, could have potential adverse effects on the central nervous system. Therefore, an efficient, sensitive rapid-resolution LC-MS/MS method for the simultaneous determination of morphine, ephedrine, and pseudoephedrine in rat plasma and brain tissue homogenate has been developed. The method was validated in the plasma and brain tissue samples, showed good linearity over a wide concentration range (r(2) > 0.99). The intra- and interday assay variability was less than 15% for all analytes, and the accuracy was between -8.8 and 5.7%. The study provided the pharmacokinetics profiles and the brain regional distribution of the three active alkaloids after oral administration of Keke capsule. The results also indicated that significant difference in pharmacokinetics parameters of the epimers was observed between ephedrine and pseudoephedrine. PMID:24318005

  4. Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior.

    PubMed

    Arezoomandan, Reza; Haghparast, Abbas

    2016-03-01

    Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 μg/0.5 μL) or saline (0.5 μL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse. PMID:26745749

  5. Morphine Liposomal--SkyePharma: C 0401, D 0401, morphine--DepoFoam, SKY 0401.

    PubMed

    2003-01-01

    The SkyePharma PLC subsidiary SkyePharma Inc. (formerly DepoTech) is developing a sustained-release formulation of morphine sulphate [DepoMorphine, C 0401, D 0401, SKY 0401] using its DepoFoam proprietary drug delivery technology. It is intended for epidural administration in the treatment of acute postoperative pain. DepoFoam consists of microscopic spherical particles with internal aqueous chambers separated by lipid membranes containing the encapsulated drug. DepoFoam particles are synthetic replicas of natural lipids that are biodegradable and biocompatible. DepoFoam can be administered subcutaneously, intramuscularly and intrathecally. In December 2002, SkyePharma and Endo Pharmaceuticals signed a development and commercialisation agreement providing Endo Pharmaceuticals with exclusive marketing and distribution rights in the US and Canada for Depomorphine and another product, Propofol IDD-D trade mark, with options for other development products. Under the terms of the agreement, SkyePharma will receive an upfront payment and may receive further milestone payments. Skye-Pharma will also receive a share of each product's sales revenue. SkyePharma is responsible for clinical development towards the US FDA approval and for product manufacture and associated costs. Following the approval, SkyePharma will as act as a supplier, while Endo will market each product in the US and Canada. SkyePharma has received 30 million US dollars from Paul Capital Partners, a US private equity group, to develop DepoMorphine. This capital will enable SkyePharma to fund phase III clinical trials without raising extra funds. Paul Capital will have rights to 15% of any revenues from DepoMorphine until 2014, and also receive some royalties on three other SkyePharma products. However, if DepoMorphine fails in clinical trials or is declined for registration, Paul Capital will not be compensated for the investment. SkyePharma expect to conclude a European license by the end of 2003, and

  6. Site and mechanism of morphine tolerance in the gastrointestinal tract

    PubMed Central

    AKBARALI, H. I.; INKISAR, A.; DEWEY, W. L.

    2015-01-01

    Opioid-induced constipation is a major clinical problem. The effects of morphine, and other narcotics, on the gastrointestinal tract persist over long-term use thus limiting the clinical benefit of these excellent pain relievers. The effects of opioids in the gut, including morphine, are largely mediated by the μ-opioid receptors at the soma and nerve terminals of enteric neurons. Recent studies demonstrate that regional differences exist in both acute and chronic morphine along the gastrointestinal tract. While tolerance develops to the analgesic effects and upper gastrointestinal motility upon repeated morphine administration, tolerance does not develop in the colon with chronic opioids resulting in persistent constipation. Here, we review the mechanisms by which tolerance develops in the small but not the large intestine. The regional differences lie in the signaling and regulation of the μopioid receptor in the various segments of the gastrointestinal tract. The differential role of β-arrestin2 in tolerance development between central and enteric neurons defines the potential for therapeutic approaches in developing ligands with analgesic properties and minimal constipating effects. PMID:25257923

  7. Effects of high-dose selegiline on morphine reinforcement and precipitated withdrawal in dependent rats.

    PubMed

    Grasing, K; He, S

    2005-02-01

    Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects. Several lines of evidence suggest that treatment with selegiline at doses that exceed levels required for inhibition of MAO can produce distinct pharmacologic effects. The purpose of this study was to evaluate the effects of chronic treatment with high-dose selegiline on extinction responding, cue-induced reinstatement, morphine reinforcement and naloxone-precipitated withdrawal. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of 3.2 mg/kg per injection of morphine under a progressive ratio schedule. Daily treatment with saline or 6.4 mg/kg per day of selegiline was then administered over extinction, reinstatement and re-acquisition of morphine self-administration. To enhance or diminish the potential for psychostimulant effects, selegiline was administered either immediately prior to (pre-session) or 1 h following (post-session) extinction, reinstatement and self-administration sessions. Pre-session selegiline decreased the number of ratios completed on days 2, 3 and 4 of extinction, and decreased morphine self-administration during all four re-acquisition sessions. When administered at the same dose level, post-session selegiline decreased responding on the fourth extinction session, and was ineffective in modifying re-acquisition of self-administration. Selegiline administered by either schedule did not modify cue-induced reinstatement. Daily treatment with 6.4 mg/kg per day of selegiline did not modify self-administration of food under a progressive ratio schedule. Acute treatment with single, 6.4 mg/kg doses of selegiline attenuated naloxone-induced increases in ptosis and global withdrawal score, but did not modify any other sign of withdrawal or global withdrawal score calculated without ratings of ptosis. In conclusion, high-dose selegiline can attenuate extinction responding

  8. Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

    PubMed Central

    Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.

    2009-01-01

    Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818

  9. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice.

    PubMed

    Fakurazi, Sharida; Rahman, Shamima Abdul; Hidayat, Mohamad Taufik; Ithnin, Hairuszah; Moklas, Mohamad Aris Mohd; Arulselvan, Palanisamy

    2013-01-01

    Mitragynine (MG) is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt) combined with morphine (5 mg/kg b.wt) respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP) and cAMP response element binding (CREB) was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05) increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05) in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine. PMID:23292329

  10. Evidence for the involvement of excitatory amino acid pathways in the development of precipitated withdrawal from acute and chronic morphine: an in vivo voltammetric study in the rat locus coeruleus.

    PubMed

    Hong, M; Milne, B; Jhamandas, K

    1993-09-24

    Previous studies have demonstrated that activation of excitatory amino acid (EAA) pathways projecting to the locus coeruleus may be involved in the increased firing of locus coeruleus (LC) neurons during opioid withdrawal. Using differential normal pulse voltammetry to monitor catechol oxidation current (CA.OC), an index of neuronal activity in the LC, the role of EAA pathways in naloxone precipitated withdrawal after acute and chronic morphine treatment was examined. Acute morphine treatment (10 micrograms i.c.v.) significantly reduced the CA.OC signal in the LC to 54.3 +/- 3.1% of baseline. Naloxone challenge (1 mg/kg i.v.) completely reversed the morphine effect and produced a significant increase in the CA.OC signal above baseline, peak 145.4 +/- 10.1% of baseline. This naloxone-induced rebound response was attenuated by pretreatment with the EAA receptor antagonists gamma-D-glutamylglycine (DGG) (2, 20, 200 micrograms i.c.v.) and (-)-2-amino-7-phosphonoheptanoic acid (D-APH), but not L-APH (25 micrograms i.c.v.). In chronically morphine-treated rats (25 micrograms/h i.c.v., 5 days), naloxone challenge (1 mg/kg i.v.) produced a significant increase in CA.OC signal, peak 466.5 +/- 112.7% of baseline. This naloxone-induced response was attenuated by pretreatment with DGG (200 micrograms i.c.v.) or D-APH (25 micrograms i.c.v.). To the extent that CA.OC reflects locus coeruleus neuronal activity, the present findings further suggest that increases in locus coeruleus activity during naloxone precipitated withdrawal after both acute and chronic morphine treatment are mediated at least in part by activation of EAA pathways. PMID:8221081

  11. Morphine delays the onset of action of prasugrel in patients with prior history of ST-elevation myocardial infarction.

    PubMed

    Thomas, Mark R; Morton, Allison C; Hossain, Rashed; Chen, Beining; Luo, Lei; Shahari, Nur Nazihah B Md; Hua, Peng; Beniston, Richard G; Judge, Heather M; Storey, Robert F

    2016-07-01

    Delays in the onset of action of prasugrel during primary percutaneous coronary intervention (PPCI) have been reported and could be related to the effects of morphine on gastric emptying and subsequent intestinal absorption. The study objective was to determine whether morphine delays the onset of action of prasugrel in patients with a prior history of ST-elevation myocardial infarction (STEMI) treated with PPCI. This was a crossover study of 11 aspirin-treated patients with prior history of STEMI treated with PPCI, for which prasugrel and morphine had been previously administered. Patients were randomised to receive either morphine (5 mg) or saline intravenously followed by 60 mg prasugrel. Blood samples were collected before randomised treatment and over 24 hours after prasugrel administration. The inhibitory effects of prasugrel on platelets were determined using the VerifyNow P2Y12 assay and light transmission aggregometry. Plasma levels of prasugrel and prasugrel active metabolite were measured. Platelet reactivity determined by VerifyNow PRU, VerifyNow % Inhibition and LTA was significantly higher at 30-120 minutes (min) when morphine had been co-administered compared to when saline had been co-administered. Morphine, compared to saline, significantly delayed adequate platelet inhibition after prasugrel administration (158 vs 68 min; p = 0.006). Patients with delayed onset of platelet inhibition also had evidence of delayed absorption of prasugrel. In conclusion, prior administration of intravenous morphine significantly delays the onset of action of prasugrel. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI. PMID:27099137

  12. Effects of morphine on the disposition of ampicillin in mice.

    PubMed Central

    Garty, M; Hurwitz, A

    1985-01-01

    Morphine raised the levels of intravenously administered ampicillin in the plasma of mice. Despite higher ampicillin levels in plasma after administration of morphine, levels of this antibiotic in bile and urine were not elevated. After ligation of the common bile duct, ampicillin levels in plasma were elevated. Morphine caused a further rise in drug levels in plasma of duct-ligated mice. Ampicillin levels in plasma were higher in mice made anephric by prolonged ligation of their external urethras. In such animals, morphine also caused ampicillin levels in plasma to be even higher. These experiments suggest that morphine impairs both renal and hepatobiliary elimination of ampicillin. These effects of morphine were completely reversed by naloxone. In contrast to effects on intravenously administered ampicillin, morphine markedly reduced drug levels in plasma when ampicillin was given by gastric intubation. This resulted from delayed absorption because of retardation of gastric emptying by morphine. PMID:4073871

  13. PolyMorphine: an innovative biodegradable polymer drug for extended pain relief

    PubMed Central

    Rosario-Meléndez, Roselin; Harris, Carolyn L.; Delgado-Rivera, Roberto; Yu, Lei; Uhrich, Kathryn E.

    2012-01-01

    Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed “PolyMorphine”, was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge. PMID:22877734

  14. Enhanced Extracellular Glutamate and Dopamine in the Ventral Pallidum of Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats after Morphine

    PubMed Central

    Kemppainen, Heidi; Nurmi, Harri; Raivio, Noora; Kiianmaa, Kalervo

    2015-01-01

    The purpose of the present study was to investigate the role of ventral pallidal opioidergic mechanisms in the control of ethanol intake by studying the effects of acute administration of morphine on the levels of GABA, glutamate, and dopamine in the ventral pallidum. The study was conducted using the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding Alko Non-Alcohol (ANA) rat lines that have well-documented differences in their voluntary ethanol intake and brain opioidergic systems. Therefore, examination of neurobiological differences between the lines is supposed to help to identify the neuronal mechanisms underlying ethanol intake, since selection pressure is assumed gradually to lead to enrichment of alleles promoting high or low ethanol intake, respectively. The effects of an acute dose of morphine (1 or 10 mg/kg s.c.) on the extracellular levels of GABA and glutamate in the ventral pallidum were monitored with in vivo microdialysis. The concentrations of GABA and glutamate in the dialyzates were determined with a high performance liquid chromatography system using fluorescent detection, while electrochemical detection was used for dopamine. The levels of glutamate in the rats injected with morphine 1 mg/kg were significantly above the levels found in the controls and in the rats receiving morphine 10 mg/kg. Morphine 10 mg/kg also increased the levels of dopamine. Morphine could not, however, modify the levels of GABA. The rat lines did not differ in any of the effects of morphine. The data suggest that the glutamatergic and dopaminergic systems in the ventral pallidum may mediate some effects of morphine. Since there were no differences between the AA and ANA lines, the basic hypothesis underlying the use of the genetic animal model suggests that the effects of morphine detected probably do not underlie the different intake of ethanol by the lines and contribute to the control of ethanol intake in these animals. PMID:25653621

  15. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

    PubMed

    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior. PMID:19956087

  16. Acute effects of morphine and opioid peptides on the motility and responses of rat colon to electrical stimulation.

    PubMed Central

    Gillan, M. G.; Pollock, D.

    1980-01-01

    1 Morphine and leucine- and methionine-enkephalins inhibited the contractile response of the pithed rat colon to electrical stimulation of the spinal motor outflows and inhibited motor responses of the isolated colon to field stimulation. 2 Morphine and the opioid peptides also had an excitatory action in the colon. In the pithed rat, opiates caused regular fluctuations in intracolonic pressure and in the isolated colon, caused regular waves of contraction. This excitatory response was produced by low concentrations of the enkephalins (2 X 10(-8) M, 2 X 10(-9) M), was stereospecific and was antagonized by naloxone. 3 Opiate-induced contractions in the isolated colon were inhibited by catecholamines, adenine nucleotides and by phosphodiesterase inhibitors. These contractions were unaffected by ergotamine and tolazoline, or by propranolol. 4 The excitatory action of opiates in the isolated colon was not antagonized and usually was potentiated by atropine, (+)-tubocurarine and hexamethonium. In the absence of opiates, these drugs also produced similar waves of contraction, which were unaffected by naloxone. 5 Opiate-induced contractions occurred in colon rendered unresponsive to 5-hydroxytryptamine (5-HT) and these contractions were potentiated by the 5-HT antagonist, lysergic acid diethylamide, which, when administered alone, caused similar contractions. The 5-HT antagonist, cyproheptadine, inhibited opiate-induced contractions but was non-specific, since it also inhibited responses of the colon to carbachol and KC1. 6 Opiate-induced contractions were unaffected by procaine and were potentiated by tetrodotoxin. Both of these drugs, when administered alone, produced waves of contractions, which were similar to those produced by opiates but were unaffected by naloxone. 7 Contractions produced in the isolated colon either by opiates, atropine or (+)-tubocurarine, or any combination of these drugs, were inhibited by field stimulation applied at the peak of a wave of

  17. Acute and chronic tramadol administration impair spatial memory in rat

    PubMed Central

    Hosseini-Sharifabad, Ali; Rabbani, Mohammad; Sharifzadeh, Mohammad; Bagheri, Narges

    2016-01-01

    Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain. PMID:27051432

  18. Morphine-theophylline interaction: antagonism or facilitation?

    PubMed Central

    Brailowsky, S.; Guerrero-Muñoz, F.; Luján, M.; Shkurovich, M.

    1981-01-01

    1 Morphine-theophylline interactions were investigated in both acute and narcotic-dependent preparations, in vitro and in vivo, using four different experimental models: LD50 doses of morphine and naloxone in the mouse; naloxone-induced contractions in the electrically-stimulated and opiate-dependent isolated ileum of the guinea-pig; naloxone-induced jumps in the mouse; an calcium uptake in synaptosomal preparations. 2 The LD50 of morphine was significantly increased by theophylline. 3 The lethal effect of theophylline was potentiated by pretreatment of the animals with naloxone. 4 Theophylline displayed protective effects in the inhibitory response to morphine and antagonism to the withdrawal response induced by naloxone in the electrically-stimulated isolated ileum of the guinea-pig. 5 The number of jumps induced by naloxone in morphine-dependent mice was significantly diminished by theophylline. 6 The inhibitory effect of morphine on the synaptosomal uptake of calcium was decreased by theophylline. 7 The effects of both morphine and theophylline on the cyclic nucleotides and the possible role of calcium in these actions are discussed. PMID:7272590

  19. Spinal mediators that may contribute selectively to antinociceptive tolerance but not other effects of morphine as revealed by deletion of GluR5

    PubMed Central

    Gregus, Ann M.; Inra, Christopher N.; Giordano, Thomas P.; Costa, Alberto C.S.; Rajadhyaksha, Anjali M.; Inturrisi, Charles E.

    2010-01-01

    Several groups maintain that morphine tolerance and dependence correlate with increased activity of protein kinases ERK1/2 and P38 MAPK and PKC as well as elevated levels of the neuropeptides dynorphin (DYN), substance P (sP) and calcitonin gene-related peptide (CGRP) in spinal cord dorsal horn (SCDH). They demonstrate that tolerance and dependence can be prevented, and sometimes reversed, by constitutive genetic deletion or pharmacological inhibition of these factors. Recently, we showed that mice with a constitutive deletion of the GluR5 subunit of kainate receptors (GluR5 KO) are not different from wildtype (WT) littermates with respect to baseline nociceptive thresholds as well as acute morphine antinociception, morphine physical dependence and conditioned place preference. However, unlike WT, GluR5 KO mice do not develop antinociceptive tolerance following systemic morphine administration. In this report, we examined levels of these mediators in SCDH of WT and GluR5 KO mice following subcutaneous implantation of placebo or morphine pellets. Surprisingly, spinal DYN and CGRP, along with phosphorylated ERK1/2 (pERK1/2), P38 (pP38) and PKCgamma (pPKCγ) are elevated by deletion of GluR5. Additionally, chronic systemic morphine administration increased spinal pERK1/2, pP38 and pPKCγ levels in both tolerant WT and non-tolerant GluR5 KO mice. In contrast, while morphine increased spinal DYN and CGRP in WT mice, DYN remained unchanged and CGRP was reduced in GluR5 KO mice. These observations suggest that spinal ERK1/2, P38 and PKCγ are likely involved in multiple adaptive responses following systemic morphine administration, whereas DYN and CGRP may contribute selectively to the development of antinociceptive tolerance. PMID:20359526

  20. Morphine: Myths and Reality

    MedlinePlus

    ... and Families Take the Quiz Morphine: Myths and Reality February, 2013 The mere mention of “Morphine” can ... due to misinformation and lack of training. The reality is that Morphine (and other opiates that work ...

  1. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    PubMed

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. PMID:27102159

  2. Upregulation of the opioid receptor complex by the chronic administration of morphine: a biochemical marker related to the development of tolerance and dependence.

    PubMed

    Rothman, R B; Long, J B; Bykov, V; Xu, H; Jacobson, A E; Rice, K C; Holaday, J W

    1991-01-01

    Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the "resolving power" of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6 beta-fluoronaltreone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible mu-receptor antagonist, beta-funaltrexamine (beta-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, beta-FNA failed to upregulate opioid receptors and 2) both beta-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrex-one-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at beta-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine. PMID:1646998

  3. Impact of administrative technology on acute care bed need.

    PubMed Central

    Martin, J B; Dahlstrom, G A; Johnston, C M

    1985-01-01

    This article reports an evaluation of the impact of three administrative technologies--Admission Scheduling (AS) Systems, Outpatient Surgery (OPS) Programs, and Preadmission Testing (PAT) Programs--on the number of acute care beds required by a hospital. The evaluation mechanism reported here is called the ADTECH Computerized Planning Model. ADTECH uses parameters of each technology, identified from previous literature and discussions with health care professionals, to predict the changes in bed requirements resulting from implementation of these programs. Data from eight hospitals of various characteristics and sizes were run to test the ADTECH model. The results from these test runs indicate that the proper implementation of AS, OPS, and PAT can significantly influence a hospital's required bed complement. PMID:3988530

  4. Morphine is an arteriolar vasodilator in man

    PubMed Central

    Afshari, Reza; Maxwell, Simon R J; Webb, David J; Bateman, D Nicholas

    2009-01-01

    AIM The mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects. METHODS Three separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp. RESULTS Morphine caused an increase in FBF at doses of 30 µg min−1[3.25 (0.26) ml min−1 100 ml−1][mean (SEM)] doubling at 100 µg min−1 to 5.23 (0.53) ml min−1 100 ml−1. Acute tolerance was not seen to 50 µg min−1 morphine, with increased FBF [3.96 (0.35) ml min−1 100 ml−1] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min−1 100 ml−1 after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min−1 100 ml−1. CONCLUSIONS Intra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration. PMID:19371311

  5. Direct intrawound administration of dimethylsulphoxide relieves acute pain in rats.

    PubMed

    Gautam, Mayank; Prasoon, Pranav; Kumar, Rahul; Singh, Anurag; Shrimal, Prawal; Ray, Subrata B

    2016-04-01

    Wounds associated with injuries such as burns can produce moderate to severe pain. Besides causing distress to the patient, unrelieved pain could delay healing owing to stress-related problems. Thus, pain needs to be treated as early as possible after injury. It was hypothesised that local treatment of wounds with appropriate analgesic drugs could attenuate pain. HOE 140, a bradykinin receptor antagonist, reduced acute inflammatory pain in rats after intrawound administration. In this study, the analgesic effect of dimethylsulphoxide (DMSO) was investigated in a similar hind-paw incision model in rats. An extremely small quantity (10 µl) of 100% DMSO was administered into the incision site just before closure of the wound. It persistently attenuated guarding behaviour in rats over a period of 3 days without affecting thermal hyperalgesia or allodynia. Accumulated evidence indicates that guarding is equivalent to pain at rest in humans. The possible mechanisms of the analgesic effect could be inhibition of C group of peripheral nerve fibres or even free radical scavenging. Healing of the wound was found to be normal at the end of the study period. In conclusion, DMSO could be useful in the treatment of acute pain resulting from tissue injuries such as burns. PMID:24750992

  6. Acute caffeine administration affects zebrafish response to a robotic stimulus.

    PubMed

    Ladu, Fabrizio; Mwaffo, Violet; Li, Jasmine; Macrì, Simone; Porfiri, Maurizio

    2015-08-01

    Zebrafish has been recently proposed as a valid animal model to investigate the fundamental mechanisms regulating emotional behavior and evaluate the modulatory effects exerted by psychoactive compounds. In this study, we propose a novel methodological framework based on robotics and information theory to investigate the behavioral response of zebrafish exposed to acute caffeine treatment. In a binary preference test, we studied the response of caffeine-treated zebrafish to a replica of a shoal of conspecifics moving in the tank. A purely data-driven information theoretic approach was used to infer the influence of the replica on zebrafish behavior as a function of caffeine concentration. Our results demonstrate that acute caffeine administration modulates both the average speed and the interaction with the replica. Specifically, zebrafish exposed to elevated doses of caffeine show reduced locomotion and increased sensitivity to the motion of the replica. The methodology developed in this study may complement traditional experimental paradigms developed in the field of behavioral pharmacology. PMID:25907748

  7. Fibrinogen α-chain-derived peptide is upregulated in hippocampus of rats exposed to acute morphine injection and spontaneous alternation testing

    PubMed Central

    Maki, Agatha E; Morris, Kenneth A; Catherman, Kasia; Chen, Xian; Hatcher, Nathan G; Gold, Paul E; Sweedler, Jonathan V

    2014-01-01

    Fibrinogen is a secreted glycoprotein that is synthesized in the liver, although recent in situ hybridization data support its expression in the brain. It is involved in blood clotting and is released in the brain upon injury. Here, we report changes in the extracellular levels of fibrinogen α-chain-derived peptides in the brain after injections of saline and morphine. More specifically, in order to assess hippocampus-related working memory, an approach pairing in vivo microdialysis with mass spectrometry was used to characterize extracellular peptide release from the hippocampus of rats in response to saline or morphine injection coupled with a spontaneous alternation task. Two fibrinopeptide A-related peptides derived from the fibrinogen α-chain – fibrinopeptide A (ADTGTTSEFIEAGGDIR) and a fibrinopeptide A-derived peptide (DTGTTSEFIEAGGDIR) – were shown to be consistently elevated in the hippocampal microdialysate. Fibrinopeptide A was significantly upregulated in rats exposed to morphine and spontaneous alternation testing compared with rats exposed to saline and spontaneous alternation testing (P < 0.001), morphine alone (P < 0.01), or saline alone (P < 0.01), respectively. The increase in fibrinopeptide A in rats subjected to morphine and a memory task suggests that a complex interaction between fibrinogen and morphine takes place in the hippocampus. PMID:24855564

  8. The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain

    PubMed Central

    Holtman, Joseph R.; Crooks, Peter A.; Johnson-Hardy, Jaime K.; Wala, Elzbieta P.

    2009-01-01

    Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(−)- and R(+)- enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(−)- rather than the R(+)- enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)- enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(−)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(−)-nornicotine (sub-analgesic dose) was combined with a low-dose of the μ-opioid, morphine. These preclinical data suggest that S(−)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, mixed pain). PMID:19800911

  9. P-glycoprotein Modulates Morphine Uptake into the CNS: A Role for the Non-steroidal Anti-inflammatory Drug Diclofenac

    PubMed Central

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M.; Thompson, Brandon J.; Zhang, Yifeng; Laracuente, Mei-Li; DeMarco, Kristin M.; Ronaldson, Patrick T.; Davis, Thomas P.

    2014-01-01

    Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP), induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp) that is endogenously expressed at the blood-brain barrier (BBB). The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h), as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction. PMID:24520393

  10. Increased brain uptake of morphine in the presence of the antihistamine tripelennamine.

    PubMed

    Vadlamani, N L; Pontani, R B; Misra, A L

    1984-01-01

    Disposition of [6 3H (N)]morphine in plasma, brain and liver of rats was studied 15 min after intravenous injection of either a 2 mg kg-1 dose of morphine or a combination of the same dose of morphine with a 6 mg kg-1 dose of tripelennamine. The concentrations of morphine in brain and the brain to plasma morphine ratios in animals receiving the combination of drugs concurrently were significantly higher than those in the control morphine group. No significant differences were seen in the morphine or morphine metabolite concentrations in plasma and liver or liver to plasma morphine concentration ratios in the 2 groups. Data suggest that pharmacokinetic factors play a role in the potentiation of opiate effects by antihistamine on concurrent i.v. administration of the two drugs. PMID:6141270

  11. Complex motivated behaviors for natural rewards following a binge-like regimen of morphine administration: mixed phenotypes of anhedonia and craving after short-term withdrawal

    PubMed Central

    Bai, Yunjing; Li, Yingying; Lv, Yaodi; Liu, Zhengkui; Zheng, Xigeng

    2014-01-01

    The anhedonia-like behaviors following about 1-week withdrawal from morphine were examined in the present study. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. Three types of natural reward were used, food reward (2.5, 4, 15, 30, 40, and 60% sucrose solutions), social reward (male rat) and sexual reward (estrous female rat). For each type of natural stimulus, consummatory behavior and motivational behaviors under varied testing conditions were investigated. The results showed that the morphine-treated rats significantly reduced their consumption of 2.5% sucrose solution during the 1-h consumption testing and their operant responding for 15, 30, and 40% sucrose solutions under a fixed ratio 1 (FR1) schedule. However, performance under a progressive ratio (PR) schedule increased in morphine-treated rats reinforced with 60% sucrose solution, but not in those reinforced with sucrose concentrations lower than 60%. Pretreatment with morphine significantly decreased the male rats' ejaculation frequency (EF) during the 1-h copulation testing, and impaired the maintenance of appetitive motivations to sexual and social stimuli under a free-approach condition. Moreover, the morphine-treated rats demonstrated a diminished motivation to approach social stimulus in the effort-based appetitive behavior test but showed a remarkable increase in motivation to approach sexual stimulus in the risky appetitive behavior test. These results demonstrated some complex motivated behaviors following about 1 week of morphine withdrawal: (1) The anhedonia-like behavior was consistently found in animals withdrawn from morphine. However, for a given reward, there was often a dissociation of the consummatory behaviors from the motivational behaviors, and whether the consummatory or the motivational anhedonia-like behaviors could be discovered heavily depended on the type and magnitude of the reward and the type of testing task; (2) These

  12. Synergy between the antinociceptive effects of morphine and NSAIDs.

    PubMed

    Miranda, H F; Silva, E; Pinardi, G

    2004-05-01

    The intraperitoneal administration of morphine, diclofenac, ketoprofen, meloxicam, metamizol, paracetamol and piroxicam induced dose-dependent antinociception in mice tested with the acetic acid writhing test. The isobolographic analysis of the simultaneous intraperitoneal administration of fractions of the ED50's of morphine with each nonsteroidal anti-inflammatory drug (NSAID) demonstrated the existence of a supra-additive interaction (synergy). The selective antagonist of micro -opioid receptors naltrexone partially reversed the supra-additive interactions to additive interactions; however, the combinations of morphine/metamizol and morphine/paracetamol were completely antagonized, resulting in subadditive interactions. The selective antagonist of delta-opioid receptors naltrindole failed to significantly attenuate the combinations of morphine with ketoprofen, meloxicam and piroxicam, but decreased the activity of the combinations of morphine with diclofenac, metamizol and paracetamol, transforming the interactions from supra-additive to additive. Nor-binaltorphimine was used to evaluate the involvement of kappa-opioid receptors. Nor-binaltorphimine did not modify the supra-additive interaction of morphine and NSAIDs and the additive interaction of the co-administration of morphine and metamizol. The synergy between morphine and NSAIDs could be related to different pathways of pain transmission, probably related to the different intracellular signal transduction mechanisms of action of opioid and non-opioid agents. PMID:15213733

  13. The selective D₃ receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference.

    PubMed

    Rice, Onarae V; Heidbreder, Christian A; Gardner, Eliot L; Schonhar, Charles D; Ashby, Charles R

    2013-08-01

    We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D₃ dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D₃ receptor antagonists constitute promising compounds for treating addiction. PMID:23404528

  14. Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine tolerant infant rats

    PubMed Central

    Stoller, Dawn C.; Sim-Selley, Laura J.; Smith, Forrest L.

    2011-01-01

    We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine- than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The delta-opioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [35S]GTPγS and [3H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [35S]GTPγS binding. Furthermore, [3H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups. PMID:17300766

  15. Effect of Acute and Chronic Calcium Administration on Plasma Renin

    PubMed Central

    Kotchen, Theodore A.; Mauli, Kimball I.; Luke, Robert; Rees, Douglas; Flamenbaum, Walter

    1974-01-01

    To evaluate the effect of Ca++ on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca++ administration. 1% CaCl2 was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EFca++) and EFNa+ from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h±5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca++ for 15, 30, and 45 min (20 ng/ml/h±4.6, 16 ng/ml/h±4.0, and 13 ng/ml/h±2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca++ loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl2 for 17 days. At sacrifice, serum Ca++, Na+, and K+ of controls (n = 12) did not differ (P > 0.60) from Ca++-loaded rats (n = 12). Ca++ excretion (467 μeq/24 h±51) was elevated (P < 0.001) compared to controls (85 μeq/24 h±12). PRA (8.6 ng/ml/h±1.4) and renal renin content of Ca++-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion. PMID:4436432

  16. Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake

    PubMed Central

    Holtz, Nathan A.; Radke, Anna K.; Zlebnik, Natalie E.; Harris, Andrew C.; Carroll, Marilyn E.

    2015-01-01

    Rational Sweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays. Objective The current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats. Methods Rats were administered morphine (10 mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28 h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1 mg/kg) administration (precipitated withdrawal). Results Twenty-four hr following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts. Conclusions LoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability. PMID:25582876

  17. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine.

    PubMed

    Zadina, James E; Nilges, Mark R; Morgenweck, Jenny; Zhang, Xing; Hackler, Laszlo; Fasold, Melita B

    2016-06-01

    Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine. PMID:26748051

  18. Changes in [3H]-UK 14304 binding to alpha 2-adrenoceptors in morphine-dependent guinea-pigs.

    PubMed Central

    Varani, K.; Beani, L.; Bianchi, C.; Borea, P. A.; Simonato, M.

    1995-01-01

    1. The aim of this study was to investigate the effect of a noradrenergic input in the cortex of morphine-dependent animals. Binding of the alpha 1-adrenoceptor ligand [3H]-prazosin did not change in cortical membranes taken from morphine-dependent as compared to control guinea-pigs. However, binding of the alpha 2-adrenoceptor ligand [3H]-UK 14304 showed decreased KD (-30%) in the absence of significant changes in Bmax, either in cortical membranes or in synaptosomes. 2. Several characteristics of this phenomenon were identified. First, it occurs in a time-dependent fashion, in that it takes 5 days of chronic morphine treatment to start developing. Second, it can be observed after acute administration of high doses of morphine (100 mg kg-1). Third, it does not require a connection with the locus coeruleus or with other subcortical structures, in that it can be reproduced in vitro in isolated cortical slices. Fourth, it requires the integrity of cortical structures, since it cannot be reproduced in vitro in cortical synaptosomes. 3. Release studies were run to attempt identification of a functional correlate of the above observations. No changes were observed in the ability of the alpha 2-adrenoceptor agonist UK 14304 to inhibit 35 mM K(+)-evoked [3H]-noradrenaline outflow from cortical synaptosomes taken from morphine-dependent as compared to control guinea-pigs. However, a large decrease in the IC50 of UK 14304 for the inhibition of 35 mM K(+)-evoked [3H]-gamma-aminobutyric acid ([3H]-GABA) outflow (41 vs. 501 nM) was observed in morphine-dependent as compared to control animals. 4. These data suggest that, in the guinea-pig, chronic morphine treatment is associated with a shift from a low to high affinity agonist state in alpha 2-adrenoceptors on cortical GABA terminals. PMID:8719786

  19. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    PubMed

    Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

    2015-09-14

    Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome. PMID:26222257

  20. Parkinson's disease, L-DOPA, and endogenous morphine: a revisit.

    PubMed

    Stefano, George B; Mantione, Kirk J; Králíčková, Milena; Ptacek, Radek; Kuzelova, Hana; Esch, Tobias; Kream, Richard M

    2012-08-01

    Clinical observations stemming from widespread employment of restorative L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for management of dyskinesia in Parkinson's Disease (PD) patients implicate a regulatory role for endogenous morphine in central nervous system dopamine neurotransmission. Reciprocally, it appears that restorative L-DOPA administration has provided us with a compelling in vivo pharmacological model for targeting peripheral sites involved in endogenous morphine expression in human subjects. The biological activities underlying endogenous morphine expression and its interaction with its major precursor dopamine strongly suggest that endogenous morphine systems are reciprocally dysregulated in PD. These critical issues are examined from historical and current perspectives within our short review. PMID:22847214

  1. Increased probability of GABA release during withdrawal from morphine.

    PubMed

    Bonci, A; Williams, J T

    1997-01-15

    Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAA synapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAA IPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment. PMID:8987801

  2. Valproate attenuates the development of morphine antinociceptive tolerance.

    PubMed

    Dobashi, Tamae; Tanabe, Serabi; Jin, Hisayo; Nishino, Takashi; Aoe, Tomohiko

    2010-11-19

    Morphine is a potent opioid analgesic. Repeated administration of morphine induces tolerance, thus reducing the effectiveness of analgesic treatment. Although some adjuvant analgesics can increase morphine analgesia, the precise molecular mechanism behind their effects remains unclear. Opioids bind to the mu opioid receptor (MOR). Morphine tolerance may be derived from alterations in the intracellular signal transduction after MOR activation. Chronic morphine treatment activates glycogen synthase kinase 3β (GSK3β), whose inhibition diminishes morphine tolerance. Valproate is widely prescribed as an anticonvulsant and a mood stabilizer for bipolar disorders because it increases the amount of γ-aminobutyric acid (GABA) in the central nervous system. Although the activation of GABAergic neurons may be responsible for the chief pharmacologic effect of valproate, recent studies have shown that valproate also suppresses GSK3β activity. We examined the effect of valproate on the development of morphine antinociceptive tolerance in a mouse model of thermal injury. Mice were treated with morphine alone or with morphine and valproate twice daily for 5 days. The resulting antinociceptive effects were assessed using a hot plate test. While mice treated with morphine developed tolerance, co-administration of valproate attenuated the development of tolerance and impaired the activation of GSK3β in mice brains. Valproate alone did not show analgesic effects; nevertheless, it functioned as an adjuvant analgesic to prevent the development of morphine tolerance. These results suggest that the modulation of GSK3β activity by valproate may be useful and may play a role in the prevention of morphine tolerance. PMID:20816918

  3. Role of phosphodiesterase inhibitor Ibudilast in morphine-induced hippocampal injury

    PubMed Central

    Zhaleh, Mohsen; Panahi, Marzieh; Ghafurian Broujerdnia, Mehri; Ghorbani, Rostam; Ahmadi Angali, Kambiz; Saki, Ghasem

    2014-01-01

    Abstract: Background: Opioid drugs are used in the treatment of acute post-surgical pain and chronic pain, such as those associated with cancer. Opioid used is associated with complications such as analgesic tolerance, dependence and opioid abuse. The molecular mechanisms of unwanted opioid responses are varied but recent advances have highlighted elevations in pro-inflammatory cytokines and pro-inflammatory glial following chronic administration of morphine. In this study we investigated the neurodegenerative effects of morphine through its effects on Toll-Like Receptor 4 (TLR4) in the male rat hippocampus and evaluated the level of Interleukin-1 beta (IL-1β). Then we compared the difference between inhibitory effects on mu opioid receptors (by β-Funaltrexamine, β-FNA) and TLR4 (by Ibudilast). Subsequently, we assessed the amount of IL-1β and the number of granular cells in male rat hippocampus. Methods: Adult male rats (n=24) were treated with sucrose, morphine, Ibudilast (7.5 mg/kg) and β-FNA (20 mg/kg) for 30 days. Their brains were isolated and hemisected with one hippocampus for granular cell and the other used for IL-1 β immunoblotting. Results: Data showed that Ibudilast suppresses IL-1 β expression significantly more than β-FNA. The granular cell count displayed significant differences. Conclusions: Our results suggested that Ibudilast can be used for controlling and treatment of morphine-induced CNS inflammations or traumatic conditions. PMID:24121451

  4. Effect of cinitapride in isolated ileum obtained from guinea-pigs treated with morphine.

    PubMed

    Colado, M I; Alfaro, M J; del Val, V L; Martín, M I

    1991-01-01

    1. Cinitapride enhanced the contractile response induced by electrical stimulation in the guinea-pig myenteric plexus-longitudinal muscle strip preparations. 2. The contractile force was significantly increased in strips pretreated with morphine "in vitro" and in tolerant strips. 3. However when tissues were obtained from tolerant guinea-pigs and morphine was not added to the organ bath (morphine-abstinence), the cinitapride effect was significantly decreased. 4. Although further work is required to explain the changes in the effect of cinitapride after acute morphine treatment and in morphine tolerant tissues, the changes observed suggest that some of the cinitapride effects could be linked with the peripheral opioid system. PMID:1662171

  5. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice

    PubMed Central

    Amin, Bahareh; Nakhsaz, Alireza; Hosseinzadeh, Hossein

    2015-01-01

    Objective: The present study was designed to investigate the putative antidepressant effects of crocin and crocetin, two major active ingredients of Crocus sativus L. (saffron) using mice in two different regimens of acute and sub-acute administration. Material and Methods: In acute treatment, antidepressant-like activities of crocin and crocetin (10, 20 and 40 mg/kg, i.p.) were evaluated using forced swim test (FST). In sub-acute study (21 times with 24-h intervals), antidepressant-like effects of oral administration of drugs were examined using FST and tail suspension test (TST). Locomotor activity and motor coordination were studied using open field and rotarod tests, respectively. Results: Acute treatment with crocin (40 mg/kg) and crocetin (20 and 40 mg/kg) produced antidepressant-like effect in FST without affecting the baseline locomotion in mice. Sub-acute oral administration of crocin significantly decreased immobility time only at the highest dose (100 mg/kg). Crocetin (12.5, 25 and 50 mg/kg) was able to decrease immobility time in FST and TST. Locomotor activity and coordination of mice were not affected by crocin or crocetin. Conclusion: Since higher doses of crocin was required to show antidepressant effects, more efficacy of crocetin may be concluded. This observation provides further support for metabolism of crocin to crocetin following oral administration. PMID:26468466

  6. Methamphetamine, morphine, and their combination: acute changes in striatal dopaminergic transmission evaluated by microdialysis in awake rats.

    PubMed

    Pereira, Frederico C; Lourenço, Elita; Milhazes, Nuno; Morgadinho, Teresa; Ribeiro, Carlos F; Ali, Syed F; Macedo, Tice R

    2006-08-01

    The co-administration of methamphetamine (METH) and MOR (MOR)-like compounds is becoming increasingly popular among drug abusers. Recently, it was demonstrated that rats would self-inject METH-heroin combination and that this combination produced a greater rewarding effect than the identical doses of METH alone and it was further suggested that enhanced reward might underlie the popularity of this combination. However, there is null information on the effects of the MOR-METH combination on striatal dopaminergic transmission. In the present article, in vivo brain microdialysis was used to examine the effects of two METH doses (1 and 5 mg/kg, i.p.; [METH1: hyperlocomotion-inducing] and [METH5: stereotypy-inducing], respectively) and MOR (10 mg/kg, i.p. [MOR10]) either alone or in combination on dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) release in caudate putamen (CPu) in freely moving rats. METH1 evoked a transient threefold increase in DA overflow in only one-third of dosed rats. On the contrary, METH5 elicited a 11-fold increase in the extracellular DA levels 30 min after dosing and stayed significantly (P < 0.05) above control levels up to 1.5 h. On the other hand, MOR10 did not significantly change DA extracellular levels. MOR10-METH1 combination prolonged DA outflow for 1 h in all rats dosed without changing peak effect compared to METH1. On the other hand, MOR10-METH5 combination did not change the peak effect nor the DA outflow profile compared to METH5 alone. Consistently, there is a concentration-dependent decrease in DOPAC efflux evoked by METH: METH1 evoked a smaller decrease in DOPAC outflow showing a tendency for returning to basal values whereas METH5 kept DOPAC extracellular levels reduced throughout the experiment. Again, MOR10 did not significantly change DOPAC extracellular levels. MOR delayed the onset without changing METH effect on the DOPAC output. These findings provide suggestive evidence that MOR potentiated the increase in

  7. Glutamatergic Mechanisms of Comorbidity Between Acute Stress and Cocaine Self-administration

    PubMed Central

    Garcia-Keller, Constanza; Kupchik, Yonatan; Gipson, Cassandra D; Brown, Robyn M; Spencer, Sade; Bollati, Flavia; Esparza, Maria A; Roberts-Wolfe, Doug; Heinsbroek, Jasper; Bobadilla, Ana-Clara; Cancela, Liliana M; Kalivas, Peter W

    2015-01-01

    There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining if the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate mediated synaptic currents, and dendritic spine morphology. We also determined if acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport, and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders. PMID:26821978

  8. Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.

    PubMed

    Garcia-Keller, C; Kupchik, Y M; Gipson, C D; Brown, R M; Spencer, S; Bollati, F; Esparza, M A; Roberts-Wolfe, D J; Heinsbroek, J A; Bobadilla, A-C; Cancela, L M; Kalivas, P W

    2016-08-01

    There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders. PMID:26821978

  9. Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice.

    PubMed

    Hassanipour, Mahsa; Amini-Khoei, Hossein; Shafaroodi, Hamed; Shirzadian, Armin; Rahimi, Nastaran; Imran-Khan, Muhammad; Rezayat, Seyed-Mahdi; Dehpour, Ahmadreza

    2016-07-01

    The development of morphine-induced antinociceptive tolerance limits its therapeutic efficacy in pain management. Atorvastatin, or competitive inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, is mainstay agent in hypercholesterolemia treatment. Beyond the cholesterol-lowering activity, exploration of neuroprotective properties of this statin indicates its potential benefit in central nervous disorders. The aim of the present study was to assess the effects of atorvastatin in development and expression of morphine-induced analgesic tolerance in male mice and probable involvement of nitric oxide. Chronic and acute treatment with atorvastatin 10 and 20mg/kg, respectively, could alleviate morphine tolerance in development and expression phases. Chronic co-administration of nitric oxide synthase (NOS) inhibitors including L-NAME (non selective NOS inhibitor; 2mg/kg), aminoguanidine (selective inducible NOS inhibitor; 50mg/kg) and 7-NI (selective neuronal NOS inhibitor; 15mg/kg) with atorvastatin blocked the protective effect of atorvastatin in tolerance reversal. Moreover, reversing the atorvastatin effect was also observed in acute simultaneous treatment of L-NAME (5mg/kg) and aminoguanidine (100mg/kg) with atorvastatin. Co-treatment of guanylyl cyclase inhibitor, ODQ (chronic dose: 10mg/kg and acute dose: 20mg/kg) was associated with prevention of atorvastatin anti-tolerance properties. Our results revealed that the atorvastatin modulating role in morphine antinociceptive tolerance is mediated at least in part via nitric oxide in animal pain models of hot plate and tail flick. PMID:27381980

  10. D-cycloserine facilitates extinction of naloxone-induced conditioned place aversion in morphine-dependent rats

    PubMed Central

    Myers, Karyn M.; Carlezon, William A.

    2016-01-01

    BACKGROUND Cues paired with drug administration trigger relapse to drug-seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US) with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. METHOD Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the NMDA receptor partial agonist D-cycloserine (DCS) was administered prior to extinction training. RESULTS Morphine withdrawal-induced CPA persists in the absence of extinction training. Administration of DCS prior to extinction training facilitates extinction. CONCLUSIONS DCS facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction. PMID:19782965

  11. Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice.

    PubMed

    Molet, Jenny; Hervé, Denis; Thiébot, Marie-Hélène; Hamon, Michel; Lanfumey, Laurence

    2013-12-01

    Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5mg/kg) or morphine (10mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age. PMID:23619165

  12. Ellagic acid enhances morphine analgesia and attenuates the development of morphine tolerance and dependence in mice.

    PubMed

    Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Ghorbanzadeh, Behnam

    2014-10-15

    According to our previous study, ellagic acid has both dose-related central and peripheral antinociceptive effect through the opioidergic and l-arginine-NO-cGMP-ATP sensitive K(+) channel pathways. In the present study, the systemic antinociceptive effects of ellagic acid in animal models of pain, and functional interactions between ellagic acid and morphine in terms of analgesia, tolerance and dependence were investigated. Ellagic acid (1-30mg/kg; i.p.) showed significant and dose-dependent antinociceptive effects in the acetic acid-induced writhing test. Intraperitoneal ellagic acid acutely interacted with morphine analgesia in a synergistic manner in this assay. Ellagic acid (1-10mg/kg; i.p.) also exerted analgesic activity in the hot-plate test. Pre-treatment with naloxone (1mg/kg; i.p.) significantly reversed ellagic acid, morphine as well as ellagic acid-morphine combination-induced antinociceptin in these two tests. More importantly, when co-administered with morphine, ellagic acid (1-10mg/kg) effectively blocked the development of tolerance to morphine analgesia in the hot-plate test. Likewise, ellagic acid dose-dependently prevented naloxone-precipitated withdrawal signs including jumping and weight loss. Ellagic acid treatment (1-30mg/kg; i.p.) had no significant effect on the locomotion activity of animals using open-field task. Therefore, these results showed that ellagic acid has notable systemic antinociceptive activity for both tonic and phasic pain models. Altogether, ellagic acid might be used in pain relief alone or in combination with opioid drugs because of enhancing morphine analgesia and preventing morphine-induced tolerance to analgesia and dependence. PMID:25179576

  13. Sex Differences in the Morphine-Sparing Effects of Intraoperative Dexmedetomidine in Patient-Controlled Analgesia Following General Anesthesia

    PubMed Central

    Li, Yuan-Yuan; Ge, Dong-Jian; Li, Jin-Yu; Qi, Bin

    2016-01-01

    Abstract Previous studies have reported that intraoperative dexmedetomidine has morphine-sparing effects in patient-controlled analgesia (PCA). The present study was designed to investigate the possible sex differences in the morphine-sparing effects of intraoperative dexmedetomidine following general anesthesia. A total of 223 patients scheduled for surgeries under general anesthesia were divided into female and male groups. Each group was then subdivided into 2 subgroups that were maintained using propofol/remifentanil/dexmedetomidine (PRD) or propofol/remifentanil/saline (PRS). During the first 24 hours postsurgery, both female and male PRD patients had lower scores on a visual analog scale (VAS) (fPRS vs fPRD, P < 0.05 or P < 0.01; mPRS mPRD, P < 0.05, P < 0.01, or P < 0.001) and consumed less morphine than their controls from the PRS group (fPRS vs fPRD, P = 0.0392; mPRS vs mPRD, P = 0.0041). Interestingly, the female PRD patients had similar VAS scores (fPRD vs mPRD, P > 0.05) and consumed comparable morphine compared to the male PRD patients (fPRD vs mPRD, P = 0.4238). However, when normalized to body weight, they consumed much more morphine than male PRD patients (fPRD vs mPRD, P < 0.001), and this effect was not seen in the PRS patients. Intraoperative administration of dexmedetomidine appeared to have a stronger morphine-sparing effect in controlling postoperative acute pain in male patients than in female patients. PMID:27149500

  14. Interaction of prenatal stress and morphine alters prolactin and seizure in rat pups.

    PubMed

    Saboory, Ehsan; Ebrahimi, Loghman; Roshan-Milani, Shiva; Hashemi, Paria

    2015-10-01

    Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylenetetrazol (PTZ) induced epileptic behaviors and prolactin blood level (PBL) was investigated in rat offspring. Pregnant Wistar rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, pregnant rats were placed in 25°C water on gestation days 17, 18 and 19 (GD17, GD18 and GD19) for 30 min. In the morphine/saline group, pregnant rats received morphine (10, 12 and 15 mg/kg, IP, on GD17, GD18 and GD19, respectively) or saline (1 ml, IP). In the morphine/saline-stressed group, the rats received morphine or saline and then exposed to stress. On postnatal days 6 and 15 (P6 and P15), blood samples were obtained and PBL was determined. At P15 and P25, the rest of the pups was injected with PTZ to induce seizure. Then, epileptic behaviors of each rat were observed individually. Latency of first convulsion decreased in control-morphine and stressed-saline groups while increased in stressed-morphine rats compared to control-saline group on P15 (P=0.04). Number of tonic-clonic seizures significantly increased in control-morphine and stressed-saline rats compared to control-saline group at P15 (P=0.02). PBL increased in stressed-saline, control-morphine and stress-morphine groups compared to control-saline rats. It can be concluded that prenatal exposure of rats to forced-swim stress and morphine changed their susceptibility to PTZ-induced seizure and PBL during infancy and prepubertal period. Co-administration of morphine attenuated effect of stress on epileptic behaviors. PMID:26056076

  15. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial

    PubMed Central

    Kubica, Jacek; Adamski, Piotr; Ostrowska, Małgorzata; Sikora, Joanna; Kubica, Julia Maria; Sroka, Wiktor Dariusz; Stankowska, Katarzyna; Buszko, Katarzyna; Navarese, Eliano Pio; Jilma, Bernd; Siller-Matula, Jolanta Maria; Marszałł, Michał Piotr; Rość, Danuta; Koziński, Marek

    2016-01-01

    Aims The currently available data indicate a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. Methods and results In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0–12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Conclusions Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878. PMID:26491112

  16. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques.

    PubMed

    Mather, S J; Peutrell, J M

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be as effective as opioid analgesia following tonsillectomy in children. Opioids are still frequently used but tonsillectomy is associated with a high incidence of vomiting. This study has attempted to assess postoperative analgesic consumption and nausea and vomiting after general anaesthesia for tonsillectomy using either paracetamol premedication, paracetamol plus a NSAID or intravenous morphine to provide postoperative analgesia. Some children required a rescue dose of morphine in the recovery room, including some who had received intravenous morphine at induction. Least supplementary morphine was required by those who had received paracetamol plus ketorolac. Postoperative nausea and vomiting was significantly less in the two groups which were not given intraoperative morphine. The number of vomiting incidents was also much less. We conclude that the preoperative administration of paracetamol alone provides satisfactory analgesia in many children but that supplementary analgesia is still required for some. PMID:7489439

  17. Effect of Pre- and Postoperative Phenylbutazone and Morphine Administration on the Breathing Response to Skin Incision, Recovery Quality, Behavior, and Cardiorespiratory Variables in Horses Undergoing Fetlock Arthroscopy: A Pilot Study

    PubMed Central

    Conde Ruiz, Clara; Cruz Benedetti, Inga-Catalina; Guillebert, Isabelle; Portier, Karine Genevieve

    2015-01-01

    This prospective blinded randomized study aimed to determine whether the timing of morphine and phenylbutazone administration affects the breathing response to skin incision, recovery quality, behavior, and cardiorespiratory variables in horses undergoing fetlock arthroscopy. Ten Standardbred horses were premedicated with acepromazine (0.04 mg kg−1 IM) and romifidine (0.04 mg kg−1 IV). Anesthesia was induced with diazepam (0.05 mg kg−1) and ketamine (2.2 mg kg−1) IV at T0. Horses in group PRE (n = 5) received morphine (0.1 mg kg−1) and phenylbutazone (2.2 mg kg−1) IV after induction and an equivalent amount of saline after surgery. Horses in group POST (n = 5) received the inversed treatment. Anesthesia was maintained with isoflurane 2% in 100% oxygen. Hypotension (mean arterial pressure <60 mmHg) was treated with dobutamine. All horses breathed spontaneously. Dobutamine requirements, respiratory rate (fR), heart rate (HR), mean arterial blood pressure, end-tidal CO2, inspired (i) and expired (e) tidal and minute volume (VT and V˙E), inspiratory time (IT), and the inspiratory gas flow (VTi/IT) were measured every 5 min. Data were averaged during four 15 min periods before (P1 and P2) and after the incision (P3 and P4). Serial blood–gas analyses were also performed. Recoveries were unassisted, video recorded, and scored by three anesthetists blinded to the treatment. The postoperative behavior of the horses (25 demeanors), HR, and fR were recorded at three time points before induction (T0–24 h, T0–12 h, and T0–2 h) and six time points after recovery (TR) (TR + 2, 4, 6, 12, 24, 48 h). Data were compared between groups using a Wilcoxon test and within groups using a Friedman test or a Kruskal–Wallis signed-rank test when applicable. Tidal volumes (VTe and VTi) were higher in PRE than in POST during all the considered periods but the difference between groups was only significant during P2 (VTe in mL kg−1

  18. Effect of Pre- and Postoperative Phenylbutazone and Morphine Administration on the Breathing Response to Skin Incision, Recovery Quality, Behavior, and Cardiorespiratory Variables in Horses Undergoing Fetlock Arthroscopy: A Pilot Study.

    PubMed

    Conde Ruiz, Clara; Cruz Benedetti, Inga-Catalina; Guillebert, Isabelle; Portier, Karine Genevieve

    2015-01-01

    This prospective blinded randomized study aimed to determine whether the timing of morphine and phenylbutazone administration affects the breathing response to skin incision, recovery quality, behavior, and cardiorespiratory variables in horses undergoing fetlock arthroscopy. Ten Standardbred horses were premedicated with acepromazine (0.04 mg kg(-1) IM) and romifidine (0.04 mg kg(-1) IV). Anesthesia was induced with diazepam (0.05 mg kg(-1)) and ketamine (2.2 mg kg(-1)) IV at T0. Horses in group PRE (n = 5) received morphine (0.1 mg kg(-1)) and phenylbutazone (2.2 mg kg(-1)) IV after induction and an equivalent amount of saline after surgery. Horses in group POST (n = 5) received the inversed treatment. Anesthesia was maintained with isoflurane 2% in 100% oxygen. Hypotension (mean arterial pressure <60 mmHg) was treated with dobutamine. All horses breathed spontaneously. Dobutamine requirements, respiratory rate (f R), heart rate (HR), mean arterial blood pressure, end-tidal CO2, inspired (i) and expired (e) tidal and minute volume (V T and [Formula: see text]), inspiratory time (IT), and the inspiratory gas flow (V Ti/IT) were measured every 5 min. Data were averaged during four 15 min periods before (P1 and P2) and after the incision (P3 and P4). Serial blood-gas analyses were also performed. Recoveries were unassisted, video recorded, and scored by three anesthetists blinded to the treatment. The postoperative behavior of the horses (25 demeanors), HR, and f R were recorded at three time points before induction (T0-24 h, T0-12 h, and T0-2 h) and six time points after recovery (TR) (TR + 2, 4, 6, 12, 24, 48 h). Data were compared between groups using a Wilcoxon test and within groups using a Friedman test or a Kruskal-Wallis signed-rank test when applicable. Tidal volumes (V Te and V Ti) were higher in PRE than in POST during all the considered periods but the difference between groups was only significant during P2 (V Te in

  19. Morphine: Myths and Reality

    MedlinePlus

    ... ve heard that Morphine has lots of side effects, and I feel bad enough already.” All opiates can cause nausea, drowsiness and constipation. However, all side effects will generally stop after a few days, as ...

  20. Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

    PubMed Central

    Thibault, Karine; Calvino, Bernard; Rivals, Isabelle; Marchand, Fabien; Dubacq, Sophie; McMahon, Stephen B.; Pezet, Sophie

    2014-01-01

    Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone. PMID:24618941

  1. Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

    PubMed

    Thibault, Karine; Calvino, Bernard; Rivals, Isabelle; Marchand, Fabien; Dubacq, Sophie; McMahon, Stephen B; Pezet, Sophie

    2014-01-01

    Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone. PMID:24618941

  2. Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities.

    PubMed

    Elhabazi, Khadija; Ayachi, Safia; Ilien, Brigitte; Simonin, Frédéric

    2014-01-01

    Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols. We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild-type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy. PMID:25145878

  3. Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

    PubMed Central

    Elhabazi, Khadija; Ayachi, Safia; Ilien, Brigitte; Simonin, Frédéric

    2014-01-01

    Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols. We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild-type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy. PMID:25145878

  4. Stress and opioids: role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference.

    PubMed

    Bali, Anjana; Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2015-04-01

    Research studies have defined the important role of endogenous opioids in modulating stress-associated behavior. The release of β-endorphins in the amygdala in response to stress helps to cope with a stressor by inhibiting the over-activation of HPA axis. Administration of mu opioid agonists reduces the risk of developing post-traumatic stress disorder (PTSD) following a traumatic event by inhibiting fear-related memory consolidation. Similarly, the release of endogenous enkephalin and nociceptin in the basolateral amygdala and the nucleus accumbens tends to produce the anti-stress effects. An increase in dynorphin levels during prolonged exposure to stress may produce learned helplessness, dysphoria and depression. Stress also influences morphine-induced conditioned place preference (CPP) depending upon the intensity and duration of the stressor. Acute stress inhibits morphine CPP, while chronic stress potentiates CPP. The development of dysphoria due to increased dynorphin levels may contribute to chronic stress-induced potentiation of morphine CPP. The activation of ERK/cyclic AMP responsive element-binding (CREB) signaling in the mesocorticolimbic area, glucocorticoid receptors in the basolateral amygdala, and norepinephrine and galanin system in the nucleus accumbens may decrease the acute stress-induced inhibition of morphine CPP. The increase in dopamine levels in the nucleus accumbens and augmentation of GABAergic transmission in the median prefrontal cortex may contribute in potentiating morphine CPP. Stress exposure reinstates the extinct morphine CPP by activating the orexin receptors in the nucleus accumbens, decreasing the oxytocin levels in the lateral septum and amygdala, and altering the GABAergic transmission (activation of GABAA and inactivation of GABAB receptors). The present review describes these varied interactions between opioids and stress along with the possible mechanism. PMID:25636946

  5. Micturition in naive and morphine-dependent rats.

    PubMed Central

    Carpenter, F. G.

    1986-01-01

    Voiding responses were recorded in conscious water-loaded rats. Morphine sulphate (5 mg kg-1) elevated the volume threshold for micturition (MV); the group mean MV of 16 rats after morphine was 40% larger than control. Micturition was nevertheless complete since no urine remained in the bladder afterwards. The implantation of 2 or 4 morphine-base pellets (150 or 300 mg morphine) elevated for 12 days the MV in water-loaded rats. On the 3rd to the 10th day following implantation the group mean was approximately twice that of untreated controls. After micturition was over no residual urine was found in the bladder. Within 3 days the rats became tolerant to the antinociceptive action of the morphine-base pellets but little apparent tolerance developed to their action on micturition. On the 1st day after the pellets were removed, the mean MV was reduced. When withdrawal was precipitated by the administration of naloxone the MV was often too small to measure. This component of a withdrawal syndrome could be elicited in the rats throughout the 12 days of morphine pellet implantation. The administration of 20 mg kg-1 morphine sulphate to anaesthetized rats did not decrease the contractions of the urinary bladder to repetitive stimulation of its motor nerves at 1 and 20 Hz. PMID:3708205

  6. Self administration of cocaine in monkeys receiving LAAM acutely or chronically.

    PubMed

    Gerak, Lisa R; Galici, Ruggero; France, Charles P

    2008-01-28

    Polydrug abuse remains a common problem among opioid abusers as well as patients in opioid maintenance programs. Although cocaine abuse has been reported in patients receiving methadone, the incidence of cocaine use in patients receiving l-alpha-acetylmethadol (LAAM) has not been well established. The goal of this study was to determine whether acute or chronic administration of LAAM modified the reinforcing effects of cocaine using a self-administration procedure in rhesus monkeys. Four monkeys responded under a fixed ratio (FR) 30 schedule to receive i.v. infusions of cocaine (0.0032-0.32 mg/kg/infusion) in the absence of other treatment, after acute LAAM administration (0.1-1.0 mg/kg, s.c.), and during daily administration of 1.0 mg/kg of LAAM. Cocaine maintained self-administration responding that exceeded responding maintained by saline; acutely administered LAAM had small and variable effects on self administration of cocaine. Daily LAAM administration increased the number of infusions received of at least one dose of cocaine. These studies indicated that LAAM administration did not attenuate the reinforcing effects of cocaine, suggesting that LAAM would not likely alter cocaine abuse in patients undergoing treatment for opioid abuse. PMID:17764707

  7. Stress antagonizes morphine-induced analgesia in rats

    NASA Technical Reports Server (NTRS)

    Vernikos, J.; Shannon, L.; Heybach, J. P.

    1981-01-01

    Exposure to restraint stress resulted in antagonism of the analgesic effect of administered morphine in adult male rats. This antagonism of morphine-induced analgesia by restraint stress was not affected by adrenalectomy one day prior to testing, suggesting that stress-induced secretion of corticosteroids is not critical to this antagonism. In addition, parenteral administration of exogenous adrenocorticotropin (ACTH) mimicked the effect of stress in antagonizing morphine's analgesic efficacy. The hypothesis that ACTH is an endogenous opiate antagonist involved in modulating pain sensitivity is supported.

  8. Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats.

    PubMed

    Ramos, Andrea C; Ferreira, Gabriela K; Carvalho-Silva, Milena; Furlanetto, Camila B; Gonçalves, Cinara L; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-08-01

    Tyrosinemia type II is an inborn error of metabolism caused by mutations in the gene that encodes tyrosine aminotransferase, which leads to increased blood tyrosine levels. Considering that tyrosine levels are highly elevated in fluids of patients with tyrosinemia type II, and that previous studies demonstrated significant alterations in brain energy metabolism of young rats caused by l-tyrosine, the present study aimed to evaluate the effect of acute administration of l-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase, and mitochondrial respiratory chain complexes I, II, II-III, and IV in posterior cortex, hippocampus, and striatum of infant rats. Wistar rats (10 days old) were killed 1h after a single intraperitoneal injection of tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated in brain of rats. Our results demonstrated that acute administration of l-tyrosine inhibited the activity of citrate synthase activity in striatum and increased the activities of malate dehydrogenase and succinate dehydrogenase in hippocampus. On the other hand, these enzymes were not affected in posterior cortex. The activities of complex I and complex II were inhibited by acute administration of l-tyrosine in striatum. On the other hand, the acute administration of l-tyrosine increased the activity of activity of complex II-III in hippocampus. Complex IV was not affected by acute administration of l-tyrosine in infant rats. Our results indicate an alteration in the energy metabolism in hippocampus and striatum of infant rats after acute administration of l-tyrosine. If the same effects occur in the brain of the patients, it is possible that energy metabolism impairment may be contribute to possible damage in memory and cognitive processes in patients with tyrosinemia type II. PMID:23602810

  9. [Morphine by external route, prescribed to Heinrich Heine by David Gruby].

    PubMed

    Chast, F

    1998-01-01

    The exhibition held in Paris commemorating the bicentenial of Heinrich Heine showed three prescriptions by Dr. D. Gruby, through which morphine was prescribed for the poet by external route. The use of morphine was justified in a patient with unrelieved pain caused by neurosyphilis during the last twelve years of his life. This way of morphine administration (endemic method) was quite popular between 1830 and 1860. The process consisted in stripping the derm with the help of a vesicant and in applying directly on it morphine salts crystals. Several authors commented the interest of this way of administration rather uncomfortable for the patient but apparently very effective. PMID:11625475

  10. Morphine Suppository versus Indomethacin Suppository in the Management of Renal Colic: Randomized Clinical Trial.

    PubMed

    Zamanian, Forough; Jalili, Mohammad; Moradi-Lakeh, Maziar; Kia, Maryam; Aghili, Rokhsareh; Aghili, Seyed Mojtaba

    2016-01-01

    Background. Renal colic is a medical emergency due to the rapid onset and devastating nature of its pain. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are both used as first-line choices in its management. Aim. This study aimed to compare the efficacy and safety of opioids and NSAIDs in the management of acute renal colic. Methods. One hundred and fifty-eight patients were divided into two groups (n = 79) and received either 10 mg morphine or 100 mg indomethacin suppositories. The severity of pain was measured using verbal numeric rating scale at baseline and 20, 40, 60, and 90 minutes after the administration of analgesics. Drug side effects as well as patients' vital signs were also recorded. Results. The mean decrease in the pain score during the first 20 minutes was significantly higher among those who received morphine suppository. However, no significant difference was observed between the two groups regarding the mean decrease in pain score during the first 40, 60, and 90 minutes after the admission. Prevalence of drug side effects or changes in the vital signs was not significantly different between the two groups. Conclusions. Morphine suppositories seem to be more efficient in achieving rapid pain relief comparing to indomethacin. PMID:27073696

  11. Morphine Suppository versus Indomethacin Suppository in the Management of Renal Colic: Randomized Clinical Trial

    PubMed Central

    Zamanian, Forough; Jalili, Mohammad; Moradi-Lakeh, Maziar; Kia, Maryam; Aghili, Rokhsareh; Aghili, Seyed Mojtaba

    2016-01-01

    Background. Renal colic is a medical emergency due to the rapid onset and devastating nature of its pain. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are both used as first-line choices in its management. Aim. This study aimed to compare the efficacy and safety of opioids and NSAIDs in the management of acute renal colic. Methods. One hundred and fifty-eight patients were divided into two groups (n = 79) and received either 10 mg morphine or 100 mg indomethacin suppositories. The severity of pain was measured using verbal numeric rating scale at baseline and 20, 40, 60, and 90 minutes after the administration of analgesics. Drug side effects as well as patients' vital signs were also recorded. Results. The mean decrease in the pain score during the first 20 minutes was significantly higher among those who received morphine suppository. However, no significant difference was observed between the two groups regarding the mean decrease in pain score during the first 40, 60, and 90 minutes after the admission. Prevalence of drug side effects or changes in the vital signs was not significantly different between the two groups. Conclusions. Morphine suppositories seem to be more efficient in achieving rapid pain relief comparing to indomethacin. PMID:27073696

  12. Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

    PubMed Central

    Vahdati Hassani, Faezeh; Hashemzaei, Mahmoud; Akbari, Edris; Imenshahidi, Mohsen; Hosseinzadeh, Hossein

    2016-01-01

    Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice. Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine. The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP. Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction. PMID:27222833

  13. Adenosine receptor antagonists inhibit the development of morphine sensitization in the C57BL/6 mouse.

    PubMed

    Weisberg, S P; Kaplan, G B

    1999-04-01

    We examined the effects of adenosine antagonists on the development of morphine sensitization in C57BL/6 mice. Adenosine antagonists or vehicle were repeatedly co-administered intraperitoneally with morphine (10 mg/kg, s.c.) to mice once every other day for 9 days. Two days later, a 10 mg/kg morphine-only challenge was administered to each group. Consistent with sensitization, mice receiving morphine alone developed enhanced ambulatory activity responses to subsequent morphine administrations and, upon morphine-only challenge, had a significantly greater response to morphine than vehicle pretreated animals. The nonselective adenosine antagonist, caffeine, at 10 and 20 mg/kg but not at 5 mg/kg, attenuated the development of sensitization during co-administration with morphine and also following morphine-only challenge. The adenosine A1 selective antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX), at 0.001 and 0.002 mg/kg but not at 0.2 mg/kg, similarly attenuated the development of morphine sensitization. We propose a mechanism which involves an adenosine receptor role in the mesolimbic dopamine system. PMID:10320021

  14. Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

    PubMed Central

    Anoush, Mahdieh; Jani, Ali; Sahebgharani, Moosa; Jafari, Mohammad Reza

    2015-01-01

    Objective: In this study, the effects of estradiol valerate and raloxifenea selective estrogen receptor modulator; (SERM) on morphine induced sensitization were examined in mice memory, according to the step-down passive avoidance task. Method: The mice received morphine or estradiol and raloxifene for three days alone or in combination with morphine. After a drug free period of 5 days, the subjects received saline or morphine as pre- training treatments followed by a pre-test saline administration. The memory retrieval was evaluated using step-down passive avoidance test both on the training and test day. Results: The results illustrated that the three- day administration of morphine induced sensitization through the enhancement of memory retrieval (morphine induced sensitization in mice memory). Both the three- day administration of estradiol valerate alone and with morphine (5 mg/kg) restored memory. On the other hand, the three- day administration of raloxifene had no effect on memory retrieval alone, but declined morphine induced sensitization in mice memory. Conclusion: The results of the study indicated that there is an interaction between estrogen receptor modulators and morphine induced sensitization in mice memory. PMID:26877753

  15. Effect of acute thioacetamide administration on rat brain phospholipid metabolism

    SciTech Connect

    Osada, J.; Aylagas, H.; Miro-Obradors, M.J.; Arce, C.; Palacios-Alaiz, E.; Cascales, M. )

    1990-09-01

    Brain phospholipid composition and the ({sup 32}P)orthophosphate incorporation into brain phospholipids of control and rats treated for 3 days with thioacetamide were studied. Brain phospholipid content, phosphatidylcholine, phosphatidylethanolamine, lysolecithin and phosphatidic acid did not show any significant change by the effect of thioacetamide. In contrast, thioacetamide induced a significant decrease in the levels of phosphatidylserine, sphingomyelin, phosphatidylinositol and diphosphatidylglycerol. After 75 minutes of intraperitoneal label injection, specific radioactivity of all the above phospholipids with the exception of phosphatidylethanolamine and phosphatidylcholine significantly increased. After 13 hours of isotope administration the specific radioactivity of almost all studied phospholipid classes was elevated, except for phosphatidic acid, the specific radioactivity of which did not change and for diphosphatidylglycerol which showed a decrease in specific radioactivity. These results suggest that under thioacetamide treatment brain phospholipids undergo metabolic transformations that may contribute to the hepatic encephalopathy induced by thioacetamide.

  16. Protective effect of crocin on liver toxicity induced by morphine

    PubMed Central

    Salahshoor, Mohammad Reza; khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  17. Protective effect of crocin on liver toxicity induced by morphine.

    PubMed

    Salahshoor, Mohammad Reza; Khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  18. Brain and Muscle Redox Imbalance Elicited by Acute Ethylmalonic Acid Administration

    PubMed Central

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2’,7’-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy. PMID:26010931

  19. Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

    PubMed

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7'-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy. PMID:26010931

  20. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.

    PubMed

    Mika, Joanna; Wawrzczak-Bargiela, Agnieszka; Osikowicz, Maria; Makuch, Wioletta; Przewlocka, Barbara

    2009-01-01

    We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain. PMID:18684397

  1. The effects of acute alcohol administration on the human brain: Insights from neuroimaging

    PubMed Central

    Bjork, James M.; Gilman, Jodi M.

    2014-01-01

    Over the last quarter century, researchers have peered into the living human brain to develop and refine mechanistic accounts of alcohol-induced behavior, as well as neurobiological mechanisms for development and maintenance of addiction. These in vivo neuroimaging studies generally show that acute alcohol administration affects brain structures implicated in motivation and behavior control, and that chronic intoxication is correlated with structural and functional abnormalities in these same structures, where some elements of these decrements normalize with extended sobriety. In this review, we will summarize recent findings about acute human brain responses to alcohol using neuroimaging techniques, and how they might explain behavioral effects of alcohol intoxication. We then briefly address how chronic alcohol intoxication (as inferred from cross-sectional differences between various drinking populations and controls) may yield individual brain differences between drinking subjects that may confound interpretation of acute alcohol administration effects. PMID:23978384

  2. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models.

    PubMed

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models. PMID:26199634

  3. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    PubMed Central

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models. PMID:26199634

  4. Attenuation of morphine tolerance and dependence by thymoquinone in mice

    PubMed Central

    Hosseinzadeh, Hossein; Parvardeh, Siavash; Masoudi, Alireza; Moghimi, Mahsa; Mahboobifard, Fatemeh

    2016-01-01

    Objective: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively) during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p.) was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p.) significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days) and also single injection of thymoquinone (40 mg/kg, on the fourth day) attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg) produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg). Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine. PMID:27247922

  5. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  6. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality. PMID:25485642

  7. Renal colic in adults: NSAIDs and morphine are effective for pain relief.

    PubMed

    2009-10-01

    (1) Renal colic is an acute syndrome involving unilateral flank pain, linked to an obstruction in the upper urinary tract. The pain is often intense. After having considered other diagnoses and checked for signs of complication (fever, oligoanuria), the first step is to control the pain; (2) Which non-invasive treatments have a positive risk-benefit balance in relieving this type of pain? To answer this question, we reviewed the available evidence, based on the standard Prescrire methodology; (3) According to a meta-analysis of 20 trials, nonsteroidal antiinflammatory drugs (NSAIDs) and strong opioid analgesics have comparable efficacy. The most widely studied NSAID is diclofenac, given intramuscularly at a dose of 50 mg or 75 mg. Pethidine is the best-assessed strong opioid, given intramuscularly at a dose of 50 mg to 100 mg, which corresponds to about 5 mg to 10 mg of morphine. Morphine is given intravenously; subcutaneous administration is an alternative although it has not been evaluated in renal colic; (4) In clinical trials, NSAIDs were associated with fewer adverse effects than opioids, which cause vomiting in about 20% of patients (versus about 6% with an NSAID); (5) NSAIDs expose patients to a risk of functional renal impairment, especially in patients with heart failure, renal artery stenosis, dehydration, renal impairment or ongoing treatment with a nephrotoxic drug, and the very elderly. NSAIDs should never be used during pregnancy; (6) According to one trial in 130 patients, the analgesic effect of the morphine and NSAID combination was greater than either agent used alone, in about 10% of patients; (7) Paracetamol has not been evaluated in comparative trials of renal colic, even for moderate pain; (8) Scopolamine is the only antispasmodic to have been evaluated in a comparative trial. Adding scopolamine to morphine did not seem to provide additional efficacy; (9) Other drugs, which have not been adequately tested as of early 2009, have no documented

  8. Pharmacological characterization of standard analgesics on oxaliplatin-induced acute cold hypersensitivity in mice.

    PubMed

    Zhao, Meng; Nakamura, Saki; Miyake, Takahito; So, Kanako; Shirakawa, Hisashi; Tokuyama, Shogo; Narita, Minoru; Nakagawa, Takayuki; Kaneko, Shuji

    2014-01-01

    Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced acute cold hypersensitivity. Gabapentin, tramadol, mexiletine, and calcium gluconate significantly inhibited and morphine and milnacipran decreased the acute cold hypersensitivity, while diclofenac and amitriptyline had no effects. These results suggest that gabapentin, tramadol, mexiletine, and calcium gluconate are effective against oxaliplatin-induced acute peripheral neuropathy. PMID:24671055

  9. Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/KATP signaling pathway

    PubMed Central

    Cunha, Thiago M.; Roman-Campos, Danilo; Lotufo, Celina M.; Duarte, Hugo L.; Souza, Guilherme R.; Verri, Waldiceu A.; Funez, Mani I.; Dias, Quintino M.; Schivo, Ieda R.; Domingues, Andressa C.; Sachs, Daniela; Chiavegatto, Silvana; Teixeira, Mauro M.; Hothersall, John S.; Cruz, Jader S.; Cunha, Fernando Q.; Ferreira, Sergio H.

    2010-01-01

    Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kγ/AKT protein kinase B (AKT) and culminated in increased activation of KATP channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development. PMID:20147620

  10. Morphine-6beta-glucuronide modulates the expression of inducible nitric oxide synthase.

    PubMed

    Lysle, D T; Carrigan, K A

    2001-08-01

    The immunomodulatory effects of morphine are well established; however, suprisingly little is known about the immunomodulatory properties of the major metabolites of morphine. The present study tests the hypothesis that expression of inducible nitric oxide synthase (iNOS) is modulated by the administration of the morphine metabolite, morphine-6beta-glucuronide. The initial study using rats shows that morphine-6beta-glucuronide administration (0, 1.0, 3.163, 10 mg/kg s.c.) results in a pronounced reduction in lipopolysaccharide (LPS)-induced expression of iNOS (inducible nitricoxide synthease) in spleen, lung, and liver tissue as measured by western blotting. Morphine-6beta-glucuronide also produces a reduction in the level of plasma nitrite/nitrate, the more stable end-product of nitric oxide degradation. In a subsequent study, administration of the opioid receptor antagonist, naltrexone (0.1 mg/kg) prior to the injection of morphine-6beta-glucuronide (10 mg/kg) blocks the morphine-6beta-glucuronide induced reduction of iNOS expression and plasma nitrite/nitrite levels indicating that the effect is mediated via the opioid-receptor. This study provides the first evidence that morphine-6beta-glucuronide alters the expression of iNOS. PMID:11580103

  11. Sex Differences in the Morphine-Sparing Effects of Intraoperative Dexmedetomidine in Patient-Controlled Analgesia Following General Anesthesia: A Consort-Prospective, Randomized, Controlled Clinical Trial.

    PubMed

    Li, Yuan-Yuan; Ge, Dong-Jian; Li, Jin-Yu; Qi, Bin

    2016-05-01

    Previous studies have reported that intraoperative dexmedetomidine has morphine-sparing effects in patient-controlled analgesia (PCA). The present study was designed to investigate the possible sex differences in the morphine-sparing effects of intraoperative dexmedetomidine following general anesthesia. A total of 223 patients scheduled for surgeries under general anesthesia were divided into female and male groups. Each group was then subdivided into 2 subgroups that were maintained using propofol/remifentanil/dexmedetomidine (PRD) or propofol/remifentanil/saline (PRS). During the first 24 hours postsurgery, both female and male PRD patients had lower scores on a visual analog scale (VAS) (fPRS vs fPRD, P < 0.05 or P < 0.01; mPRS mPRD, P < 0.05, P < 0.01, or P < 0.001) and consumed less morphine than their controls from the PRS group (fPRS vs fPRD, P = 0.0392; mPRS vs mPRD, P = 0.0041). Interestingly, the female PRD patients had similar VAS scores (fPRD vs mPRD, P > 0.05) and consumed comparable morphine compared to the male PRD patients (fPRD vs mPRD, P = 0.4238). However, when normalized to body weight, they consumed much more morphine than male PRD patients (fPRD vs mPRD, P < 0.001), and this effect was not seen in the PRS patients. Intraoperative administration of dexmedetomidine appeared to have a stronger morphine-sparing effect in controlling postoperative acute pain in male patients than in female patients. PMID:27149500

  12. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    PubMed

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy. PMID:27424012

  13. Efficacy and Safety of Ropivacaine Addition to Intrathecal Morphine for Pain Management in Intractable Cancer

    PubMed Central

    Huang, Ying; Li, Xihan; Zhu, Tong; Lin, Jian; Tao, Gaojian

    2015-01-01

    Objective. Although intrathecal drug infusion has been commonly adopted for terminal cancer pain relief, its adverse effects have made many clinicians reluctant to employ it for intractable cancer pain. The objective of this study is to compare the efficacy and security of an intrathecal continuous infusion of morphine and ropivacaine versus intrathecal morphine alone for cancer pain. Methods. Thirty-six cancer patients received either a continuous morphine (n = 19) or morphine and ropivacaine (n = 17) infusion using an intrathecal catheter through a subcutaneous port. Numerical Rating Scale (NRS) scores and the Barthel Index were analyzed. Adverse effects and complications on postoperative days 1, 3, 7, and 15 were also analyzed. Results. All patients experienced pain relief. Compared to those who received morphine alone, patients receiving morphine and ropivacaine had significantly lower postoperative morphine requirements and higher Barthel Index scores on the 15th postsurgical day (P < 0.05). Patients receiving morphine and ropivacaine had lower NRS scores than patients receiving morphine alone on postoperative days 1, 3, 7, and 15 (P < 0.05). Negative postsurgical effects were similar in both groups. Conclusions. Morphine and ropivacaine administration through intrathecal access ports is efficacious and safe and significantly improves quality of life. PMID:26556955

  14. Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy.

    PubMed

    Haydari, Sakineh; Miladi-Gorji, Hossein; Mokhtari, Amin; Safari, Manouchehr

    2014-08-22

    Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (P<0.0001) and entries (P<0.05) as compared with the sedentary groups. In animal models of craving showed that voluntary consumption of morphine in the rat pups borne from exercising morphine-dependent mothers was less in the second (P<0.032) and third (P<0.014) periods of intake as compared with the sedentary group. This study showed that maternal exercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups. PMID:24973610

  15. Temporal effects of topical morphine application on cutaneous wound healing

    PubMed Central

    Rook, Jerri M.; Hasan, Wohaib; McCarson, Kenneth E.

    2008-01-01

    Background Studies have shown that topical administration of exogenous opioid drugs impairs wound healing by inhibiting the peripheral release of neuropeptides, thereby inhibiting neurogenic inflammation. This delay is immediate and peaks during the first days of wound closure. This study examined the effects of topical morphine treatment in a cutaneous wound healing model in the rat. Methods Full-thickness 4mm diameter wounds were placed on the periscapular region of rats that subsequently received twice-daily topical applications of IntraSite Gel (Smith+Nephew, Hull, United Kingdom) alone or gel infused with 5 mM morphine sulfate on days 0–3 or 4–10 post-wounding or throughout the time course. Wound tissue was taken on days 1, 3, 5, 8, and 18 post-wounding and immunostained for myofibroblast and macrophage markers or stained with hematoxylin and eosin. Results Delays in wound closure observed during morphine application on days 0–3 post-wounding mimicked those seen in wounds treated with morphine throughout the entire healing process. However, no significant delays in closure were seen in wounds treated with morphine beginning on day 4 post-wounding. Treatment of wounds with morphine significantly reduced the number of myofibroblasts and macrophages in the closing wound. Additionally, morphine application resulted in decreases in skin thickness and an increase in residual scar tissue in healed skin. Conclusions These findings demonstrate the time-dependent and persistent nature of the detrimental effects of topical morphine on cutaneous wound healing. The data identify specific limitations that could be ameliorated to optimize topical opioid administration as an analgesic therapeutic strategy in the treatment of painful cutaneous wounds. PMID:18580183

  16. Effects of opioids in morphine-treated pigeons trained to discriminate among morphine, the low-efficacy agonist nalbuphine, and saline.

    PubMed

    Walker, Ellen A; Picker, Mitchell J; Granger, Arthur; Dykstra, Linda A

    2004-07-01

    In opioid-dependent subjects, the low-efficacy mu agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The kappa agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy micro agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment. PMID:15044559

  17. Modulation of ethanol-intake by morphine: Evidence for a central site of action

    SciTech Connect

    Wild, K.D.; Reid, L.D. )

    1990-01-01

    Previous studies have shown that subcutaneous administration of low doses of morphine increase, while subcutaneous naloxone decreases, ethanol-intake in rats. However, the site of action of morphine modulation of ethanol-intake remains unclear. In an attempt to elucidate this issue, seven graded doses of morphine were given intracerebroventricularly to rats 15 min prior to an opportunity to consume water and sweetened alcoholic beverage for 2 hr. Two lower doses of intracerebroventricular morphine reliably increased ethanol-intake, while higher doses decreased intake of water. Preference ratios were reliably increased by morphine doses of 1 {mu}g and higher. The present data provide support for a central site of morphine modulation of ethanol-intake.

  18. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs* **

    PubMed Central

    Torres, Ronaldo Lopes; Torres, Iraci Lucena da Silva; Laste, Gabriela; Ferreira, Maria Beatriz Cardoso; Cardoso, Paulo Francisco Guerreiro; Belló-Klein, Adriane

    2014-01-01

    Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID:25029646

  19. Blockade and reversal of spinal morphine tolerance by P2X3 receptor antagonist.

    PubMed

    Ma, Xiaqing; Xu, Tao; Xu, Hao; Jiang, Wei

    2015-04-01

    In recent years, studies have substantiated the view that P2X3 receptors play a part in the generation and transmission of purinergic signals in inflammatory and chronic neuropathic pain. Data have also been presented to suggest that the process of P2X3 receptor antagonism inhibits inflammatory hyperalgesia, involving the spinal opioid system. The aim of this study was to investigate the effect of the selective P2X3 receptor antagonist A-317491 on the development of antinociceptive tolerance to chronic morphine administration in mice. Daily systemic injection of A-317491 attenuated the morphine-induced antinociceptive tolerance to von Frey and thermal stimuli. Repeated morphine injections alone led to a significant rightward shift in the morphine dose-response curve compared with that with A-317491. A single dose of A-317491 also showed a reversal effect in morphine-tolerant mice. In a withdrawal test, co-administration of A-317491 and morphine also reduced the naloxone-induced withdrawal symptoms compared with the morphine-alone group. Thus, we propose that the P2X3 receptor is involved in the process of morphine antinociceptive tolerance and may be a new therapeutic target in the prevention of tolerance to morphine-induced antinociception. PMID:25350728

  20. Brain cholinergic involvement during the rapid development of tolerance to morphine

    NASA Technical Reports Server (NTRS)

    Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

    1987-01-01

    The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

  1. Use of morphine in cholescintigraphy for obstructive cholecystitis

    SciTech Connect

    Kim, E.E.; Nguyen, M.; Pjura, G.; Pollack, M.; Gobuty, A.

    1985-05-01

    Non-visualization of the gallbladder (GB) during the first hour of cholescintigraphy is observed in cystic duct obstruction (e.g. in acute cholecystitis) but may also occur in chronic cholecystitis, hepatocellular disease, alcoholism and prolonged total parenteral nutrition. Low dose morphine is shown to improve the specificity of the diagnosis of acute cholecystitis (from 85% to 100%) with no loss in sensitivity (98%) at a small cost in terms of additional study time. The authors reviewed 27 selected cholescintigraphic examinations augmented by intravenous (IV) morphine (0.04 mg/Kg). Of the 16 cases with persistent nonvisualization of the GB, ultrasound revealed gallstones in 5 cases, sludge in 4, acalculous cholecystitis in 3, one distended GB, one contracted GB and 2 normal GB's. Of the 4 patients taken to surgery, one with gallstones and one with acalculous cholecystitis were confirmed to have acute cholecystitis while another with gallstones had chronic cholecystitis and the final patient, who was sonographically normal, presented a single common duct stone. The authors conclude that the use of IV morphine is an effective adjunct to cholescintigraphy in the evaluation of gallbladder disease, especially when visualization post morphine rules out acute cholecystitis.

  2. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    PubMed

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  3. Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons

    PubMed Central

    Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena, Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn; Henderson, Graeme

    2013-01-01

    Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance. PMID:23716621

  4. Regional cerebral glucose utilization during morphine withdrawal in the rat.

    PubMed Central

    Wooten, G F; DiStefano, P; Collins, R C

    1982-01-01

    Regional cerebral glucose utilization was studied by 2-deoxy[14C]glucose autoradiography in morphine-dependent rats and during naloxone-induced morphine withdrawal. In morphine-dependent rats, glucose utilization was increased compared with naive controls uniformly (23-54%) in hippocampus, dentate gyrus, and subiculum and reduced in frontal cortex, striatum, anterior ventral thalamus, and medial habenular nucleus. On precipitation of morphine withdrawal by subcutaneous administration of naloxone at 0.5 mg/kg to morphine-dependent rats, glucose utilization was increased in the central nucleus of amygdala (51%), lateral mammillary nucleus (40%), lateral habenular nucleus (39%), medial mammillary nucleus (35%), and medial septal nucleus (35%) (all, P less than 0.01). Significant increases also occurred in several other limbic structures including interpeduncular nucleus, anterior medial and ventral thalamic nuclei, and lateral septal nucleus. Knowledge of the functional cerebral anatomy of the morphine-withdrawal syndrome should facilitate studies directed toward understanding the molecular mechanisms of opiate withdrawal. Images PMID:6954484

  5. SWIM (sickle with ibuprofen and morphine) randomised controlled trial fails to recruit: lessons learnt

    PubMed Central

    Cho, Gavin; Anie, Kofi A; Buckton, Jacky; Kiilu, Patricia; Layton, Mark; Alexander, Lydia; Hemmaway, Claire; Sutton, Dorothy; Amos, Claire; Doré, Caroline J; Kahan, Brennan; Meredith, Sarah

    2016-01-01

    Objectives Sickle With Ibuprofen and Morphine (SWIM) trial was designed to assess whether co-administration of ibuprofen (a non-steroidal anti-inflammatory drug) resulted in a reduction of opioid consumption delivered by patient-controlled analgesia (PCA) for acute pain in sickle cell disease. Design A randomised, placebo-controlled, double-blind trial. Setting UK multicentre trial in acute hospital setting. Participants Adults with sickle cell disease of any gender and phenotype aged 16 years and over. Interventions Oral ibuprofen at a dose of 800 mg three times daily or placebo in addition to opioids (morphine or diamorphine) administered via PCA pump for up to 4 days. Main outcome measures The primary outcome measure was opioid consumption over 4 days following randomisation. Results The SWIM trial closed early because it failed to randomise to its target of 316 patients within a reasonable time. Conclusions The key issues identified include the unanticipated length of time between informed consent and randomisation, difficulties in randomisation of patients in busy emergency departments, availability of trained staff at weekends and out of hours, fewer centres than expected using PCA routinely for sickle cell pain treatment, lack of research staff and support for participation, and the trial design. There are implications for future UK trials in sickle cell disease. Trial registration number ISRCTN97241637, NCT00880373; Pre-results. PMID:27288381

  6. Proteome Analysis of Rat Hippocampus Following Morphine-induced Amnesia and State-dependent Learning

    PubMed Central

    Jafarinejad-Farsangi, Saeideh; Farazmand, Ali; Rezayof, Ameneh; Darbandi, Niloufar

    2015-01-01

    Morphine’s effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry (MS and MS/MS). Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT (Modular Approach to Software Construction Operation and Test) scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomicscreensuggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity. PMID:25901168

  7. Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

    PubMed

    Henderson-Redmond, Angela N; Yuill, Matthew B; Lowe, Tammy E; Kline, Aaron M; Zee, Michael L; Guindon, Josée; Morgan, Daniel J

    2016-05-01

    The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response. PMID:26521067

  8. Acute dichloroacetate administration increases skeletal muscle free glutamine concentrations after burn injury.

    PubMed Central

    Ferrando, A A; Chinkes, D L; Wolf, S E; Matin, S; Herndon, D N; Wolfe, R R

    1998-01-01

    OBJECTIVE: To investigate the hypothesis that the stimulation of pyruvate oxidation by dichloroacetate (DCA) administration would increase the level of intramuscular glutamine in severely burned patients. SUMMARY BACKGROUND DATA: The level of intramuscular glutamine decreases in response to severe injury, and the rate of intramuscular glycolysis and pyruvate oxidation is elevated. Intramuscular glutamine concentrations have been correlated to muscle protein synthesis. METHODS: Six studies were conducted on five patients with burns >40% total body surface area. Patients were studied in the fed state during an 8-hour stable isotope infusion. After 5 hours, DCA (30 mg/kg) was administered for 30 minutes. RESULTS: Analysis of muscle biopsy samples taken at 5 and 8 hours of the study revealed a 32% increase in intracellular glutamine levels after DCA administration. Increased intracellular glutamine concentrations did not affect skeletal muscle protein synthesis as determined by a three-pool arteriovenous model or by the direct incorporation of isotope into skeletal muscle protein. DCA administration resulted in a decrease in plasma lactate but no change in alanine de novo synthesis or intracellular concentration. CONCLUSIONS: These results suggest that acute DCA administration can increase intramuscular glutamine concentration, but that this acute elevation does not affect muscle protein metabolism. Images Figure 4. PMID:9712571

  9. BK channels in microglia are required for morphine-induced hyperalgesia.

    PubMed

    Hayashi, Yoshinori; Morinaga, Saori; Zhang, Jing; Satoh, Yasushi; Meredith, Andrea L; Nakata, Takahiro; Wu, Zhou; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi

    2016-01-01

    Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance. PMID:27241733

  10. BK channels in microglia are required for morphine-induced hyperalgesia

    PubMed Central

    Hayashi, Yoshinori; Morinaga, Saori; Zhang, Jing; Satoh, Yasushi; Meredith, Andrea L.; Nakata, Takahiro; Wu, Zhou; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi

    2016-01-01

    Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca2+-activated K+ (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance. PMID:27241733

  11. Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

    PubMed Central

    Svob Strac, Dubravka; Vlainic, Josipa; Samardzic, Janko; Erhardt, Julija; Krsnik, Zeljka

    2016-01-01

    Background Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. Methods DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes. Results DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Conclusion Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status

  12. Potentiation of morphine analgesia by subanesthetic doses of pentobarbital.

    PubMed

    Pontani, R B; Vadlamani, N L; Misra, A L

    1985-03-01

    Pentobarbital pretreatment reportedly either inhibits, enhances or has no effect on morphine analgesia. The effect of subanesthetic doses of sodium pentobarbital (8-12 mg kg-1, SC) delivered via a delivery system on analgesia of morphine (5 mg kg-1, SC or 1 mg kg-1, IV) acutely administered 45 min after the sodium pentobarbital pellet implantation was assessed using the warm water (55 degrees C)-induced tail-withdrawal reflex in male Wistar rats. Significant potentiation of morphine analgesia was observed in sodium pentobarbital as compared to the placebo-pelleted animals. Pharmacokinetic or dispositional factors were not involved in this potentiation, which was possibly due to the activation of the descending inhibitory control pathways of nociceptive spinal tail-withdrawal reflex by a combined interaction of two drugs at spinal and supraspinal sites of action, that mediate opiate antinociception. PMID:3991755

  13. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study

    PubMed Central

    Vincent, Jean-Louis; Sakr, Yasser; Reinhart, Konrad; Sprung, Charles L; Gerlach, Herwig; Ranieri, V Marco

    2005-01-01

    Introduction Albumin administration in the critically ill has been the subject of some controversy. We investigated the use of albumin solutions in European intensive care units (ICUs) and its relationship to outcome. Methods In a cohort, multicenter, observational study, all patients admitted to one of the participating ICUs between 1 May and 15 May 2002 were followed up until death, hospital discharge, or for 60 days. Patients were classified according to whether or not they received albumin at any time during their ICU stay. Results Of 3,147 admitted patients, 354 (11.2%) received albumin and 2,793 (88.8%) did not. Patients who received albumin were more likely to have cancer or liver cirrhosis, to be surgical admissions, and to have sepsis. They had a longer length of ICU stay and a higher mortality rate, but were also more severely ill, as manifested by higher simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) scores than the other patients. A Cox proportional hazard model indicated that albumin administration was significantly associated with decreased 30-day survival. Moreover, in 339 pairs matched according to a propensity score, ICU and hospital mortality rates were higher in the patients who had received albumin than in those who had not (34.8 versus 20.9% and 41.3 versus 27.7%, respectively, both p < 0.001). Conclusion Albumin administration was associated with decreased survival in this population of acutely ill patients. Further prospective randomized controlled trials are needed to examine the effects of albumin administration in sub-groups of acutely ill patients. PMID:16356223

  14. Reduced fear-recognition sensitivity following acute buprenorphine administration in healthy volunteers.

    PubMed

    Ipser, Jonathan C; Terburg, David; Syal, Supriya; Phillips, Nicole; Solms, Mark; Panksepp, Jaak; Malcolm-Smith, Susan; Thomas, Kevin; Stein, Dan J; van Honk, Jack

    2013-01-01

    In rodents, the endogenous opioid system has been implicated in emotion regulation, and in the reduction of fear in particular. In humans, while there is evidence that the opioid antagonist naloxone acutely enhances the acquisition of conditioned fear, there are no corresponding data on the effect of opioid agonists in moderating responses to fear. We investigated whether a single 0.2mg administration of the mu-opioid agonist buprenorphine would decrease fear sensitivity with an emotion-recognition paradigm. Healthy human subjects participated in a randomized placebo-controlled within-subject design, in which they performed a dynamic emotion recognition task 120min after administration of buprenorphine and placebo. In the recognition task, basic emotional expressions were morphed between their full expression and neutral in 2% steps, and presented as dynamic video-clips with final frames of different emotional intensity for each trial, which allows for a fine-grained measurement of emotion sensitivity. Additionally, visual analog scales were used to investigate acute effects of buprenorphine on mood. Compared to placebo, buprenorphine resulted in a significant reduction in the sensitivity for recognizing fearful facial expressions exclusively. Our data demonstrate, for the first time in humans, that acute up-regulation of the opioid system reduces fear recognition sensitivity. Moreover, the absence of an effect of buprenorphine on mood provides evidence of a direct influence of opioids upon the core fear system in the human brain. PMID:22651957

  15. Alterations in rat brain polyphosphoinositide metabolism due to acute ethanol administration.

    PubMed

    Chandrasekhar, R; Huang, H M; Sun, G Y

    1988-04-01

    The effects of acute ethanol administration on the polyphosphoinositide metabolism of rat brain cerebral cortex were examined. Intracerebral injections of [gamma-32P]ATP proved to be an effective in vivo method to prelabel brain phospholipids, especially the polyphosphoinositides. High acute doses of ethanol (8 or 6 g/kg b.wt.) administered by gavage significantly inhibited the breakdown of polyphosphoinositides as judged by an elevation in the concentration as well as the labeling of these compounds. Concomitantly, there was a significant reduction in the level of diacylglycerols. Low acute doses of ethanol (2 g/kg b.wt.) did not seem to have any effects on the basal levels or labeling of these compounds. The changes in polyphosphoinositide labeling due to ethanol intoxication were reverted to near control values when animals regained their righting reflex (approximately 4 hr). These studies demonstrate that, under normal conditions, polyphosphoinositides and diacylglycerols are maintained in a dynamic equilibrium and that acute doses of ethanol can suppress the signal transduction process and disturb this equilibrium. PMID:2834532

  16. The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice.

    PubMed

    Paula-Freire, L I G; Andersen, M L; Gama, V S; Molska, G R; Carlini, E L A

    2014-02-15

    Trans-caryophyllene is a sesquiterpene present in many medicinal plants' essential oils, such as Ocimum gratissimum and Cannabis sativa. In this study, we evaluated the antinociceptive activity of trans-caryophyllene in murine models of acute and chronic pain and the involvement of trans-caryophyllene in the opioid and endocannabinoid systems. Acute pain was determined using the hot plate test (thermal nociception) and the formalin test (inflammatory pain). The chronic constriction injury (CCI) of the sciatic nerve induced hypernociception was measured by the hot plate and von Frey tests. To elucidate the mechanism of action, mice were pre-treated with naloxone or AM630 30 min before the trans-caryophyllene treatment. Afterwards, thermal nociception was evaluated. The levels of IL-1β were measured in CCI-mice by ELISA. Trans-caryophyllene administration significantly minimized the pain in both the acute and chronic pain models. The antinociceptive effect observed during the hot plate test was reversed by naloxone and AM630, indicating the participation of both the opioid and endocannabinoid system. Trans-caryophyllene treatment also decreased the IL-1β levels. These results demonstrate that trans-caryophyllene reduced both acute and chronic pain in mice, which may be mediated through the opioid and endocannabinoid systems. PMID:24055516

  17. Role of calcium in morphine dependence and naloxone-precipitated withdrawal in mice

    PubMed Central

    Seth, Vikas; Upadhyaya, Prerna; Moghe, Vijay; Ahmad, Mushtaq

    2011-01-01

    Purpose To explore the role of calcium in morphine withdrawal syndrome using various agents affecting calcium levels in cytoplasm. Methods Mice were rendered dependent on morphine by subcutaneous injection of morphine, and withdrawal was induced 4 hours later by injecting the opioid antagonist, naloxone. Mice were observed for 30 minutes for signs of withdrawal, ie, characteristic jumping, hyperactivity, urination, and diarrhea. Various calcium channel blockers were injected intraperitoneally 30 minutes before naloxone to evaluate their influence on the severity of the withdrawal syndrome. We also tested the effect of combination levodopa-carbidopa pretreatment and its interaction with a selective alpha-1 blocker, terazosin, on naloxone-precipitated withdrawal in mice acutely dependent on morphine. Results A significant dose-dependent attenuation of naloxone-induced morphine withdrawal syndrome was observed with calcium channel blockers, ie, verapamil 20 mg/kg (P < 0.05) and diltiazem 30 mg/kg (P < 0.01). Combination levodopa-carbidopa pretreatment facilitated the morphine withdrawal syndrome, and this was found to be blocked by terazosin, although not to a statistically significant (P > 0.05) extent. Conclusion The results indicate that calcium plays an important role in the genesis of morphine dependence and withdrawal, and suggest the usefulness of calcium channel blockers in the management of morphine withdrawal syndrome.

  18. A Conjugate Vaccine Attenuates Morphine- and Heroin-Induced Behavior in Rats

    PubMed Central

    Li, Qian-Qian; Sun, Cheng-Yu; Luo, Yi-Xiao; Xue, Yan-Xue; Meng, Shi-Qiu; Xu, Ling-Zhi; Chen, Na; Deng, Jia-Hui; Zhai, Hai-Feng; Kosten, Thomas R.; Shi, Jie

    2015-01-01

    Background: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. Methods: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. Results: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. Conclusion: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin. PMID:25522425

  19. Acute hemodynamic effects and blood pool kinetics of polystyrene microspheres following intravenous administration

    SciTech Connect

    Slack, J.D.; Kanke, M.; Simmons, G.H.; DeLuca, P.P.

    1981-06-01

    The acute hemodynamic effect of intravenous administration of polystyrene microspheres was investigated and correlated with their distribution pattern and kinetics. Microspheres of three diameters (3.4, 7.4, and 11.6 micrometer) were administered. The 7.4- and 11.6-micrometer diameter microspheres were filtered by the pulmonary capillary network following intravenous administration, the majority during the first pass. There was no significant hemodynamic effect following administrations of the 7.4- and 11.6-micrometer diameter microspheres in doses as high as 3.0 X 10(9) and 6.1 X 10(8) respectively (total cross-sectional area of 1.3 X 10(11) and 6.4 X 10(10) micrometer2, respectively). Intravenous administration of 3.4-micrometer diameter microspheres produced significant dose-dependent systemic hypotension and depression of myocardial performance at dosages as slow as 1.0 X 10(10) (cross-sectional area of 9.1 X 10(10) micrometer2). These differences in acute hemodynamic effect from the 7.4- and 11.6-micrometer diameter microspheres may be due to the differences in distribution kinetics and fate of the 3.4-micrometer diameter microspheres, which readily pass through the lungs to the spleen. Although elimination of the smaller spheres from the blood during the first 6-8 min was rapid, i.e., t 1/2 . 1.62 and 1.72 min from the venous and arterial blood circulation, respectively, levels of 10(3) spheres/g of blood were present in the circulation for greater than 1 hr. These findings must be considered in the planning of intravenous administration of microspheres as a drug delivery system to target organs.

  20. [Opium (heroin * morphine)].

    PubMed

    Hiramatsu, Masayuki

    2010-08-01

    The number of people dependent on opiate drugs, including heroin, is still high, and these abused drugs are major social issues, both in the social science and medically. The mechanisms of physical dependence and withdrawal symptoms in laboratory animals are becoming clear; however, no useful method to detoxify abusers with opioid dependence in clinical situation has been established, and alternative therapy with methadone, used in Europe and America, cannot be used in Japan. Here, I will outline the global trend of opium abuse, including heroin and morphine, and summarize the problems of heroin abuse. PMID:20715484

  1. Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke.

    PubMed

    Llull, Laura; Amaro, Sergio; Chamorro, Ángel

    2016-01-01

    Oxidative stress is one of the main mechanisms implicated in the pathophysiology of inflammatory and neurodegenerative diseases of the central nervous system (CNS). Uric acid (UA) is the end product of purine catabolism in humans, and it is the main endogenous antioxidant in blood. Low circulating UA levels have been associated with an increased prevalence and worse clinical course of several neurodegenerative and inflammatory diseases of the CNS, including Parkinson's disease and multiple sclerosis. Moreover, the exogenous administration of UA exerts robust neuroprotective properties in experimental models of CNS disease, including brain ischemia, spinal cord injury, meningitis, and experimental allergic encephalitis. In experimental brain ischemia, exogenous UA and the thrombolytic agent alteplase exert additive neuroprotective effects when administered in combination. UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with a better outcome and reduced infarct growth at follow-up. A recent phase II trial demonstrated that the combined intravenous administration of UA and alteplase is safe and prevents an early decrease of circulating UA levels in acute ischemic stroke patients. Moreover, UA prevents the increase in the circulating levels of the lipid peroxidation marker malondialdehyde and of active matrix metalloproteinase (MMP) 9, a marker of blood-brain barrier disruption. The moderately sized URICOICTUS phase 2b trial showed that the addition of UA to thrombolytic therapy resulted in a 6% absolute increase in the rate of excellent outcome at 90 days compared to placebo. The trial also showed that UA administration resulted in a significant increment of excellent outcome in patients with pretreatment hyperglycemia, in females and in patients with moderate strokes. Overall, the encouraging neuroprotective effects of UA therapy in acute ischemic stroke warrants further investigation in adequately

  2. Differential effects of acute and chronic fructose administration on pyruvate dehydrogenase activity and lipogenesis

    SciTech Connect

    Wilson, L.

    1988-01-01

    These studies were undertaken to distinguish between the acute and chronic effects of fructose administration. In vivo, liver lipogenesis, as measured by {sup 3}H{sub 2}O incorporation, was greater in rats fed 60% fructose than in their glucose fed controls. Both fructose feeding, and fructose feeding plus intraperitoneal fructose injection increased the activities of 6-phosphogluconate dehydrogenase and malic enzyme. Liver PDH activity was increased by fructose feeding, and was increased even more by fructose feeding and injection of fructose, but this was not associated with any changes in hepatic ATP concentrations.

  3. Acute Hemoperitoneum after Administration of Prostaglandin E2 for Induction of Labour

    PubMed Central

    Zhang, Zhenyu; Lou, Jiangyan

    2015-01-01

    Prostaglandin E2 is widely used in obstetrics and is thought to be relatively safe for cervical ripening and induction of labour. Here we present a case in which acute hemoperitoneum was observed after administration of prostaglandin E2 in a pregnant woman. The patient had a history of endometriosis, and a severe pelvic adhesion (ASRM stage IV) was found during her last laparoscopic surgery 3 years previously. In cases with endometriosis, use of prostaglandin E2 for induction of labour in pregnant women must be done cautiously. PMID:26495145

  4. Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

    NASA Astrophysics Data System (ADS)

    Trujillo, Keith A.; Akil, Huda

    1991-01-01

    The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

  5. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Morphine test system. 862.3640 Section 862.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  6. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Morphine test system. 862.3640 Section 862.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems §...

  7. Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain

    PubMed Central

    Xu, Ji-Tian; Sun, Linlin; Lutz, Brianna Marie; Bekker, Alex; Tao, Yuan-Xiang

    2015-01-01

    Repeated and long-term administration of opioids is often accompanied by the initiation of opioid-induced analgesic tolerance and hyperalgesia in chronic pain patients. Our previous studies showed that repeated intrathecal morphine injection activated the mammalian target of rapamycin complex 1 (mTORC1) in spinal dorsal horn neurons and that blocking this activation prevented the initiation of morphine-induced tolerance and hyperalgesia in healthy rats. However, whether spinal mTORC1 is required for morphine-induced tolerance and hyperalgesia under neuropathic pain conditions remains elusive. We here observed the effect of intrathecal infusion of rapamycin, a specific mTORC1 inhibitor, on morphine-induced tolerance and hyperalgesia in a neuropathic pain model in rats induced by the fifth lumbar spinal nerve ligation (SNL). Continuous intrathecal infusion of morphine for one week starting on day 8 post-SNL led to morphine tolerance demonstrated by morphine-induced reduction in maximal possible analgesic effect (MPAE) to tail heat stimuli and ipsilateral paw withdrawal threshold (PWT) to mechanical stimuli in SNL rats. Such reduction was attenuated by co-infusion of rapamycin. Co-infusion of rapamycin also blocked morphine tolerance demonstrated by attenuation of morphine-induced reduction in MPAE in sham rats and morphine-induced hyperalgesia demonstrated by the reverse of morphine-induced reduction in PWT on both sides of sham rats and on the contralateral side of SNL rats. The results suggest that mTORC1 inhibitors could serve as promising medications for use as adjuvants with opioids in clinical neuropathic pain management. PMID:26339682

  8. Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release

    PubMed Central

    Rook, Jerri M.; McCarson, Kenneth E.

    2007-01-01

    Topically applied morphine is routinely used to alleviate pain in cutaneous wounds such as burns and pressure sores. Evidence suggests the topical administration of exogenous opioid drugs may impair wound closure. This study examined the effects of topical morphine on a standardized model of cutaneous wound healing in the rat. Full-thickness 4mm diameter circular skin flaps were excised from the intrascapular region of male Sprague-Dawley rats. IntraSite™® Gel infused with either morphine-sulfate, neurokinin-1 (NK-1) or neurokinin-2 (NK-2) receptor antagonists, substance P (SP), neurokinin A (NKA), SP + morphine-sulfate, or NKA + morphine-sulfate was applied to the wound twice daily. Results demonstrated a significant overall delay in the time course of wound contraction in morphine-treated animals when compared with gel-only treated controls. The delay in wound contraction seen in morphine-treated animals increased in a concentration-dependent manner. Topical application of NK-1 or NK-2 receptor antagonists mimicked the effects of morphine in delaying wound closure, suggesting topical opioids impair wound closure via the inhibition of SP and NKA release peripherally into the healing wound. Additionally, no significant delays in closure were seen in rats receiving morphine combined with SP or NKA, demonstrating the ability of each neuropeptide to attenuate the effects of morphine in delaying wound closure and restore normal wound closure rates. The combination of SP or NKA and morphine-sulfate for wound therapy may provide local analgesia while maintaining normal closure rates. PMID:17632084

  9. Protective role of taurine against morphine-induced neurotoxicity in C6 cells via inhibition of oxidative stress.

    PubMed

    Zhou, Jiaqing; Li, Yan; Yan, Guangyan; Bu, Qian; Lv, Lei; Yang, Yanzhu; Zhao, Jinxuan; Shao, Xue; Deng, Yi; Zhu, Ruimin; Zhao, Yinglan; Cen, Xiaobo

    2011-11-01

    This study was carried out to investigate the protective role of taurine (2-aminoethanesulphonicacid) against morphine-induced neurotoxicity in C6 cells. It was found that taurine significantly increased the viability of C6 cells treated by morphine, showing the neuroprotective role against morphine-induced neurotoxicity. However, such neuroprotective effect of taurine could not be blocked by bicuculline, an antagonist of gamma-amino butyrate (GABA) receptor. To determine the oxidative damage induced by morphine, the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured in C6 cells. The decreased activities of SOD, CAT, and GPx in C6 cells were observed after morphine treatment for 48 h. However, taurine administration effectively ameliorated morphine-induced oxidative insult. To estimate anti-apoptosis effect of taurine, flow cytometry analysis as well as detection for caspase-3 and Bcl-2 expressions was performed after morphine exposure for 48 h. It was found that Bcl-2 expression was down regulated by morphine, whereas taurine could reverse morphine-induced decrease in Bcl-2 expression. Taurine showed no effect on caspase-3 expression. Collectively, the results show that taurine possesses the capability to ameliorate morphine-induced oxidative insult and apoptosis in C6 cells, probably due to its antioxidant activity rather than activation of GABA receptors. PMID:21611853

  10. Reversal of morphine analgesic tolerance by ethanol in the mouse.

    PubMed

    Hull, L C; Gabra, B H; Bailey, C P; Henderson, G; Dewey, W L

    2013-06-01

    The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)(B) receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABA(A) antagonist bicuculline but not by the GABA(B) antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment. PMID:23528610

  11. Reversal of Morphine Analgesic Tolerance by Ethanol in the Mouse

    PubMed Central

    Hull, L. C.; Gabra, B. H.; Bailey, C. P.; Henderson, G.

    2013-01-01

    The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)B receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABAA antagonist bicuculline but not by the GABAB antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment. PMID:23528610

  12. Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats.

    PubMed

    Hansen, M B; Olsen, N V; Hyldegaard, O

    2013-11-01

    Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication. PMID:23970528

  13. Administration of Reconstituted Polyphenol Oil Bodies Efficiently Suppresses Dendritic Cell Inflammatory Pathways and Acute Intestinal Inflammation

    PubMed Central

    Cavalcanti, Elisabetta; Vadrucci, Elisa; Delvecchio, Francesca Romana; Addabbo, Francesco; Bettini, Simona; Liou, Rachel; Monsurrò, Vladia; Huang, Alex Yee-Chen; Pizarro, Theresa Torres

    2014-01-01

    Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation. PMID:24558444

  14. Morphine withdrawal dramatically reduces lymphocytes in morphine-dependent macaques.

    PubMed

    Weed, Michael R; Carruth, Lucy M; Adams, Robert J; Ator, Nancy A; Hienz, Robert D

    2006-09-01

    The immune effects of chronic opiate exposure and/or opiate withdrawal are not well understood. The results of human studies with opiate abusers are variable and may not be able to control for important factors such as subjects' drug histories, health and nutritional status. Nonhuman primate models are necessary to control these important factors. A model of opiate dependence in macaques was developed to study the effects of opiate dependence and withdrawal on measures of immune function. Four pigtailed macaques drank a mixture of morphine (20 mg/kg/session) and orange-flavored drink every 6 h for several months. During stable morphine dependence, absolute numbers of neutrophils, monocytes and lymphocytes did not change relative to pre-morphine levels. However, there was a significant decrease in the absolute number and percentage of natural killer (NK) cells in morphine dependence. Either precipitated withdrawal or abstinence for 24 h resulted in behavioral withdrawal signs in all animals. Absolute lymphocyte counts decreased and absolute netrophil counts increased significantly in withdrawal, relative to levels during morphine dependence. Lymphocyte subset (CD4+, CD8+, CD20+) cells were also decreased in absolute numbers with little change in their percentage distributions. There was, however, a significant increase in the percentage of NK cells in withdrawal relative to levels during morphine dependence. This study demonstrates the usefulness of voluntary oral self-dosing procedures for maintaining morphine dependence in nonhuman primates and demonstrates that the morphine withdrawal syndrome includes large alterations in blood parameters of immune system function, including nearly 50% reduction in numbers of CD4+, CD8+ and CD20+ cells. PMID:18040802

  15. Effects of morphine on the renal handling of sodium and lithium in conscious rats.

    PubMed

    el-Awady, E S; Walker, L A

    1990-09-01

    The present study was carried out in order to assess the renal response to i.v. morphine in the rat, particularly the effects on tubular handling of sodium and lithium. Rats were prepared surgically with arterial and venous catheters and bladder cannulas. Clearance experiments and measurements of blood pressure and heart rate were carried out at least 4 days after surgery in unanesthetized animals. Intravenous administration of morphine (4 mg/kg b.wt.) caused a decrease in fractional sodium excretion, (at 90 min after injection, vehicle, 2.49 +/- 0.30% vs. morphine, 1.12 +/- 0.17%, P less than .05), in the absence of significant changes in systemic hemodynamics or glomerular filtration rate. This effect was prevented by pretreatment with naloxone. Enhanced proximal tubular reabsorption of sodium was considered as a possible explanation for the decrease in sodium excretion which followed morphine administration. Proximal tubular fluid reabsorption was estimated utilizing the lithium clearance method. Results indicated a reduction in fractional excretion of lithium by morphine administration (at 90 min, vehicle, 34.2 +/- 3.3% vs. morphine, 18.8 +/- 2.3%, P less than .05), which was also prevented by naloxone pretreatment. It is concluded that, under the present experimental conditions, morphine enhances tubular reabsorption of sodium by an opiate receptor-dependent mechanism and that this effect is, at least in part, localized in the proximal tubule. PMID:2395123

  16. Harpagophytum procumbens extract potentiates morphine antinociception in neuropathic rats.

    PubMed

    Parenti, Carmela; Aricò, Giuseppina; Pennisi, Marzio; Venditti, Alessandro; Scoto, Giovanna M

    2016-06-01

    The association of opioids and non-steroidal anti-inflammatory drugs, to enhance pain relief and reduce the development of side effects, has been demonstrated. Given many reports concerning the antinociceptive and anti-inflammatory effects of Harpagophytum procumbens extracts, the aim of our study was to investigate the advantage of a co-administration of a subanalgesic dose of morphine preceded by a low dose of H. procumbens to verify this therapeutically useful association in a neuropathic pain model. Time course, registered with the association of the natural extract, at a dose that does not induce an antinociceptive effect, followed by a subanalgesic dose of morphine showed a well-defined antiallodynic and antihyperalgesic effect, suggesting a synergism as a result of the two-drug association. H. procumbens cooperates synergistically with morphine in resolving hyperalgesia and allodynia, two typical symptoms of neuropathic pain. The results support the strategy of using an adjuvant drug to improve opioid analgesic efficacy. PMID:26189616

  17. 3-Methoxynaltrexone is not a selective antagonist for the acute psychomotor stimulating effects of heroin and 6-monoacetylmorphine in mice.

    PubMed

    Eriksen, Guro Søe; Andersen, Jannike Mørch; Boix, Fernando; Mørland, Jørg

    2014-07-01

    The opioid receptor antagonist 3-methoxynaltrexone (3-MeONtx) has previously been shown in rodents to selectively reverse the analgesic actions of heroin and its metabolites 6-monoacetylmorphine (6-MAM), and morphine-6-glucuronide (M6G), but not that of morphine. Based on these and other results, a heroin/6-MAM/M6G μ-opioid receptor binding site or subreceptor mediating their analgesic activity has been proposed. It is however unknown whether this also accounts for the acute psychomotor stimulating properties of these opioids. The aim of the present study was therefore to explore if the acute psychomotor stimulating effects of heroin, 6-MAM, and morphine are mediated by distinct μ-opioid receptor binding sites or subreceptors. To address this aim, we examined how pretreatment with 3-MeONtx or naltrexone (NTX) affected the acute increase in locomotor activity induced by heroin, 6-MAM, or morphine in mice. The pharmacokinetic profiles of 3-MeONtx and NTX were also assessed in mouse brain. We found that 3-MeONtx similarly antagonized the acute increase in locomotor activity induced by equipotent doses of heroin, 6-MAM, or morphine. This antagonistic effect was comparable to the one observed following administration of NTX, and both antagonists gave similar pharmacokinetic profiles in mouse brain. Our findings do not support that different μ-opioid receptor subtypes or a distinct binding site at the μ-opioid receptor is involved in morphine-induced versus heroin/6-MAM-induced psychomotor activation. This might suggest that the opioid-induced psychomotor stimulation is mediated by different μ-opioid subreceptors than those responsible for their analgesic effects. PMID:24699386

  18. Regional dependence of morphine-induced mu-opiate receptor down-regulation in perinatal rat brain.

    PubMed

    Hammer, R P; Seatriz, J V; Ricalde, A R

    1991-12-17

    The effect of perinatal morphine administration was examined in various brain regions using in vitro receptor autoradiography. Morphine was administered by continuous s.c. infusion of 10 mg/kg per day; brains of offspring were examined at five days of age. Morphine exposure reduced mu-receptor binding density in the preoptic area of hypothalamus, but not in the primary somatosensory cortex. mu-Receptor density was greater in the medial preoptic area of females than males, and in superficial layers of cortex in males than females. The results suggest that morphine has selective regional effects on mu-receptor ontogeny in rat brain. PMID:1665797

  19. Role of CD38, a cyclic ADP-ribosylcyclase, in morphine antinociception and tolerance.

    PubMed

    Hull, Lynn C; Rabender, Christopher; Gabra, Bichoy H; Zhang, Fan; Li, Pin-Lan; Dewey, William L

    2010-09-01

    Our previous studies have demonstrated that an increase in intracellular levels of Ca(2+) in neurons is an important component of both the antinociception produced by morphine and morphine's tolerance. The present study tested the hypothesis that the Ca(2+) signaling second messenger, cyclic ADP-ribose (cADPR), derived from CD38 activation participates in morphine antinociception and tolerance. We first showed that morphine's antinociceptive potency was increased by the intracerebroventricular injection of CD38 substrate beta-NAD(+) in mice. Furthermore, morphine tolerance was reversed by intracerebroventricular administration of each of three different inhibitors of the CD38-cADPR-ryanodine receptor Ca(2+) signaling pathway. These inhibitors were the ADP-ribosylcyclase inhibitor nicotinamide, cADPR analog 8-bromo-cADPR, and a large dose of ryanodine (>50 muM) that blocks the ryanodine receptor. In CD38 gene knockout [CD38(-/-)] mice, the antinociceptive action of morphine was found to be less potent compared with wild-type (WT) mice, as measured by tail-flick response, hypothermia assay, and observations of straub tail. However, there was no difference in locomotor activation between CD38(-/-) and WT animals. It was also found that less tolerance to morphine developed in CD38(-/-) mice compared with WT animals. These results indicate that cADRP-ryanodine receptor Ca(2+) signaling associated with CD38 plays an important role in morphine tolerance. PMID:20551293

  20. Stress-induced changes in the analgesic and thermic effects of morphine administered centrally.

    PubMed

    Appelbaum, B D; Holtzman, S G

    1985-12-01

    Stress (e.g. restraint) potentiates analgesia and changes in body temperature induced by morphine administered systemically to rats. In order to determine if stress-induced potentiation of these effects of morphine are mediated within the central nervous system, restrained and unstressed groups of rats were injected in the lateral ventricle (i.c.v.) with graded doses of morphine, and their analgesic and body temperature responses were measured. Compared to unstressed animals, restrained rats had a greater analgesic response at each dose of morphine, characterized by an increase in both the magnitude and duration of the drug effect. The unstressed group of rats responded consistently to 1.0-100 micrograms of morphine with a 1.5-2.0 degrees C increase in core temperature. Restrained rats had either a smaller increase in body temperature or a hypothermia at these doses of morphine. Thus, restraint stress can modify the effects of morphine administered i.c.v. on analgesia and body temperature in a manner similar to that seen after systemic administration of morphine, indicating that this phenomenon is mediated centrally. PMID:4075121

  1. Role of CD38, a Cyclic ADP-Ribosylcyclase, in Morphine Antinociception and Tolerance

    PubMed Central

    Hull, Lynn C.; Rabender, Christopher; Gabra, Bichoy H.; Zhang, Fan; Li, Pin-Lan

    2010-01-01

    Our previous studies have demonstrated that an increase in intracellular levels of Ca2+ in neurons is an important component of both the antinociception produced by morphine and morphine's tolerance. The present study tested the hypothesis that the Ca2+ signaling second messenger, cyclic ADP-ribose (cADPR), derived from CD38 activation participates in morphine antinociception and tolerance. We first showed that morphine's antinociceptive potency was increased by the intracerebroventricular injection of CD38 substrate β-NAD+ in mice. Furthermore, morphine tolerance was reversed by intracerebroventricular administration of each of three different inhibitors of the CD38–cADPR–ryanodine receptor Ca2+ signaling pathway. These inhibitors were the ADP–ribosylcyclase inhibitor nicotinamide, cADPR analog 8-bromo-cADPR, and a large dose of ryanodine (>50 μM) that blocks the ryanodine receptor. In CD38 gene knockout [CD38(−/−)] mice, the antinociceptive action of morphine was found to be less potent compared with wild-type (WT) mice, as measured by tail-flick response, hypothermia assay, and observations of straub tail. However, there was no difference in locomotor activation between CD38(−/−) and WT animals. It was also found that less tolerance to morphine developed in CD38(−/−) mice compared with WT animals. These results indicate that cADRP–ryanodine receptor Ca2+ signaling associated with CD38 plays an important role in morphine tolerance. PMID:20551293

  2. Use of sedation and ropivacaine-morphine epidural for femoral head and neck ostectomy in a dog.

    PubMed

    Aarnes, T K; Hubbell, J A E; Hildreth, B E

    2014-06-01

    A five-year-old male German shepherd dog presented with traumatic craniodorsal luxation of the right coxofemoral joint with pre-existing moderate hip dysplasia. A femoral head and neck ostectomy was performed. The patient was sedated with acepromazine and morphine administered intramuscularly. A lumbosacral epidural was performed using a combination of morphine and ropivacaine. Intraoperatively, an infusion of medetomidine, morphine, lidocaine, and ketamine was administered intravenously, and oxygen was administered via facemask. Heart rate, respiratory rate and oscillometric arterial blood pressures were monitored. Postoperatively, carprofen was administered once subcutaneously. On the day of hospital discharge, carprofen and tramadol were administered orally every 12 hours. Twenty-one days later, the dog was doing well and the surgical staples were removed. Sedation with acepromazine and morphine, administration of an epidural containing morphine and ropivacaine, and intraoperative sedation with medetomidine, morphine, lidocaine and ketamine were suitable for femoral head and neck ostectomy. PMID:24602054

  3. The Effect of Morphine on Regional Cerebral Blood Flow Measured by 99mTc-ECD SPECT in Dogs

    PubMed Central

    Adriaens, Antita; Peremans, Kathelijne; Waelbers, Tim; Vandermeulen, Eva; Croubels, Siska; Duchateau, Luc; Dobbeleir, André; Audenaert, Kurt; Eersels, Jos; Vermeire, Simon; De Spiegeleer, Bart; Polis, Ingeborgh

    2014-01-01

    To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points. PMID:25295733

  4. Analgesic tolerance to morphine is regulated by PPARγ

    PubMed Central

    de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Stopponi, Serena; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

    2014-01-01

    Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. Experimental Approach We monitored analgesia on alternate days using the tail immersion test. Key Results Daily administration of morphine (30 mg·kg−1, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg−1, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg−1, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg−1, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. Conclusions and Implications Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse. PMID:25048682

  5. Individual differences in initial morphine sensitivity as a predictor for the development of opiate addiction in rats.

    PubMed

    Nishida, Kevin S; Park, Thomas Y; Lee, Bong Hyo; Ursano, Robert J; Choi, Kwang H

    2016-10-15

    Individuals report a wide range of analgesia to similar doses of opiates, and not all opiate users become addicted. This suggests that there may be certain predispositions that influence one to develop opiate addiction. We investigated the relationship between the individual differences in initial morphine sensitivity and the subsequent development of opiate addiction-like behavior using a hot plate test and an intravenous morphine self-administration (MSA) paradigm in rats. Using a median split of initial morphine antinociception, animals were defined as low antinociception (LA) and high antinociception (HA) groups. Thus, the LA group represents the animals that were less sensitive to initial morphine antinociception as compared to those of the HA group. The animals were allowed to self-administer either saline or morphine (0.5mg/kg/infusion, 4hr/day) 5days per week for 3 weeks. Spontaneous locomotor activity was measured on self-administration days 10 and 15. Individual differences in initial morphine sensitivity were not correlated with the amount of morphine self-administered by the animals on day 1. In the second-week of MSA, the LA group exhibited increased morphine intake and locomotor hyperactivity as compared to those of the HA group. Therefore, certain animals that are less sensitive to initial morphine antinociception may be susceptible to developing opiate addiction. The current findings may have clinical implications for future research on the biological mechanisms of opiate addiction and preclinical medication development. PMID:27457135

  6. Effect of intraperitoneal selenium administration on liver glycogen levels in rats subjected to acute forced swimming.

    PubMed

    Akil, Mustafa; Bicer, Mursel; Kilic, Mehmet; Avunduk, Mustafa Cihat; Mogulkoc, Rasim; Baltaci, Abdulkerim Kasim

    2011-03-01

    There are a few of studies examining how selenium, which is known to reduce oxidative damage in exercise, influences glucose metabolism and exhaustion in physical activity. The present study aims to examine how selenium administration affects liver glycogen levels in rats subjected to acute swimming exercise. The study included 32 Sprague-Dawley type male rats, which were equally allocated to four groups: Group 1, general control; Group 2; selenium-supplemented control (6 mg/kg/day sodium selenite); Group 3, swimming control; Group 4, selenium-supplemented swimming (6 mg/kg/day sodium selenite). Liver tissue samples collected from the animals at the end of the study were fixed in 95% ethyl alcohol. From the tissue samples buried into paraffin, 5-µm cross-sections were obtained using a microtome, put on a microscope slide, and stained with PAS. Stained preparations were assessed using a Nikon Eclipse E400 light microscope. All images obtained with the light microscope were transferred to a PC and evaluated using Clemex PE 3.5 image analysis software. The highest liver glycogen levels were found in groups 1 and 2 (p < 0.05). The levels in group 4 were lower than those in groups 1 and 2 but higher than the levels in group 3 (p < 0.05). The lowest liver glycogen levels were obtained in group 3 (p < 0.05). Results of the study indicate that liver glycogen levels that decrease in acute swimming exercise can be restored by selenium administration. It can be argued that physiological doses of selenium administration can contribute to performance. PMID:20340052

  7. Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration.

    PubMed

    Chong, Samuel L; Claussen, Catherine M; Dafny, Nachum

    2012-03-10

    Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal's neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 min baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to ED9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration. PMID:22248440

  8. Disruption of auditory function by acute administration of a room odorizer containing butyl nitrite in rats

    SciTech Connect

    Fechter, L.D.; Richard, C.L.; Mungekar, M.; Gomez, J.; Strathern, D.

    1989-01-01

    Butyl nitrite is the predominant and presumed active ingredient in a variety of commercial preparations sold as ''room odorizers.'' These compounds have significant abuse potential, giving the user the sensation of a ''rush'', which may be related to their intense cardiovascular effects. The pharmacological properties of butyl nitrites are similar to those of amyl nitrite which is also abused for its psychological effects, but whose availability is limited by prescription for treatment of angina. A significant body of literature suggests that the inner ear is vulnerable to acute hypoxic exposure. Since butyl nitrite induces high levels of methemoglobin and also reduces blood pressure due to peripheral vasodilation, we hypothesized that this compound might produce auditory dysfunction. We studied the effect of acute exposure to a butyl nitrite ''room odorizer'' on 10- and 40-kHz auditory function in rats. A loss in auditory sensitivity was found at both frequencies on the day following administration of the compound. Auditory dysfunction tended to subside over the next several days at 40 kHz, although a significant loss of sensitivity for tones of 10 kHz was observed over a 6-day period after administration of the agent. Methemoglobin levels measured in rats of the same age were elevated significantly 30 and 60 min after butyl nitrite to levels of 30-45%. Methemoglobin levels were found to be normal 18 hr after administration when the first audiometric tests were conducted. The data suggest that auditory function in the middle of the rats' auditory range, 10 kHz, was disrupted for a longer period than was high-frequency (40 kHz) auditory function.

  9. The effect of Gly-Gln [ß-endorphin30-31] on morphine-evoked serotonin and GABA efflux in the nucleus accumbens of conscious rats.

    PubMed

    Basaran, Nesrin F; Buyukuysal, R Levent; Sertac Yilmaz, M; Aydin, Sami; Cavun, Sinan; Millington, William R

    2016-08-01

    Glycyl-L-glutamine (Gly-Gln; β-endorphin30-31) is an endogenous dipeptide synthesized through the post-translational processing of β-endorphin1-31. Central Gly-Gln administration inhibits the rewarding properties of morphine and attenuates morphine tolerance, dependence and withdrawal although it does not interfere with morphine analgesia. In an earlier study, we found that Gly-Gln inhibits morphine-induced dopamine efflux in the nucleus accumbens (NAc), consistent with its ability to inhibit morphine reward. To further investigate the mechanism responsible for its central effects we tested whether i.c.v. Gly-Gln administration influences the rise in extracellular serotonin and GABA concentrations evoked by morphine in the NAc. Conscious rats were treated with Gly-Gln (100nmol/5μl) or saline i.c.v. followed, 2min later, by morphine (2.5mg/kg) or saline i.p. and extracellular serotonin and GABA concentrations were analyzed by microdialysis and HPLC. Morphine administration increased extracellular serotonin and GABA concentrations significantly within 20min, as shown previously. Unexpectedly, Gly-Gln also increased extracellular serotonin concentrations significantly in control animals. Combined treatment with Gly-Gln+morphine also elevated extracellular serotonin concentrations although the magnitude of the response did not differ significantly from the effect of Gly-Gln or morphine, given alone suggesting that Gly-Gln suppressed morphine induced serotonin efflux. Gly-Gln abolished the morphine-induced rise in extracellular GABA concentrations but had no effect on extracellular GABA when given alone to otherwise untreated animals. These data show that Gly-Gln stimulates NAc serotonin efflux and, together with earlier studies, support the hypothesis that Gly-Gln inhibits the rewarding effects of morphine by modulating morphine induced dopamine, GABA and serotonin efflux in the NAc. PMID:26861257

  10. Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands

    PubMed Central

    Boronat, M Assumpció; Olmos, Gabriel; García-Sevilla, Jesús A

    1998-01-01

    Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov et al., 1996). The main aim of this study was to assess if idazoxan, an α2-adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. Antinociceptive responses to opioid drugs were determined by the tail-flick test. The acute administration of morphine (10 mg kg−1, i.p., 30 min) or pentazocine (10 mg kg−1, i.p., 30 min) resulted in marked increases in tail-flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg−1, i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71–143% at day 13). Idazoxan alone did not modify TFLs. The concurrent chronic administration (10 mg kg−1, i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I2-imidazoline receptor ligands, and morphine (10 mg kg−1, i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64–172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphine-induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I2-imidazoline receptors in the modulation of opioid tolerance. The concurrent chronic (13 days) administration of RX821002 (10 mg kg−1, i.p.) and RS-15385-197 (1 mg kg−1, i.p.), selective α2-adrenoceptor antagonists, and morphine (10 mg kg−1, i.p.), did not

  11. Improved memory for reward cues following acute buprenorphine administration in humans.

    PubMed

    Syal, Supriya; Ipser, Jonathan; Terburg, David; Solms, Mark; Panksepp, Jaak; Malcolm-Smith, Susan; Bos, Peter A; Montoya, Estrella R; Stein, Dan J; van Honk, Jack

    2015-03-01

    In rodents, there is abundant evidence for the involvement of the opioid system in the processing of reward cues, but this system has remained understudied in humans. In humans, the happy facial expression is a pivotal reward cue. Happy facial expressions activate the brain's reward system and are disregarded by subjects scoring high on depressive mood who are low in reward drive. We investigated whether a single 0.2mg administration of the mixed mu-opioid agonist/kappa-antagonist, buprenorphine, would influence short-term memory for happy, angry or fearful expressions relative to neutral faces. Healthy human subjects (n38) participated in a randomized placebo-controlled within-subject design, and performed an emotional face relocation task after administration of buprenorphine and placebo. We show that, compared to placebo, buprenorphine administration results in a significant improvement of memory for happy faces. Our data demonstrate that acute manipulation of the opioid system by buprenorphine increases short-term memory for social reward cues. PMID:25569708

  12. Validity of Diagnostic Codes for Acute Stroke in Administrative Databases: A Systematic Review

    PubMed Central

    McCormick, Natalie; Bhole, Vidula; Lacaille, Diane; Avina-Zubieta, J. Antonio

    2015-01-01

    Objective To conduct a systematic review of studies reporting on the validity of International Classification of Diseases (ICD) codes for identifying stroke in administrative data. Methods MEDLINE and EMBASE were searched (inception to February 2015) for studies: (a) Using administrative data to identify stroke; or (b) Evaluating the validity of stroke codes in administrative data; and (c) Reporting validation statistics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), or Kappa scores) for stroke, or data sufficient for their calculation. Additional articles were located by hand search (up to February 2015) of original papers. Studies solely evaluating codes for transient ischaemic attack were excluded. Data were extracted by two independent reviewers; article quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Results Seventy-seven studies published from 1976–2015 were included. The sensitivity of ICD-9 430-438/ICD-10 I60-I69 for any cerebrovascular disease was ≥ 82% in most [≥ 50%] studies, and specificity and NPV were both ≥ 95%. The PPV of these codes for any cerebrovascular disease was ≥ 81% in most studies, while the PPV specifically for acute stroke was ≤ 68%. In at least 50% of studies, PPVs were ≥ 93% for subarachnoid haemorrhage (ICD-9 430/ICD-10 I60), 89% for intracerebral haemorrhage (ICD-9 431/ICD-10 I61), and 82% for ischaemic stroke (ICD-9 434/ICD-10 I63 or ICD-9 434&436). For in-hospital deaths, sensitivity was 55%. For cerebrovascular disease or acute stroke as a cause-of-death on death certificates, sensitivity was ≤ 71% in most studies while PPV was ≥ 87%. Conclusions While most cases of prevalent cerebrovascular disease can be detected using 430-438/I60-I69 collectively, acute stroke must be defined using more specific codes. Most in-hospital deaths and death certificates with stroke as a cause-of-death correspond to true stroke deaths. Linking vital

  13. Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

    PubMed

    May, Walter J; Henderson, Fraser; Gruber, Ryan B; Discala, Joseph F; Young, Alex P; Bates, James N; Palmer, Lisa A; Lewis, Stephen J

    2013-08-28

    This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO2, decreases in pO2 and sO2) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated. PMID:25045592

  14. Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice.

    PubMed

    Yun, Jaesuk; Lee, Yeonju; Yun, Kyunghwa; Oh, Seikwan

    2015-06-01

    Oxidative stress plays a role in the development of physical dependence induced by morphine. Bergenin, a polyphenol found in many Asian, African, and South American medicinal plants, is a potent antinarcotic agent with wide spectrum of pharmacological activities including antioxidant action. In the present study, we observed that bergenin decreased the development of physical dependence induced by morphine in mice and the antioxidant activity of bergenin plays a role in the antinarcotic effects through adapting to morphine-induced oxidative stress in the brain. The naloxone-precipitated withdrawal symptom (jumping frequency) was significantly ameliorated (50% of control group) by administration of bergenin (20 mg/kg) in morphine-treated mice. Furthermore, morphine-induced down-regulation of glutathione (GSH) contents was reversed by bergenin administration in the frontal cortex and liver. Bergenin had no effects on the increased levels of nfr2-dependent antioxidant enzyme HO1 and NQO1 in the frontal cortex, striatum, and liver of morphine-treated mice. However, the morphine-induced increase in nrf2 nuclear translocation in the frontal cortex and striatum was inhibited by bergenin treatment. These results suggest that bergenin has a potential antinarcotic effect via regulation of GSH contents and oxidative stress. PMID:25542428

  15. Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus.

    PubMed

    Miller, Laurence L; Altarifi, Ahmad A; Negus, S Stevens

    2015-10-01

    Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were 3 main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for 6 days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. PMID:26375515

  16. Continuous regional arterial infusion for acute pancreatitis: a propensity score analysis using a nationwide administrative database

    PubMed Central

    2013-01-01

    Introduction Although continuous regional arterial infusion (CRAI) of a protease inhibitor and an antibiotic may be effective in patients with severe acute pancreatitis, CRAI has not yet been validated in large patient populations. We therefore evaluated the effectiveness of CRAI based on data from a national administrative database covering 1,032 Japanese hospitals. Methods In-hospital mortality, length of stay and costs were compared in the CRAI and non-CRAI groups, using propensity score analysis to adjust for treatment selection bias. Results A total of 17,415 eligible patients with acute pancreatitis were identified between 1 July and 30 September 2011, including 287 (1.6%) patients who underwent CRAI. One-to-one propensity-score matching generated 207 pairs with well-balanced baseline characteristics. In-hospital mortality rates were similar in the CRAI and non-CRAI groups (7.7% vs. 8.7%; odds ratio, 0.88; 95% confidence interval, 0.44–1.78, P = 0.720). CRAI was associated with significantly longer median hospital stay (29 vs. 18 days, P < 0.001), significantly higher median total cost (21,800 vs. 12,600 United States dollars, P < 0.001), and a higher rate of interventions for infectious complications, such as endoscopic/surgical necrosectomy or percutaneous drainage (2.9% vs. 0.5%, P = 0.061). Conclusions CRAI was not effective in reducing in-hospital mortality rate in patients with acute pancreatitis, but was associated with longer hospital stay and higher costs. Randomized controlled trials in large numbers of patients are required to further evaluate CRAI for this indication. PMID:24088324

  17. Administration of MPTP acutely increases glucose utilization in the substantia nigra of primates.

    PubMed

    Palombo, E; Porrino, L J; Bankiewicz, K S; Crane, A M; Kopin, I J; Sokoloff, L

    1988-06-21

    The quantitative 2-[14C]deoxyglucose autoradiographic method was used to map the regional distribution of the acute effects of administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on local cerebral glucose utilization in rhesus monkeys. Metabolic activity was increased (+80%) in the substantia nigra pars compacta, which has been shown to be the main target site of MPTP toxicity. Metabolic activity was also increased in the nucleus paranigralis, nucleus parabrachialis pigmentosus, and ventral lamella of the inferior olive. In contrast, substantial decreases in glucose utilization were found diffusely distributed throughout many of the other structures examined, most prominently in portions of the cerebral cortex, thalamus, and cerebellum. PMID:3261197

  18. Effects of acute ethanol administration on nocturnal pineal serotonin N-acetyltransferase activity

    SciTech Connect

    Creighton, J.A.; Rudeen, P.K.

    1988-01-01

    The effect of acute ethanol administration on pineal serotonin N-acetyltransferase (NAT) activity, norepinephrine and indoleamine content was examined in male rats. When ethanol was administered in two equal doses (2 g/kg body weight) over a 4 hour period during the light phase, the nocturnal rise in NAT activity was delayed by seven hours. The nocturnal pineal norepinephrine content was not altered by ethanol except for a delay in the reduction of NE with the onset of the following light phase. Although ethanol treatment led to a significant reduction in nocturnal levels of pineal serotonin content, there was no significant effect upon pineal content of 5-hydroxyindoleacetic acid (5-HIAA). The data indicate that ethanol delays the onset of the rise of nocturnal pineal NAT activity.

  19. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli.

    PubMed

    Riahi, Esmail; Khodagholi, Fariba; Haghparast, Abbas

    2013-08-01

    In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP. PMID:23787292

  20. Role of C-fibers in pain and morphine induced analgesia/hyperalgesia in rats

    PubMed Central

    Alizadeh, Zahra; Behnam-Rassouli, Morteza; Hosseini, Shirin

    2014-01-01

    Background Usual dosage of morphine (10 mg/kg) induces analgesia and ultra-low dose (ULD) of morphine (1 µg/kg); hyperalgesia, and C-fibers are also bearing µ-opioid receptors; here the importance of C-fibers on pain and morphine induced analgesia/hyperalgesia is questioned and investigated using pain evaluation methods and infant capsaicin treating for C-fibers lesioning. Methods Wistar male rats (200-250 grams) were assigned to three categories i.e. control, sham (receiving neonatal capsaicin vehicle) and c-lesion (receiving neonatal capsaicin), each one with three groups (n=7). They were injected intraperitoneally with single dosage of saline, 10 mg/kg or 1 µg/kg morphine, respectively. Thermal pain threshold was evaluated using the tail flick test before and 30 minutes after the injections. Chemical pain was assessed using the formalin test (FT) 30 minutes after the administrations. Results Results indicated that thermal (P < 0.001) and chemical pains in both neurogenic and inflammatory phases of FT (P < 0.05) were reduced in C-lesion animals. In the C-normal and C-lesion animals, 10 mg/kg morphine exerted analgesia both in thermal (P < 0.001) and two phases of FT (P < 0.01), but it was more potent in C-lesion animals (P < 0.05). Although ULD of morphine in C-normal animals produced hyperalgesic effect in thermal and chemical pains (P < 0.001), in C-lesion animals, it produced analgesia (P < 0.05) at the neurogenic phase of FT. Conclusion Results can raise the C-fibers involvement for a significant portion of nociceptive transmission, because C-lesioning potentiated morphine induced analgesia and eliminated ULD of morphine induced hyperalgesia. Therefore C and Aδ fibers can be involved in morphine analgesia; while, just C-fibers are possibly responsible for only presynaptically hyperalgesic/excitatory action of ULD in morphine. PMID:24800043

  1. Morphine-induced conditioned place preference in rhesus monkeys: Resistance to inactivation of insula and extinction.

    PubMed

    Wu, XuJun; Zhao, Ning; Bai, Fan; Li, ChuanYu; Liu, CiRong; Wei, JingKuan; Zong, Wei; Yang, LiXin; Ryabinin, Andrey E; Ma, YuanYe; Wang, JianHong

    2016-05-01

    Drug addicts experience strong craving episodes in response to drug-associated cues. Attenuating these responses using pharmacological or behavioral approaches could aid recovery from addiction. Cue-induced drug seeking can be modeled using the conditioned place preference procedure (CPP). Our previous work showed that conditioned place preference (CPP) can be induced by administration of increasing doses of morphine in rhesus monkeys. Here, we investigated whether expression of morphine-induced CPP can be attenuated by inhibiting activity of insular cortex or by repeated unreinforced exposures to the CPP test. The insula has been demonstrated to be involved in addiction to several drugs of abuse. To test its role in morphine CPP, bilateral cannulae were implanted into the insula in seven adult monkeys. The CPP was established using a biased apparatus by intramuscular injections of morphine at increasing doses (1.5, 3.0 and 4.5mg/kg) for each monkey. After the monkeys established morphine CPP, their insulae were reversibly inactivated by bilateral microinjection with 5% lidocaine (40μl) prior to the post-conditioning test (expression) of CPP using a within-subject design. The microinjections of lidocaine failed to affect CPP expression when compared to saline injections. We subsequently investigated morphine-associated memory during six episodes of CPP tests performed in these monkeys over the following 75.0±0.2months. While the preference score showed a declining trend with repeated testing, morphine-induced CPP was maintained even on the last test performed at 75months post-conditioning. This observation indicated strong resistance of morphine-induced memories to extinction in rhesus monkeys. Although these data do not confirm involvement of insula in morphine-induced CPP, our observation that drug-associated memories can be maintained over six drug-free years following initial experience with morphine has important implications for treatment of drug addiction

  2. Effects of acute and chronic cocaine administration on titrating-delay matching-to-sample performance.

    PubMed

    Kangas, Brian D; Branch, Marc N

    2012-03-01

    The effects of cocaine were examined under a titrating-delay matching-to-sample procedure. In this procedure, the delay between sample stimulus offset and comparison stimuli onset adjusts as a function of the subject's performance. Specifically, matches increase the delay and mismatches decrease the delay. Titrated delay values served as the primary dependent measure. After establishing stable performance in pigeons, several behaviorally-effective doses of cocaine were administered acutely. Dose-related within-session decreases in titrated delay values were observed. Following acute determinations, the dose of cocaine that produced the most rapid decline without eliminating performance was administered prior to each daily session. Chronic administration resulted in performance trending toward control levels. A redetermination of the dose-response function following chronic exposure revealed reduced potency (i.e., tolerance) under cocaine on titrated delay matching-to-sample performance. Supplemental analyses suggest that cocaine may serve as a disruptor of the stimulus conditions in which the performance was established. PMID:22389523

  3. GABAergic modulation of human social interaction in a prisoner's dilemma model by acute administration of alprazolam.

    PubMed

    Lane, Scott D; Gowin, Joshua L

    2009-10-01

    Recent work in neuroeconomics has used game theory paradigms to examine neural systems that subserve human social interaction and decision making. Attempts to modify social interaction through pharmacological manipulation have been less common. Here we show dose-dependent modification of human social behavior in a prisoner's dilemma model after acute administration of the γ-aminobutyric acid (GABA)-A modulating benzodiazepine alprazolam. Nine healthy adults received doses of placebo, 0.5, 1.0, and 2.0 mg alprazolam in a counterbalanced within-subject design, while completing multiple test blocks per day on an iterated prisoner's dilemma game. During test blocks in which peak subjective effects of alprazolam were reported, cooperative choices were significantly decreased as a function of dose. Consistent with previous reports showing that high acute doses of GABA-modulating drugs are associated with violence and other antisocial behavior, our data suggest that at sufficiently high doses, alprazolam can decrease cooperation. These behavioral changes may be facilitated by changes in inhibitory control facilitated by GABA. Game theory paradigms may prove useful in behavioral pharmacology studies seeking to measure social interaction, and may help inform the emerging field of neuroeconomics. PMID:19667972

  4. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia.

    PubMed

    Ott, Volker; Lehnert, Hendrik; Staub, Josefine; Wönne, Kathrin; Born, Jan; Hallschmid, Manfred

    2015-03-01

    Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia. PMID:25277390

  5. Acute lithium administration selectively lowers tyrosine levels in serum and brain

    PubMed Central

    McFarlane, Hewlet G.; Steele, John; Vinion, Keenan; Bongiovanni, Rodolfo; Double, Manda; Jaskiw, George E.

    2016-01-01

    Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl2) 3.0 mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl2 3.0 mEq/kg IP also augmented haloperidol (0.19 mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100 mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood–brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy. PMID:21962398

  6. Acute Administration of Natural Honey Protects Isolated Heart in Normothermic Ischemia

    PubMed Central

    Gharekhani, Afshin; Najafi, Moslem; Ghavimi, Hamed

    2012-01-01

    This study intended to assess the efficacy of acute administration of natural honey on cardiac arrhythmias and infarct size when it is used during the normothermic ischemia in isolated rat heart. During 30 min of regional normothermic ischemia followed by 120 min of reperfusion, the isolated hearts were perfused by a modified drug free Krebs-Henseleit solution (control) or the solution containing 0.125, 0.25, 0.5 and 1% of freshly prepared natural honey (test groups), respectively. Cardiac arrhythmias were analyzed and determined through the recorded ECGs. The infarct size was measured using computerized planimetry package. At the ischemic phase, honey (0.25 and 0.5%) decreased the number and duration of ventricular tachycardia (VT), total number of ventricular ectopic beats (VEBs), duration and incidence of reversible ventricular fibrillation (VF) and total VF (p < 0.05 for all). During the reperfusion, concentrations of 0.125, 0.25 and 0.5% lowered the number of VT (p < 0.05), duration of reversible VF (p < 0.01) and total number of VEBs (p < 0.05). In addition, VT duration was reduced significantly with honey 0.125 and 0.25%. Moreover, the infarct size was 45.6 ± 3.4% in the control group, while the perfusion of honey (0.125, 0.25 and 0.5%) reduced it to 14.8 ± 5.1 (p < 0.001), 24.6 ± 7.3 (p < 0.01) and 31.4 ± 7.3% (p < 0.05), respectively. Regarding the results, it is concluded that the acute administration of natural honey in normothermic ischemia conditions can protect the rat heart as the reduction of infarct size and arrhythmias. Conceivably, the antioxidant and free radical scavenging activity, the reduction of necrotized tissue and the providence of rich energy source are more important mechanisms in cardioprotective effects of natural honey. PMID:24250562

  7. Inhibition by morphine and morphine-like drugs of nicotine-induced emesis in cats.

    PubMed

    Beleslin, D B; Krstić, S K; Stefanović-Denić, K; Strbac, M; Mićić, D

    1981-05-01

    The effect of morphine, methadone and pethidine injected into the cerebral ventricle of the unanesthetized cat upon emesis produced by nicotine induced similarly was investigated. Morphine and morphine-like drugs depress or abolish the emetic effect of nicotine. The inhibitory effect of morphine, methadone and pethidine is observed after a transient emetic action of these drugs. The emetic and anti-emetic action of morphine, methadone and pethidine can perhaps be ascribed to an agonist/antagonist activity. Further, the possible site of inhibitory action of morphine and morphine-like drugs on the emesis produced by nicotine may be the area postrema of fourth ventricle. PMID:7248811

  8. Effect of cyanocobalamin (vitamin B12) in the induction and expression of morphine tolerance and dependence in mice.

    PubMed

    Ghazanfari, S; Imenshahidi, M; Etemad, L; Moshiri, M; Hosseinzadeh, H

    2014-03-01

    The antinociceptive effect of cyanocobalamin (Vit B12) has been reported in animal models and human studies. Our previous study showed the effect of Vit B12 on morphine tolerance. The dependence and tolerance were induced in male mice using subcutaneous morphine injections, 3 times a day (50, 50 and 75 mg/kg/day) for 3 days. Mice also received Vit B12 (100, 250 and 500 µg/kg), clonidine, memantine and saline intraperitoneally before morphine administration. On fourth day mice received only 7 mg /kg morphine just before tail-flick test. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The tolerance was evaluated by the tail-flick test. The effect of Vit B12 and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). Co-administration of Vit B12 (100-500 µg/kg) and morphine in 3 days reduced the development of tolerance to morphine analgesic effect (8.2±0.5 and 7.83±0.5 s. vs. normal saline, 3.57±0.3 s). Repeated administration of Vit B12, also, diminished the reduced naloxane withdrawal signs of naloxone withdrawal test (100-500 µg/kg: 5±1.9 and 1.2±0.8 jumps vs. normal saline 72.6±12.2). However, Vit B12 had no effect on the expression of morphine tolerance and physical dependence. It is concluded that co-administration of Vit B12 and morphine could reduce tolerance to analgesic effect of morphine chronic administration and also reduce its withdrawal symptoms. PMID:24105105

  9. Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus

    PubMed Central

    Pačesová, Dominika; Volfová, Barbora; Červená, Kateřina; Hejnová, Lucie; Novotný, Jiří; Bendová, Zdeňka

    2015-01-01

    Background and Purpose Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. Experimental Approach A time-dependent effect of morphine (1 mg·kg−1, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [35S]-GTPγS binding assay. Key Results Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN. Conclusions and Implications Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β. PMID:25828914

  10. The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury.

    PubMed

    Siddall, P J; Molloy, A R; Walker, S; Mather, L E; Rutkowski, S B; Cousins, M J

    2000-12-01

    We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1-2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region. PMID:11094007

  11. Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine.

    PubMed

    Provinciali, M; Di Stefano, G; Raffaeli, W; Pari, G; Desiderio, F; Fabris, N

    1991-07-01

    The cytotoxic activity of Natural Killer (NK) and Lymphokine Activated Killer (LAK) cells in neoplastic patients with or without antalgic treatment was studied. NK cell activity was found reduced in untreated neoplastic patients when compared to healthy subjects. The atalgic treatment with morphine (orally or intrathecally administered) was able to significantly reduce the mean values of NK cell activity found in cancer patients. In three patients the cytotoxicity of NK cells significantly decreased during transfer from oral to intrathecal administration of morphine. In contrast to the NK cell function, the development of LAK cell activity significantly increased in neoplastic patients when compared to healthy controls. Further increments were obtained during treatment with morphine. The oral treatment with morphine was able to determine a higher induction of LAK cells than the intrathecal administration of the drug. Besides providing new knowledge on the effect of morphine on immune system our findings suggest that, in order to include neoplastic patients in clinical trials of adoptive immunotherapy with LAK cells and interleukin-2 (IL-2), the antalgic therapy with oral administration of morphine may represent a better solution than the intrathecal administration of the drug. PMID:1774133

  12. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions.

    PubMed

    Barrett, D A; Barker, D P; Rutter, N; Pawula, M; Shaw, P N

    1996-06-01

    1. The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants (24-41 weeks gestation) who were given a loading dose of 50 micrograms kg-1 or 200 micrograms kg-1 of diamorphine followed by an intravenous infusion of 15 micrograms kg-1 h-1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2. Following both the 50 micrograms kg-1 or 200 micrograms kg-1 loading doses the mean steady-state plasma concentration (+/- s.d.) of morphine, M3G and M6G were 86 +/- 52 ng ml-1, 703 +/- 400 ng ml-1 and 48 +/- 28 ng ml-1 respectively and morphine clearance was found to be 4.6 +/- 3.2 ml min-1 kg-1. 3. M3G formation clearance was estimated to be 2.5 +/- 1.8 ml min-1 kg-1, and the formation clearance of M6G was estimated to be 0.46 +/- 0.32 ml min-1 kg-1. 4. M3G metabolite clearance was 0.46 +/- 0.60 ml min-1 kg-1, the elimination half-life was 11.1 +/- 11.3 h and the volume of distribution was 0.55 +/- 1.13 l kg-1. M6G metabolite clearance was 0.71 +/- 0.36 ml min-1 kg-1, the elimination half-life was 18.2 +/- 13.6 h and the volume of distribution was 1.03 +/- 0.88 l kg-1. 5. No significant effect of the loading dose (50 micrograms kg-1 or 200 micrograms kg-1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6. We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7. M3G: morphine and M6G: morphine steady-state plasma concentration ratios were 11.0 +/- 10.8 and 0.8 +/- 0.8, respectively. 8. The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults. PMID:8799518

  13. The effect of acute stress and long-term corticosteroid administration on plasma metabolites in an urban and desert songbird.

    PubMed

    Davies, Scott; Rodriguez, Natalie S; Sweazea, Karen L; Deviche, Pierre

    2013-01-01

    In response to stressful stimuli, animals activate the hypothalamic-pituitary-adrenal axis, which can result in transition to the "emergency life history stage." A key adaptive characteristic of this life history stage is the mobilization of energy stores. However, few data are available on the metabolic response to acute stress in wild-caught, free-ranging birds. We quantified the effect of acute capture and restraint stress on plasma glucose, free fatty acid, and uric acid in free-ranging Abert's towhees Melozone aberti. Furthermore, birds were caught from urban and desert localities of Phoenix, Arizona, to investigate potential effects of urban versus desert habitats on the corticosterone (CORT) and metabolic response to acute stress. Complementing work on free-ranging birds, captive towhees received CORT-filled Silastic capsules to investigate the response of urban and desert conspecifics to long-term CORT administration. We quantified the effect of CORT administration on baseline plasma glucose and uric acid, liver and pectoralis muscle glycogen stores, kidney phosphoenolpyruvate carboxykinase (PEPCK-C, a key gluconeogenic enzyme), and body mass. Acute stress increased plasma CORT and glucose and decreased plasma uric acid but had no effect on plasma free fatty acid. There was no difference between urban and desert localities in body mass, fat scores, and the response to acute stress. CORT administration decreased body mass but had no effect on glucose and uric acid, pectoral muscle glycogen, or kidney PEPCK-C. However, liver glycogen of CORT-treated urban birds increased compared with corresponding controls, whereas glycogen decreased in CORT-treated desert birds. This study suggests that Abert's towhees principally mobilize glucose during acute stress but urban and desert towhees do not differ in their CORT and metabolic response to acute stress or long-term CORT administration. PMID:23303320

  14. Age- and Strain- Dependent Influences of Morphine on Mouse Social Investigation Behavior

    PubMed Central

    Kennedy, Bruce C.; Panksepp, Jules B.; Wong, Jenny C.; Krause, Emily J.; Lahvis, Garet P.

    2011-01-01

    Opioid-coded neural circuits play a substantial role in how individuals respond to drugs of abuse, and most individuals begin using such drugs during adolescence and within a social context. Several studies indicate that adolescent mice exhibit a heightened sensitivity to the effects of morphine, the prototypical opiate drug, when compared with adults, but it is unclear whether these developmental differences are related to aspects of motivated behavior. Moreover, exposure to opioids within the rodent brain can alter the expression of social behavior, yet little is known about whether this relationship changes as a function of development or genetic variation. In this study, we conducted a series of experiments to characterize the relationship between genetic background, adolescent development and morphine-induced changes in mouse social investigation (SI). At two time-points during adolescent development (postnatal day [PD] 25 and 45), social interactions of test mice of the gregarious C57BL/6J (B6) strain were more tolerant to the suppressive effects of morphine (ED50 = 0.97 and 2.17 mg/kg morphine, respectively) than test mice from the less social BALB/cJ (BALB) strain (ED50 = 0.61 and 0.91 mg/kg morphine, respectively). By contrast, this strain-dependent difference was not evident among adult mice on PD 90 (ED50 = 1.07 and 1.41 mg/kg morphine for BALB and B6 mice, respectively). An additional experiment demonstrated that the ability of morphine to alter social responsiveness was not directly related to drug-induced changes in locomotor behavior. Finally, administration of morphine to stimulus mice on PD 25 reduced social interaction of test mice only when individuals were from the B6 genetic background. Overall, these results indicate that alterations in endogenous opioid systems are related to changes in SI that occur during adolescence and that morphine administration may mimic the rewarding nature of SI. PMID:21358324

  15. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress.

    PubMed

    Granjeiro, Erica M; Gomes, Felipe V; Guimarães, Francisco S; Corrêa, Fernando M A; Resstel, Leonardo B M

    2011-10-01

    Systemic administration of cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, attenuates the cardiovascular and behavioral responses to restraint stress. Although the brain structures related to CBD effects are not entirely known, they could involve brainstem structures responsible for cardiovascular control. Therefore, to investigate this possibility the present study verified the effects of CBD (15, 30 and 60 nmol) injected into the cisterna magna on the autonomic and behavioral changes induced by acute restraint stress. During exposure to restraint stress (1h) there was a significant increase in mean arterial pressure (MAP) and heart rate (HR). Also, 24h later the animals showed a decreased percentage of entries onto the open arms of the elevated plus-maze. These effects were attenuated by CBD (30 nmol). The drug had no effect on MAP and HR baseline values. These results indicate that intracisternal administration of CBD can attenuate autonomic responses to stress. However, since CBD decreased the anxiogenic consequences of restraint stress, it is possible that the drug is also acting on forebrain structures. PMID:21771609

  16. Safety and efficacy of icatibant self-administration for acute hereditary angioedema.

    PubMed

    Boccon-Gibod, I; Bouillet, L

    2012-06-01

    We evaluated the efficacy and safety of icatibant self-administration in 15 patients with hereditary angioedema (HAE) types I or III, for 55 acute attacks (mostly severe or very severe). Icatibant self-administration was generally effective: first symptom improvement occurred in 5 min-2 h (HAE type I; n = 17) and 8 min-1 h (HAE type III; n = 9) for abdominal attacks and 5-30 min (HAE type I; n = 4) and 10 min-12 h (HAE type III; n = 6) for laryngeal attacks. Complete symptom resolution occurred in 15 min-19 h (HAE type I; n = 8) and 15 min-48 h (HAE type III; n = 9) for abdominal attacks and 5-48 h (HAE type I; n = 3) and 8-48 h (HAE type III; n = 5) for laryngeal attacks. No patient required emergency hospitalization. The only adverse events were mild, spontaneously resolving injection site reactions. Patients reported that carrying icatibant with them gave them greater confidence in managing their condition. PMID:22519593

  17. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury

    PubMed Central

    Junk, Anna K.; Mammis, Antonios; Savitz, Sean I.; Singh, Manjeet; Roth, Steven; Malhotra, Samit; Rosenbaum, Pearl S.; Cerami, Anthony; Brines, Michael; Rosenbaum, Daniel M.

    2002-01-01

    Erythropoietin (EPO) plays an important role in the brain's response to neuronal injury. Systemic administration of recombinant human EPO (rhEPO) protects neurons from injury after middle cerebral artery occlusion, traumatic brain injury, neuroinflammation, and excitotoxicity. Protection is in part mediated by antiapoptotic mechanisms. We conducted parallel studies of rhEPO in a model of transient global retinal ischemia induced by raising intraocular pressure, which is a clinically relevant model for retinal diseases. We observed abundant expression of EPO receptor (EPO-R) throughout the ischemic retina. Neutralization of endogenous EPO with soluble EPO-R exacerbated ischemic injury, which supports a crucial role for an endogenous EPO/EPO-R system in the survival and recovery of neurons after an ischemic insult. Systemic administration of rhEPO before or immediately after retinal ischemia not only reduced histopathological damage but also promoted functional recovery as assessed by electroretinography. Exogenous EPO also significantly diminished terminal deoxynucleotidyltransferase-mediated dUTP end labeling labeling of neurons in the ischemic retina, implying an antiapoptotic mechanism of action. These results further establish EPO as a neuroprotective agent in acute neuronal ischemic injury. PMID:12130665

  18. A Case of Severe Acute Necrotizing Pancreatitis after Administration of Sitagliptin

    PubMed Central

    Sue, Mariko; Yoshihara, Aya; Kuboki, Koji; Hiroi, Naoki; Yoshino, Gen

    2013-01-01

    A 55-year-old Japanese man with a 3-year history of type 2 diabetes mellitus was admitted to our hospital for upper abdominal pain. Control of diabetes mellitus was good with voglibose and metformin, with sitagliptin added to this regimen 8 months prior. His pancreatic enzyme levels were elevated, and abdominal computed tomography (CT) showed diffuse pancreatic swelling with fluid accumulation and ascites of CT grade 3. The patient was diagnosed with severe acute pancreatitis. There were no obvious causes for pancreatitis except the recently administered sitagliptin. Since incretin-related drugs entered the market, the number of incretin-related drugs prescriptions rapidly increased and so did the incidence of pancreatitis. There are several reports suggesting the correlation between incretin-related drugs and pancreatitis, such as a report based on data obtained from the United States Food and Drug Administration (FDA) which revealed a significant correlation between the administration of exenatide or sitagliptin and pancreatitis. However, there also is a report that denied the evidence for such in a large cohort study. The relation between incretin based drugs and pancreatitis is still controversial. PMID:23467428

  19. Effect of extradural morphine on somatosensory evoked potentials to dermatomal stimulation.

    PubMed

    Lund, C; Selmar, P; Hansen, O B; Jensen, C M; Kehlet, H

    1987-11-01

    The effect of the extradural (L2-3) administration of morphine 6 mg on early (less than 0.5 s) somatosensory evoked cortical potentials (SEP) to electrical stimulation of the L1- and S1-dermatomes was examined in eight patients. Extradural morphine did not influence SEP amplitude. SEP latency did not change, except for a minor increase in the latencies of the onset and the P2 components following S1 stimulation. PMID:3689615

  20. Epidural buprenorphine or morphine for the relief of head and neck cancer pain.

    PubMed Central

    Hashimoto, Y.; Utsumi, T.; Tanioka, H.; Rigor, B. M.

    1991-01-01

    We present three cases in which epidural buprenorphine or morphine was used for intractable cancer pain of the head and neck. Excellent pain relief and minimal side effects offered by epidural opioids were of significant benefit. The use of epidural opioids prior to the administration of high doses of oral morphine may be the treatment of choice for pain from malignancy of the head and neck, especially when there is tumor extension or distant metastasis. PMID:1811431

  1. [Administration of Palonosetron and Phenotropil for Prophylaxis of the N-V-D Stage of Acute Radiation Syndrome].

    PubMed

    Drachouv, I S; Bykov, V N; Seleznev, A B

    2016-01-01

    Experiments on small (rats) and large (dogs) animals have shown that a sequential administration of Palonosetron and Phenotropil decreases the intensity of the main manifestations of the N-V-D stage of acute radiation syndrome. These data show the appropriateness of a combined administration of Palonosetron and Phenotropil to prevent a reduced work capacity in the individuals participating in elimination of the consequences of accidents associated with overexposure to radiation. PMID:27245006

  2. Effect of acute lithium administration on penile erection: involvement of nitric oxide system

    PubMed Central

    Sandoughdaran, Saleh; Sadeghipour, Hamed; Sadeghipour, Hamid Reza

    2016-01-01

    Background: Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown. Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction. Materials and Methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium. Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of

  3. Outcomes associated with nesiritide administration for acute decompensated heart failure in the emergency department observation unit: a single center experience.

    PubMed

    Styron, Joseph F; Jois-Bilowich, Preeti; Tallman, Thomas; Emerman, Charles; Starling, Randall C; Frank Peacock, W

    2009-01-01

    The authors' purpose was to determine 30- and 180-day readmission and mortality rates for acutely decompensated heart failure patients receiving nesiritide in the emergency department observation unit. The authors conducted a retrospective evaluation of all patients admitted to the emergency department observation unit, stratified by nesiritide administration, from January 2002 to January 2004. Eligible patients had a primary diagnosis of acutely decompensated heart failure. Observation unit treatment was by previously published protocols, except for nesiritide administration, which was per attending physician choice. Of 595 patients, 196 (33%) received nesiritide. The crude and adjusted odds ratios comparing readmission rates and mortality rates of the nesiritide group with the control group failed to demonstrate significant differences at either the 30- or the 180-day endpoints. The use of nesiritide for acute decompensated heart failure in the emergency department observation unit is not associated with mortality or readmission differences compared with standard therapy alone. PMID:19522957

  4. Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

    PubMed Central

    Hill, Michael D.; Martin, Renee H.; Palesch, Yuko Y.; Moy, Claudia S.; Tamariz, Diego; Ryckborst, Karla J.; Jones, Elizabeth B.; Weisman, David; Pettigrew, Creed; Ginsberg, Myron D.

    2015-01-01

    Background Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. Methods Ischemic stroke patients, aged 18–83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. Results Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01–5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3–26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). Conclusions ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. Trial Registration ClincalTrials.gov NCT00235495 PMID:26325387

  5. Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats.

    PubMed

    Gonçalves, Cinara L; Rezin, Gislaine T; Ferreira, Gabriela K; Jeremias, Isabela C; Cardoso, Mariane R; Valvassori, Samira S; Munhoz, Bruna J P; Borges, Gabriela D; Bristot, Bruno N; Leffa, Daniela D; Andrade, Vanessa M; Quevedo, João; Streck, Emilio L

    2013-08-01

    Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. PMID:23636618

  6. Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice.

    PubMed

    Matsumoto, Kenjiro; Umemoto, Hiroyuki; Mori, Tomohisa; Akatsu, Ryuya; Saito, Shinichiro; Tashima, Kimihito; Shibasaki, Masahiro; Kato, Shinichi; Suzuki, Tsutomu; Horie, Syunji

    2016-01-15

    Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate-dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment. PMID:26712376

  7. Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

    PubMed Central

    Ribeiro-Dasilva, MC; Shinal, RM; Glover, T; Williams, RS; Staud, R; Riley, JL; Fillingim, RB

    2011-01-01

    Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08 mg/kg) or pentazocine (0.5 mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model ANOVAs. NOC women showed slightly greater heat pain sensitivity in the follicular vs. luteal phase, while the reverse pattern emerged for OC women (p=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (p < .05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs. the luteal phase (p=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (p=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. PMID:21239109

  8. Effects of Gelam and Acacia honey acute administration on some biochemical parameters of Sprague Dawley rats

    PubMed Central

    2014-01-01

    Background Since ancient times, honey has been used for medicinal purposes in many cultures; it is one of the oldest and most enduring substances used in wound management. Scientific evidence for its efficacy is widely studied, but systemic safety studies are still lacking. It is essential to study the impact of consumption of honey on the health and proper development of the consumer. Therefore, the present study was designed to observe the effects of acute administration (14 days) of Gelam honey (GH), a wild harvesting honey and Acacia honey (AH), a beekeeping honey, on male and female Sprague Dawley (SD) rats. Methods An acute oral study was performed following OECD test guideline 423, with minor modifications. In the study, GH, AH and sucrose (S) were administered at 2000 mg/kg body weight. Animals were observed for the next 14 days. Gross pathology was performed at the end of the study. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Clinical biochemistry, gross pathology, relative organ weight and histopathological examination were performed. Results Rats fed with honey did not exhibit any abnormal signs or deaths. Results showed a decrease in weight gain and energy efficiency, but significantly increased in total food intake and total calories in female rats fed with GH, compared to control (p < 0.05). Nevertheless, a significant increase in body weight was observed in male rats in all honey-treated groups. Male rats fed with AH significantly decreased in total food intake, total calories and energy efficiency. Both male and female rats fed with GH displayed a significant decrease in triglycerides compared to control group. Hepatic and renal function levels were within acceptable range. The gross necropsy analysis did not reveal changes in any of the organs examined. Conclusions Our results suggest that acute consumption of GH and AH at 2000 mg/kg body weight of male and female SD rats has some discrepancy

  9. Acute and chronic administration of gold nanoparticles cause DNA damage in the cerebral cortex of adult rats.

    PubMed

    Cardoso, Eria; Rezin, Gislaine Tezza; Zanoni, Elton Torres; de Souza Notoya, Frederico; Leffa, Daniela Dimer; Damiani, Adriani Paganini; Daumann, Francine; Rodriguez, Juan Carlos Ortiz; Benavides, Roberto; da Silva, Luciano; Andrade, Vanessa M; da Silva Paula, Marcos Marques

    2014-01-01

    The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood-brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occurred significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one. PMID:25847268

  10. Monoamine mediation of the morphine-induced activation of mice

    PubMed Central

    Carroll, Bernard J.; Sharp, Peter T.

    1972-01-01

    1. The dose-response relationship for hyperactivity in grouped mice following the injection of morphine sulphate has been established. 2. The activation response can be modified by drugs which affect either catecholamines or indoleamines. 3. The monoamine precursors L-DOPA and 5-hydroxytryptophan potentiate the response. 4. The monoamine synthesis inhibitors α-methyl-p-tyrosine and p-chlorophenylalanine reduce the response. 5. Inhibition of monoamine oxidase activity by pargyline caused a great increase in the response. The simultaneous administration of reserpine resulted in a further potentiation. 6. Reserpine blocked the response whenever it was given alone, either before, with or after the injection of morphine. 7. Blockade of α-adrenoceptors with phentolamine or phenoxybenzamine reduced the response. 8. Blockade of tryptaminergic receptors with methysergide or cinanserin also antagonized the response. 9. The major tranquillizers haloperidol and chlorpromazine reduced the response. Haloperidol was especially effective in this regard. 10. The tricyclic antidepressant drug imipramine potentiated the response. 11. The morphine antagonist nalorphine completely prevented the response. 12. The anticholinergic agent atropine and the antihistaminic drug mepyramine did not affect the response. 13. We conclude that dopamine, noradrenaline and 5-hydroxytryptamine are all involved in the normal activation response of grouped mice to morphine, with dopaminergic mechanisms being of primary importance. PMID:4263794

  11. Activation of p38 signaling in the microglia in the nucleus accumbens contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

    PubMed

    Zhang, Xue-Qin; Cui, Yu; Cui, Yue; Chen, Yu; Na, Xiao-Dong; Chen, Feng-Ying; Wei, Xu-Hong; Li, Yong-Yong; Liu, Xian-Guo; Xin, Wen-Jun

    2012-02-01

    Several lines of evidence have suggested that activated glia contributes to morphine-induced reward (conditioned place preference, CPP). Compared to well-defined roles of astrocyte in morphine CPP, the role of microglia in the nucleus accumbens (NAc) remains poorly characterized. The aim of the present study was to investigate the distinct role of microglia in morphine-induced CPP. Systemic administration of morphine (7.5 mg/kg for 5 days) induced significant preference for the morphine-paired compartment in rats, which lasted for at least 6 days after cessation of morphine treatment. Immunohistochemistry results showed that activation of p38 in the NAc microglia induced by chronic morphine treatment maintained on day 11. Bilateral intra-NAc injection of minocycline, a putative microglia inhibitor, or SB203580, an inhibitor of p38, prior to morphine administration not only inhibited p38 activation in the microglia but impaired the acquisition of CPP. On the day following the acquisition of morphine CPP, a single injection of minocycline or SB203580 failed to block the expression of CPP. Notably, pretreatment with minocycline or SB203580 for 5 days following the acquisition of morphine CPP significantly suppressed the activation of p38 and attenuated the maintenance of morphine CPP. Collectively, our present study indicates that the p38 signaling in the NAc microglia may play an important role in the acquisition and maintenance but not the expression of morphine CPP, and provides new evidence that microglia might be a potential target for the therapy of morphine addiction. PMID:22004988

  12. Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine.

    PubMed

    Lévesque, Karine; Lamarche, Caroline; Rompré, Pierre-Paul

    2008-10-10

    This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long-Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 microg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization. PMID:18706409

  13. Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis.

    PubMed

    Nir, R-R; Nahman-Averbuch, H; Moont, R; Sprecher, E; Yarnitsky, D

    2016-08-01

    Preoperative administration of pharmacological substances, such as non-steroidal anti-inflammatory drugs or opioids, has been gaining acclaim as a preemptive measure to minimize postoperative pain. This systematic review and meta-analysis aimed at evaluating the effectiveness of this approach in adults undergoing surgical procedures. MEDLINE, EMBASE and the Cochrane Central Register were searched from inception through January 2015. Data from randomized placebo-controlled trials were screened, extracted and assessed for risk of bias according to The Cochrane Collaboration's Tool by two independent authors. The primary outcome measure was reduction in postoperative analgesic consumption during 24 h post surgery; effects were described as mean differences between the drug and placebo arms with corresponding 95% confidence intervals (CIs) and were pooled using random-effects models. Potential publication bias was tested using funnel plots and Egger's regression test for funnel plot asymmetry. Screened were 511 records, of which 39 were included in the final synthesis with data from 3172 patients. A significant reduction in postoperative analgesic consumption was observed using preoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs; 95% CI, -0.61 to -0.14; 31 comparisons), chiefly by the COX-2 inhibitors class (95% CI, -0.95 to -0.33; 13 comparisons). Significant reduction was also observed for gabapentin (95% CI, -1.60 to -0.38; 6 comparisons). No significant effects were observed using opioids, propionic acids or oxicam derivatives. WHAT DOES THIS REVIEW ADD?: Current analyses endorse the effectiveness of COX-2 inhibitors and gabapentin in reducing acute postoperative pain when administered preemptively presurgery. Such corroboration is not found for opioids and other NSAID classes. PMID:26991963

  14. Effects of acute cortisol administration on perceptual priming of trauma-related material.

    PubMed

    Holz, Elena; Lass-Hennemann, Johanna; Streb, Markus; Pfaltz, Monique; Michael, Tanja

    2014-01-01

    Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a "traumatic" context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a "traumatic" context. Two groups of healthy volunteers (N = 160) watched either neutral or "traumatic" picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the "traumatic" stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a "traumatic" context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the "traumatic" stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a "traumatic" context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support the idea that administration

  15. Acute supra-therapeutic oral terbutaline administration has no ergogenic effect in non-asthmatic athletes.

    PubMed

    Sanchez, Anthony M J; Borrani, Fabio; Le Fur, Marie Amélie; Le Mieux, Anais; Lecoultre, Virgile; Py, Guillaume; Gernigon, Christophe; Collomp, Katia; Candau, Robin

    2013-02-01

    This study aimed to investigate the effects on a possible improvement in aerobic and anaerobic performance of oral terbutaline (TER) at a supra-therapeutic dose in 7 healthy competitive male athletes. On day 1, ventilatory threshold, maximum oxygen uptake [Formula: see text] and corresponding power output were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3, 8 mg of TER or placebo were orally administered in a double-blind process to athletes who rested for 3 h, and then performed a battery of tests including a force-velocity exercise test, running sprint and a maximal endurance cycling test at Δ50 % (50 % between VT and [Formula: see text]). Lactatemia, anaerobic parameters and endurance performance ([Formula: see text] and time until exhaustion) were raised during the corresponding tests. We found that TER administration did not improve any of the parameters of aerobic performance (p > 0.05). In addition, no change in [Formula: see text] kinetic parameters was found with TER compared to placebo (p > 0.05). Moreover, no enhancement of the force-velocity relationship was observed during sprint exercises after TER intake (p > 0.05) and, on the contrary, maximal strength decreased significantly after TER intake (p < 0.05) but maximal power remained unchanged (p > 0.05). In conclusion, oral acute administration of TER at a supra-therapeutic dose seems to be without any relevant ergogenic effect on anaerobic and aerobic performances in healthy athletes. However, all participants experienced adverse side effects such as tremors. PMID:22767151

  16. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area

    PubMed Central

    García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

    2015-01-01

    Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

  17. Effects of Acute Cortisol Administration on Perceptual Priming of Trauma-Related Material

    PubMed Central

    Streb, Markus; Pfaltz, Monique; Michael, Tanja

    2014-01-01

    Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a “traumatic” context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a “traumatic” context. Two groups of healthy volunteers (N = 160) watched either neutral or “traumatic” picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the “traumatic” stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a “traumatic” context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the “traumatic” stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a “traumatic” context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support

  18. ASHP national survey of pharmacy practice in acute care settings: dispensing and administration--1999.

    PubMed

    Ringold, D J; Santell, J P; Schneider, P J

    2000-10-01

    Results of the 1999 ASHP national survey of pharmacy practice in acute care settings that pertain to drug dispensing and administration practices are presented. Pharmacy directors at 1050 general and children's medical-surgical hospitals in the United States were surveyed by mail. The response rate was 51%. About three-fourths of respondents described their inpatient pharmacy's distribution system as centralized. Of those with centralized distribution, 77.4% indicated that their system was not automated. Decentralized pharmacists were used in 29.4% of the hospitals surveyed; an average of 58.9% of their time was spent on clinical, as opposed to distributive, activities. About 67% of directors reported pharmacy computer access to hospital laboratory data, 38% reported access to automated medication-dispensing-unit data, and 19% reported computer access to hospital outpatient affiliates. Only 13% of hospitals had an electronic medication order-entry system; another 27% reported they were in the process of developing such a system. Decentralized medication storage and distribution devices were used in 49.2% of hospitals, while 7.3% used bedside information systems for medication management. Machine-readable coding was used for inpatient pharmacy dispensing by 8.2% of hospitals. Ninety percent reported a formal, systemwide committee responsible for data collection, review, and evaluation of medication errors. Virtually all respondents (98.7%) reported that their staff initiated manual reports. Only two thirds tracked these reports and reported trends to the staff. Fewer than 15% reported that staff were penalized for making or contributing to an error. Pharmacists are making a significant contribution to the safety of medication distribution and administration. The increased use of technology to improve efficiency and reduce costs will require that pharmacists continue to focus on the impact of changes on the safety of the medication-use system. PMID:11030028

  19. Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients

    PubMed Central

    Melgari, Jean-Marc; Curcio, Giuseppe; Mastrolilli, Francesca; Salomone, Gaetano; Trotta, Laura; Tombini, Mario; di Biase, Lazzaro; Scrascia, Federica; Fini, Rita; Fabrizio, Emma; Rossini, Paolo Maria; Vernieri, Fabrizio

    2014-01-01

    Aim: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. Methods: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson’s disease (PD). Each patient underwent Unified Parkinson’s Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. Results: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor. Conclusions: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients. PMID:25452725

  20. Nigella sativa extract affects conditioned place preference induced by morphine in rats

    PubMed Central

    Anvari, Milad; Seddigh, Atefeh; Shafei, Mohammad Naser; Rakhshandeh, Hassan; Talebi, Amir Hossein; Tahani, Mohammad Reza; Saeedjalali, S. Mohsen; Hosseini, Mahmoud

    2012-01-01

    Objective: Neuroprotective, antioxidant, anticonvulsant, and analgesic effects of Nigella sativa (NS) have been previously shown. The interaction of NS with opioid system has also been reported. In the present study, the effects of NS hydro-alcoholic extract on the acquisition and expression of morphine-induced conditioned place preference (CPP) in rats were evaluated. Materials and Methods: CPP was induced by injection of morphine (5 mg/kg, i.p.) on three consecutive days in compartment A of the CPP apparatus. Injection of NS extract (200 and 400 mg/kg, i.p.) 60 min before morphine administration on the conditioning days and 60 min before the post-conditioning phase was done for the evaluation of acquisition and expression effects, respectively. Conditioning effect of NS extract was also evaluated by injection of extract (200 or 400 mg/kg, i.p.) in the conditioning phase, instead of morphine in different groups. The difference in time which the animals spent in compartment A on the day before conditioning and the days after conditioning was determined and compared between groups. Results: The time spent by the rats in compartment A in the morphine group was greater than that in the saline group (P < 0.01). Both doses of NS extract decreased acquisition of morphine-induced CPP (P < 0.01 and P < 0.001), but had no significant effect on the expression of morphine CPP. Higher dose of the extract (400 mg) showed a significant conditioning effect which was comparable to the effect of morphine. Conclusion: The results of the present study showed that the hydro-alcoholic extract of NS has conditioning effect. It also decreased acquisition, but had no significant effect on the expression of morphine CPP. PMID:24167332

  1. Global Changes in the Rat Heart Proteome Induced by Prolonged Morphine Treatment and Withdrawal

    PubMed Central

    Drastichova, Zdenka; Skrabalova, Jitka; Jedelsky, Petr; Neckar, Jan; Kolar, Frantisek; Novotny, Jiri

    2012-01-01

    Morphine belongs among the most commonly used opioids in medical practice due to its strong analgesic effects. However, sustained administration of morphine leads to the development of tolerance and dependence and may cause long-lasting alterations in nervous tissue. Although proteomic approaches enabled to reveal changes in multiple gene expression in the brain as a consequence of morphine treatment, there is lack of information about the effect of this drug on heart tissue. Here we studied the effect of 10-day morphine exposure and subsequent drug withdrawal (3 or 6 days) on the rat heart proteome. Using the iTRAQ technique, we identified 541 proteins in the cytosol, 595 proteins in the plasma membrane-enriched fraction and 538 proteins in the mitochondria-enriched fraction derived from the left ventricles. Altogether, the expression levels of 237 proteins were altered by morphine treatment or withdrawal. The majority of changes (58 proteins) occurred in the cytosol after a 3-day abstinence period. Significant alterations were found in the expression of heat shock proteins (HSP27, α-B crystallin, HSP70, HSP10 and HSP60), whose levels were markedly up-regulated after morphine treatment or withdrawal. Besides that morphine exposure up-regulated MAPK p38 (isoform CRA_b) which is a well-known up-stream mediator of phosphorylation and activation of HSP27 and α-B crystallin. Whereas there were no alterations in the levels of proteins involved in oxidative stress, several changes were determined in the levels of pro- and anti-apoptotic proteins. These data provide a complex view on quantitative changes in the cardiac proteome induced by morphine treatment or withdrawal and demonstrate great sensitivity of this organ to morphine. PMID:23056601

  2. Effects of acute and 2-week administration of oral salbutamol on exercise performance and muscle strength in athletes.

    PubMed

    Hostrup, M; Kalsen, A; Auchenberg, M; Bangsbo, J; Backer, V

    2016-01-01

    Our objective was to investigate effects of acute and 2-week administration of oral salbutamol on repeated sprint ability, exercise performance, and muscle strength in elite endurance athletes. Twenty male elite athletes [VO2max: 69.4 ± 1.8 (Mean ± SE) mL/min/kg], aged 25.9 ± 1.4 years, were included in a randomized, double-blinded and placebo-controlled parallel study. At baseline, after acute administration, and again after 2-week administration of the study drugs (8 mg salbutamol or placebo), subjects' maximal voluntary contraction (MVC) of m. quadriceps and isometric endurance of m. deltoideus were measured, followed by three repeated Wingate tests. Exercise performance at 110% of VO2max was determined on a bike ergometer. Acute administration of salbutamol increased peak power during first Wingate test by 4.1 ± 1.7% (P < 0.05). Two-week administration of salbutamol increased (P < 0.05) peak power during first and second Wingate test by 6.4 ± 2.0 and 4.2 ± 1.0%. Neither acute nor 2-week administration of salbutamol had any effect on MVC, exercise performance at 110% of VO2max or on isometric endurance. No differences were observed in the placebo group. In conclusion, salbutamol benefits athletes' sprint ability. Thus, the present study supports the restriction of oral salbutamol in competitive sports. PMID:25077918

  3. Acute toxicity, histopathology, and coagulopathy in American kestrels (Falco sparverius) following administration of the rodenticie diphacinone

    USGS Publications Warehouse

    Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Day, Daniel D.; Meteyer, Carol U.; Voler, Steven F.; Eisemann, John D.; Johnston, John J.

    2011-01-01

    The acute oral toxicity of the anticoagulant rodenticide diphacinone was found to be over 20 times greater in American kestrels (Falco sparverius; median lethal dose 96.8 mg/kg body weight) compared with Northern bobwhite (Colinus virginianus) and mallards (Anas platyrhynchos). Modest evidence of internal bleeding was observed at necropsy, although histological examination of heart, liver, kidney, lung, intestine, and skeletal muscle revealed hemorrhage over a wide range of doses (35.1-675 mg/kg). Residue analysis suggests that the half-life of diphacinone in the liver of kestrels that survived was relatively short, with the majority of the dose cleared within 7 d of exposure. Several precise and sensitive clotting assays (prothrombin time, Russell's viper venom time, thrombin clotting time) were adapted for use in this species, and oral administration of diphacinone at 50 mg/kg increased prothrombin time and Russell?s viper venom time at 48 and 96 h postdose compared with controls. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and generally corresponded with the onset of overt signs of toxicity and lethality. In view of the toxicity and risk evaluation data derived from American kestrels, the involvement of diphacinone in some raptor mortality events, and the paucity of threshold effects data following short-term dietary exposure for birds of prey, additional feeding trials with captive raptors are warranted to characterize more fully the risk of secondary poisoning.

  4. Vitamin E administration at the onset of fever prevents renal scarring in acute pyelonephritis.

    PubMed

    Sadeghi, Zhina; Kajbafzadeh, Abdol-Mohammad; Tajik, Parvin; Monajemzadeh, Maryam; Payabvash, Seyedmehdi; Elmi, Azadeh

    2008-09-01

    We evaluated the protective effects of antioxidant at the onset of fever on renal damage in a rat model of acute pyelonephritis. Twenty rats were allocated to four groups. In groups 1 to 3, the animals were given direct inoculation of Escherichia coli into the right kidney, and group four served as control. All rats in groups 1 to 3 were given once-daily intraperitoneal injections of ceftriaxon for five consecutive days, beginning on the third day after inoculation. The animals' body temperatures were monitored; as soon as body temperature reaches 38 degrees C, the rats in group 2 were given allopurinol co-treatment, whereas, in group 3, vitamin E co-treatment was started at fever onset. Both kidneys were excised 6 weeks later, for the evaluation of histopathologic changes, apoptotic damage, and concentrations of transforming growth factor-beta (TGF-beta). Only minimal changes were found in control samples. Pathologic scores of inflammation and fibrosis in group 1 were higher than in the vitamin E and allopurinol groups (P < 0.05). Apoptosis index was also decreased in groups 2 and 3, compared to group 1 (P < 0.05). There was no significant difference in average TGF-beta levels between study groups. These findings suggest that administration of vitamin E or allopurinol following the onset of fever can reduce renal damage in pyelonephritis. PMID:18523811

  5. Prevention of reflex natriuresis after acute unilateral nephrectomy by neonatal administration of MSG

    SciTech Connect

    Lin, S.Y.; Wiedemann, E.; Deschepper, C.F.; Alper, R.H.; Humphreys, M.H.

    1987-02-01

    Acute unilateral nephrectomy (AUN) results in natriuresis from the remaining kidney through reflex pathways involving the central nervous system and requiring an intact pituitary gland. The natriuresis is accompanied by an increase in the plasma concentration of a peptide or peptides derived from the N-terminal fragment (NTF) of proopiomelanocortin. The authors measured plasma immunoreactive NTF-like material (IR-NTF) by radioimmunoassay, before and after AUN in control rats and rats treated neonatally with monosodium glutamate (MSG), a procedure that produces neuroendocrine dysfunction by destroying cell bodies in the hypothalamic arcuate nucleus, median eminence, and other brain regions. In control rats, IR-NTF increased from 85.8 +/- 54.9 (SD) to 207 +/- 98.1 fmol/ml after AUN as sodium excretion (U/sub Na/V) doubled. In MSG-treated rats, AUN produced no change in plasma IR-NTF concentration, nor did U/sub Na/V increase. Tissue content of IR-NTF was reduced in the arcuate nucleus and anterior lobe of pituitaries from MSG-treated rats compared with controls, but was no different in the neurointermediate lobe. These results indicate that the hypothalamic lesion produced by neonatal administration of MSG prevents both the increase in plasma IR-NTF concentration and the natruiuresis after AUN, and therefore lend further support to the concept of a casual relationship between these two consequences of AUN.

  6. Bidirectional Tachycardia after an Acute Intravenous Administration of Digitalis for a Suicidal Gesture

    PubMed Central

    Sabatini, Diletta; Truscelli, Giovanni; Ciccaglioni, Antonio; Gaudio, Carlo

    2014-01-01

    Acute digoxin intoxication is a life-threating condition associated with severe cardiotoxicity. Female gender, age, low lean body mass, hypertension, and renal insufficiency may worsen the prognosis. Arrhythmias caused by digitalis glycosides are characterized by an increased automaticity coupled with concomitant conduction delay. Bidirectional tachycardia is pathognomonic of digoxin intoxication, but it is rarely observed. An 83-year-old woman was admitted to the Emergency Department after self-administration of 5 mg of digoxin i.v. for suicidal purpose. Her digoxin serum concentration was 17.4 ng/mL. The patient developed a bidirectional tachycardia and the Poison Control Center of the hospital provided digoxin immune fab. Bidirectional tachycardia quickly reversed and the patient remained stable throughout the hospital stay. This case shows that a multiple disciplinary approach, involving cardiologists and toxicologists, is essential for the management of digoxin intoxication. The optimal treatment of this rare event depends on the clinical conditions and on the serum drug concentration of the patient. Digoxin immune fab represents a safe, effective, and specific method for rapidly reversing digitalis cardiotoxicity and should be started as soon as the diagnosis is defined. PMID:25221680

  7. Effects of acute ethanol administration of female rat liver as a function of aging

    SciTech Connect

    Rikans, L.E.; Snowden, C.D. )

    1989-01-01

    Female Fischer 344 rats, aged 4, 14, and 25 months, received 4.0 g/kg of ethanol by intraperitoneal (i.p.) injection. Blood alcohol concentrations 2.5, 6 and 16 hr after ethanol injection were similar in the three age groups. Hepatic glutathione (GSH) levels were diminished 6 hr after ethanol injection, and there were no age-dependent differences in the depleted levels (3.2 {plus minus} 0.1, 3.5 {plus minus} 0.2, and 3.0 {plus minus} 0.5 {mu}g GSH/g liver). However, GSH contents in livers of young-adult rats approached control levels after 16 hr, whereas they remained depressed in older rats. Serum levels of hepatic enzymes were significantly elevated 6 hr after ethanol administration. The increases were greater in middle-aged and old rats than in young-adult rats. The results suggest that middle-aged and old rats are more susceptible than young rats to the acute toxicity of ethanol.

  8. Pulmonary administration of a water-soluble curcumin complex reduces severity of acute lung injury.

    PubMed

    Suresh, Madathilparambil V; Wagner, Matthew C; Rosania, Gus R; Stringer, Kathleen A; Min, Kyoung Ah; Risler, Linda; Shen, Danny D; Georges, George E; Reddy, Aravind T; Parkkinen, Jaakko; Reddy, Raju C

    2012-09-01

    Local or systemic inflammation can result in acute lung injury (ALI), and is associated with capillary leakage, reduced lung compliance, and hypoxemia. Curcumin, a plant-derived polyphenolic compound, exhibits potent anti-inflammatory properties, but its poor solubility and limited oral bioavailability reduce its therapeutic potential. A novel curcumin formulation (CDC) was developed by complexing the compound with hydroxypropyl-γ-cyclodextrin (CD). This results in greatly enhanced water solubility and stability that facilitate direct pulmonary delivery. In vitro studies demonstrated that CDC increased curcumin's association with and transport across Calu-3 human airway epithelial cell monolayers, compared with uncomplexed curcumin solubilized using DMSO or ethanol. Importantly, Calu-3 cell monolayer integrity was preserved after CDC exposure, whereas it was disrupted by equivalent uncomplexed curcumin solutions. We then tested whether direct delivery of CDC to the lung would reduce severity of ALI in a murine model. Fluorescence microscopic examination revealed an association of curcumin with cells throughout the lung. The administration of CDC after LPS attenuated multiple markers of inflammation and injury, including pulmonary edema and neutrophils in bronchoalveolar lavage fluid and lung tissue. CDC also reduced oxidant stress in the lungs and activation of the proinflammatory transcription factor NF-κB. These results demonstrate the efficacy of CDC in a murine model of lung inflammation and injury, and support the feasibility of developing a lung-targeted, curcumin-based therapy for the treatment of patients with ALI. PMID:22312018

  9. Can repeated exposure to morphine change the spinal analgesic effects of lidocaine in rats?*

    PubMed Central

    Dabbagh, Ali; Moghadam, Shervin Farkhondehkish; Rajaei, Samira; Mansouri, Zahra; Manaheji, Homa Shardi

    2011-01-01

    BACKGROUND: Chronic opium exposure leads to altered response to opioid compounds. The aim of this study was to assess the behavioral effects of opium tolerance on the analgesic effects of intrathecal lidocaine in rats. METHODS: Twenty-four adult male Sprague Dawley rats with intrathecal (IT) catheters were divided into 3 groups of 8. The first group was morphine tolerant and received IT lidocaine (ML). Rats in the second group were not morphine tolerant and received IT lidocaine (L), while the third group consisted of not morphine tolerant rats that received IT placebo. Tail flick test was done and maximal possible antinociceptive effects (MPAE) were compared using analysis of variance (ANOVA). RESULTS: While percent of MPAE significantly increased in the L group, it had a significant reduction in the ML group (P < 0.001). CONCLUSIONS: After intrathecal lidocaine administration, a hyperalgesic response was seen in morphine tolerant rats and an analgesic response was seen in the lidocaine group. PMID:22973332

  10. Morphine-induced suppression of conditioned stimulus intake: Effects of stimulus type and insular cortex lesions

    PubMed Central

    Lin, Jian-You; Roman, Christopher; Reilly, Steve

    2009-01-01

    Intake of an unconditionally preferred taste stimulus (e.g., saccharin) is reduced by contingent administration of a drug of abuse (e.g., morphine). We examined the influence of insular cortex (IC) lesions on morphine-induced suppression of an olfactory cue and two taste stimuli with different levels of perceived innate reward value. Two major findings emerged from this study. First, morphine suppressed intake of an aqueous odor as well as each taste stimulus in neurologically intact rats. Second, IC lesions disrupted morphine-induced suppression of the taste stimuli but not the aqueous odor cue. These results indicate that the perceived innate reward value of the CS is not a factor that governs drug-induced intake suppression. PMID:19631620

  11. L-type calcium channel blockers, morphine and pain: Newer insights

    PubMed Central

    Kumar, Rakesh; Mehra, RD; Ray, S Basu

    2010-01-01

    Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain in clinical situations usually result from tissue injury. Thus, the aim of the current investigation was to study the analgesic effect of this combination of drugs in the rat formalin test which is associated with actual tissue injury. Wistar rats (n=60) received either L-CCB (nifedipine/nimodipine/verapamil/diltiazem i.p.) or morphine (s.c.) or both drugs. The formalin test was done 30 min after morphine or placebo injection. The naloxone reversal test was also done. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response, though statistically significant decrease was noted only with nimodipine + morphine. Naloxone reversed this analgesic effect, indicating that it was primarily an opioid-mediated effect. The results show that administration of L-CCBs alone may prove counterproductive in the therapeutic management of pain (anti-analgesic effect). However, co-administration of both drugs (morphine and nimodipine) in quick succession could lead to adequate pain relief. PMID:20661350

  12. Alteplase Treatment in Acute Stroke: Incorporating Food and Drug Administration Prescribing Information into Existing Acute Stroke Management Guide.

    PubMed

    Demaerschalk, Bart M

    2016-08-01

    Despite strong evidence that intravenous tissue plasminogen activator (tPA) improves outcomes in acute ischemic stroke patients, its use in clinical practice remains modest. Complex eligibility criteria have been postulated as barriers to greater utilization. Further complicating this has been multiple guidelines and prescribing labels that have been published since first being approved for use in 1996. In this review, several warning and exclusion criteria for tPA in acute ischemic stroke are reviewed with the goal of providing readers a nuanced understanding of historical context and available evidence to make informed decision. PMID:27363696

  13. Effects of maropitant in cats receiving dexmedetomidine and morphine.

    PubMed

    Martin-Flores, Manuel; Sakai, Daniel M; Learn, McKenzie M; Mastrocco, Alicia; Campoy, Luis; Boesch, Jordyn M; Gleed, Robin D

    2016-06-01

    OBJECTIVE To evaluate the effects of maropitant in cats receiving dexmedetomidine and morphine. DESIGN Randomized controlled trial. ANIMALS 66 healthy female domestic shorthair cats. PROCEDURES Cats were randomly assigned to receive maropitant (1 mg/kg [0.45 mg/lb], SC; maropitant group; n = 32) or saline (0.9% NaCl) solution (0.1 mL/kg [0.045 mL/lb], SC; control group; 34) 20 hours before IM administration of dexmedetomidine (20 μg/kg [9.1 μg/lb]) and morphine (0.1 mg/kg). Following administration of dexmedetomidine and morphine, the incidences of emesis, retching, and signs of nausea (sialorrhea and lip licking) were compared between the 2 groups. The aversive behavioral response of each cat to injection of maropitant or saline solution was scored on a visual analogue scale by each of 4 observers who were unaware of the treatment administered. RESULTS Only 1 of 32 cats in the maropitant group vomited, whereas 20 of 34 control cats vomited. The incidences of emesis and retching for the maropitant group were significantly lower than those for the control group. The incidence of signs of nausea did not differ between the 2 groups. Visual analogue scale scores for the maropitant group were significantly higher than those for the control group. CONCLUSIONS AND CLINICAL RELEVANCE Results of the present study indicated that administration of maropitant to healthy cats approximately 20 hours prior to administration of dexmedetomidine and morphine significantly decreased the incidence of emesis but did not decrease the incidence of signs of nausea. However, maropitant appeared to cause substantial discomfort when injected SC. PMID:27172341

  14. Oral administration of lactulose: a novel therapy for acute carbon monoxide poisoning via increasing intestinal hydrogen production.

    PubMed

    Fan, Dan-Feng; Hu, Hui-Jun; Sun, Xue-Jun; Meng, Xiang-En; Zhang, Yu; Pan, Shu-Yi

    2016-01-01

    It has been known that the pathophysiology of carbon monoxide (CO) poisoning is related to hypoxia, the increased production of reactive oxygen species (ROS) and oxidative stress. Studies have shown that the novel, safe and effective free radical scavenger, hydrogen, has neuroprotective effects in both acute CO poisoning and delayed neuropsychological sequelae in CO poisoning. Orally administered lactulose, which may be used by some intestinal bacteria as a food source to produce endogenous hydrogen, can ameliorate oxidative stress. Based on the available findings, we hypothesize that oral administration of lactulose may be a novel therapy for acute CO poisoning via increasing intestinal hydrogen production. PMID:27000012

  15. Stroke Mimic Secondary to IV Fentanyl Administration.

    PubMed

    Uhegwu, Nnamdi; Bashir, Asif; Dababneh, Haitham; Hussain, Mohammed; Misthal, Sara; Mocco, J Duffy

    2015-02-01

    Fentanyl is a potent opioid used commonly in acute care because of its rapid onset and short duration of action. It has fewer side effects when compared with commonly available opioids, such as morphine and hydromorphine. We report an unusual side effect of transient aphasia following fentanyl administration. A 61-year-old female presented for an elective embolization of a periophthalmic artery aneurysm. She developed immediate episodes of aphasia on two separate occasions following administration of intravenous (IV) fentanyl. The high lipid solubility explains the rapid onset of action of fentanyl as it rapidly passes through the blood-brain barrier and through cell membranes. Immediately following the administration of fentanyl, the patient developed aphasia. There were no other clinical or neurological imaging findings that could account for these symptoms. We believe that aphasia may be an unusual side effect of fentanyl, and it is something clinicians should be aware of. PMID:25825627

  16. Efficacy of intraoperative, single-bolus corticosteroid administration to prevent postoperative acute respiratory failure after oesophageal cancer surgery

    PubMed Central

    Park, Seong Yong; Lee, Hyun-Sung; Jang, Hee-Jin; Joo, Jungnam; Zo, Jae Ill

    2012-01-01

    OBJECTIVES Respiratory failure from acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pneumonia are the major cause of morbidity and mortality following an oesophagectomy for oesophageal cancer. This study was performed to investigate whether an intraoperative corticosteroid can attenuate postoperative respiratory failure. METHODS Between November 2005 and December 2008, 234 consecutive patients who underwent an oesophagectomy for oesophageal cancer were reviewed. A 125-mg dose of methylprednisolone was administered after performing the anastomosis. ALI, ARDS and pneumonia occurring before postoperative day (POD) 7 were regarded as acute respiratory failure. RESULT The mean age was 64.2 ± 8.7 years. One hundred and fifty-one patients were in the control group and 83 patients in the steroid group. Patients' characteristics were comparable. The incidence of acute respiratory failure was lower in the steroid group (P = 0.037). The incidences of anastomotic leakage and wound dehiscence were not different (P = 0.57 and P = 1.0). The C-reactive protein level on POD 2 was lower in the steroid group (P < 0.005). Multivariate analysis indicates that the intraoperative steroid was a protective factor against acute respiratory failure (P = 0.046, OR = 0.206). CONCLUSIONS Intraoperative corticosteroid administration was associated with a decreased risk of acute respiratory failure following an oesophagectomy. The laboratory data suggest that corticosteroids may attenuate the stress-induced inflammatory responses after surgery. PMID:22745302

  17. Effect of acute administration of L-tyrosine on oxidative stress parameters in brain of young rats.

    PubMed

    Macêdo, Livia G R P; Carvalho-Silva, Milena; Ferreira, Gabriela K; Vieira, Júlia S; Olegário, Natália; Gonçalves, Renata C; Vuolo, Francieli S; Ferreira, Gustavo C; Schuck, Patrícia F; Dal-Pizzol, Felipe; Streck, Emilio L

    2013-12-01

    Tyrosinemia type II, also known as Richner-Hanhart syndrome, is an autosomal recessive inborn error of metabolism caused by a deficiency of hepatic cytosolic tyrosine aminotransferase, and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that studies demonstrated that high concentrations of tyrosine provoke oxidative stress in vitro and in vivo in the cerebral cortex of rats, in the present study we investigate the oxidative stress parameters (enzymatic antioxidant defenses, thiobarbituric acid-reactive substances and protein carbonyl content) in cerebellum, hippocampus and striatum of 30-old-day rats after acute administration of L-tyrosine. Our results demonstrated that the acute administration of L-tyrosine increased the thiobarbituric acid reactive species levels in hippocampus and the carbonyl levels in cerebellum, hippocampus and striatum. In addition, acute administration of L-tyrosine significantly decreased superoxide dismutase activity in cerebellum, hippocampus and striatum, while catalase was increased in striatum. In conclusion, the oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia and the administration of antioxidants may be considered as a potential adjuvant therapy for tyrosinemia, especially type II. PMID:24135880

  18. Effects of acute and chronic ketoconazole administration on hypothalamo--pituitary--adrenal axis activity and brain corticotropin-releasing hormone.

    PubMed

    Smagin, Gennady N; Goeders, Nick E

    2004-11-01

    We have been investigating the effects of ketoconazole on cocaine reward in rats for several years now. However, we recently confirmed that ketoconazole-induced changes in cocaine self-administration and reinstatement do not always correspond with decreases in plasma corticosterone, which suggests that other mechanisms must be underlying the behavioral effects that we observe. This experiment was therefore designed to determine the effects of acute, repeated and chronic ketoconazole administration on corticotropin-releasing hormone (CRH) content in hypothalamic and extra-hypothalamic brain sites in rats following the same dosing regimen that we use in our behavioral studies. Although ketoconazole significantly increased the concentration of ACTH in trunk blood, there were no significant effects on plasma cortisol, corticosterone or testosterone. There was also a significant increase in CRH content in the median eminence after the acute administration of ketoconazole that just failed to reach statistical significance following repeated or chronic administration. However, acute, repeated and chronic treatment with ketoconazole each significantly increased CRH content in the medial prefrontal cortex (MPC), but did not consistently affect the peptide in any other brain region studied. Since the MPC and CRH have been implicated in the neurobiology of cocaine, CRH-induced alterations in dopaminergic neurotransmission may play an important role in this peptide's effects on cocaine responsiveness. Taken together with the results from previous studies, these data suggest that ketoconazole may affect cocaine reward, at least in part, through interactions with dopamine and CRH within the MPC. PMID:15288701

  19. Remifentanil produces cross-desensitization and tolerance with morphine on the mu-opioid receptor.

    PubMed

    Nowoczyn, M; Marie, N; Coulbault, L; Hervault, M; Davis, A; Hanouz, J L; Allouche, S

    2013-10-01

    Remifentanil is a powerful mu-opioid (MOP) receptor agonist used in anaesthesia with a very short half-life. However, per-operative perfusion of remifentanil was shown to increase morphine consumption during post-operative period to relieve pain. In the present study, we aimed to describe the cellular mechanisms responsible for this apparent reduction of morphine efficacy. For this purpose, we first examined the pharmacological properties of both remifentanil and morphine at the MOP receptor, endogenously expressed in the human neuroblastoma SH-SY5Y cell line, to regulate adenylyl cyclase and the MAP kinase ERK1/2 pathway, their potency to promote MOP receptor phosphorylation, arrestin 3-CFP (cyan fluorescent protein) recruitment and receptor trafficking during acute and sustained exposure. In the second part of this work, we studied the effects of a prior exposure of remifentanil on morphine-induced inhibition of cAMP accumulation, activation of ERK1/2 and analgesia. We showed that sustained exposure to remifentanil promoted a rapid desensitization of opioid receptors on both signalling pathways and a pretreatment with this agonist reduced signal transduction produced by a second challenge with morphine. While both opioid agonists promoted Ser(375) phosphorylation on MOP receptor, remifentanil induced a rapid internalization of opioid receptors compared to morphine but without detectable arrestin 3-CFP translocation to the plasma membrane in our experimental conditions. Lastly, a cross-tolerance between remifentanil and morphine was observed in mice using the hot plate test. Our in vitro and in vivo data thus demonstrated that remifentanil produced a rapid desensitization and internalization of the MOP receptor that would reduce the anti-nociceptive effects of morphine. PMID:23792280

  20. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

    PubMed Central

    Derry, Christopher J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Subcutaneous administration may be preferable to oral for individuals experiencing nausea and/or vomiting Objectives To determine the efficacy and tolerability of subcutaneous sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. Search methods We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using subcutaneous sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Thirty-five studies (9365 participants) compared subcutaneous sumatriptan with placebo or an active comparator. Most of the data were for the 6 mg dose. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 6 mg versus placebo the NNTs were 2.9, 2.3, 2.2, and 2.1 for pain-free at one and two hours, and headache relief at one and two hours, respectively, and 6.1 for sustained pain-free at 24 hours. Results for the 4 mg and 8 mg doses were similar to the 6 mg dose, with 6 mg significantly better than 4 mg only for pain-free at one hour, and 8 mg significantly better than 6 mg only for headache relief at one hour. There was no evidence of increased migraine relief if a second dose of sumatriptan 6

  1. Preemptive morphine suppository for postoperative pain relief after laparoscopic cholecystectomy

    PubMed Central

    Rahimi, Mojtaba; Farsani, Daryoush Moradi; Naghibi, Khosrou; Alikiaii, Babak

    2016-01-01

    Background: Postoperative pain is a major problem following laparoscopic cholecystectomy, and there is no general agreement on the effective method of pain relief. Rectal morphine suppositories are one of the newly released morphine forms. The aim of this study is to compare the impact of suppository morphine with placebo on pain relief after laparoscopic cholecystectomy. Materials and Methods: Seventy patients scheduled for elective laparoscopic cholecystectomy under general anesthesia, were randomly allocated to two groups according to the drug used for postoperative analgesia: Group morphine suppository (MS - 10 mg) just before induction of anesthesia And Group placebo suppository (PS) (the pills were made from cocoa butter, physically similar to the real drug). Pain intensity based on visual analog scale (VAS) and opioid consumption were assessed 30 and 60 min, and 2, 4, 8, 16, and 24 h after arrival of the patient to the recovery room. Results: VAS scores were significantly lower in MS group (from 3.8 ± 1 to 5.3 ± 1.6) compared with PS group (from 4.9 ± 0.9 to 6.7 ± 1) from 30 min after arrival to the recovery room until 16 h postoperatively (P < 0.05). There were no additional analgesic requirements in the first 2 h after the entrance of the patient to the recovery room in MS group. The number of patients requiring pethidine was significantly different between two groups (P < 0.05) in all periods except for 24 h postoperatively. Conclusion: Suppository morphine administration is more effective than placebo to reduce pain and analgesic requirements after laparoscopic cholecystectomy. PMID:27110554

  2. [Quality of buprenorphine and morphine as components of combined anesthesia].

    PubMed

    Knoche, E; Dick, W; Rummel, C; Konietzke, D

    1988-02-01

    Perioperative effects of buprenorphine during and after combined anesthesia for gynecological laparotomies were compared to those of morphine. In a controlled, randomized study two similar groups of patients received flunitrazepam (0.016 mg/kg) and either buprenorphine (0.008 mg/kg) or morphine (0.333 mg/kg); all patients were ventilated with a N2O/O2-mixture. To maintain adequate anesthesia, additional injections of buprenorphine or morphine and a volatile anesthetic agent (enflurane, less than 1.0 vol.%) were administered as needed. In some patients in both groups the injection of thiopental (1-2 mg/kg) became necessary for induction of anesthesia. Hemodynamic parameters showed a slight but not significant increase during intubation and remained stable intraoperatively (Figs. 1 and 2). The frequencies of additional intraoperative injections of buprenorphine or morphine and modalities of enflurane administration were similar in both groups. Based on an awakeness score, recovery from anesthesia was similar in both groups (Fig. 3). All patients were pain-free for a long period postoperatively (pain score 1-2, duration 6-10 h) (Fig. 4). In both groups respiratory depression could be demonstrated by means of ventilatory CO2 response (Figs. 6 and 7). The respiratory depression was of no clinical importance and seems to have been due to the combination of a long-acting benzodiazepine with an opiate. There were no differences in the occurrence of nausea and vomiting in both groups. Buprenorphine seems to be an alternative to morphine in combined anesthesia. PMID:3284406

  3. D-serine in the midbrain periaqueductal gray contributes to morphine tolerance in rats

    PubMed Central

    Cao, Song; Sun, Mengjie; Li, Youyan

    2016-01-01

    Background The N-methyl-D-aspartate subtype of glutamate receptor plays a critical role in morphine tolerance. D-serine, a co-agonist of N-methyl-D-aspartate receptor, participates in many physiological and pathophysiological processes via regulating N-methyl-D-aspartate receptor activation. The purinergic P2X7 receptor activation can induce the D-serine release in the central nervous system. This study aimed to investigate the role of the ventrolateral midbrain periaqueductal gray D-serine in the mechanism of morphine tolerance in rats. The development of morphine tolerance was induced in normal adult male Sprague–Dawley rats through subcutaneous injection of morphine (10 mg/kg). The analgesic effect of morphine (5 mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds in rats with an electronic von Frey anesthesiometer. The D-serine concentration and serine racemase expression levels in the ventrolateral midbrain periaqueductal gray were evaluated through enzyme-linked immunosorbent assay and Western blot analysis, respectively. The effects of intra-ventrolateral midbrain periaqueductal gray injections of the D-serine degrading enzyme D-amino acid oxidase and antisense oligodeoxynucleotide targeting the P2X7 receptor on chronic morphine-treated rats were also explored. Results We found that repeated morphine administrations decreased the antinociceptive potency of morphine evidenced by the percent changes in mechanical pain threshold in rats. By contrast, the D-serine contents and the expression levels of the serine racemase protein were upregulated in the ventrolateral midbrain periaqueductal gray in morphine-tolerant rats. The development of morphine tolerance was markedly alleviated by intra-ventrolateral midbrain periaqueductal gray injections of D-amino acid oxidase or antisense oligodeoxynucleotide targeting the P2X7 receptor. Conclusions Our data indicate that the development of antinociceptive tolerance to morphine is partially

  4. Minocycline prevents morphine-induced apoptosis in rat cerebral cortex and lumbar spinal cord: a possible mechanism for attenuating morphine tolerance.

    PubMed

    Hassanzadeh, Kambiz; Habibi-asl, Bohlool; Farajnia, Safar; Roshangar, Leila

    2011-05-01

    Tolerance to the chronic administration of opioids such as morphine reduces the utility of these drugs in pain management. Despite significant investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. It has been indicated that tolerance to the analgesic effect of morphine is associated with apoptosis in the central nervous system. The aim of this study was to examine the effects of the intracerebroventricular (icv) administration of minocycline (a second-generation tetracycline) on morphine-induced apoptosis in the cerebral cortex and lumbar spinal cord of rats after morphine-induced tolerance. Different groups of rats received either morphine (ip) and distilled water (icv) or morphine and different doses of minocycline (icv) or minocycline alone once per day. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method was used to analyze apoptosis. The anti-apoptotic factors, Bcl-2 and HSP 70 and the pro-apoptotic element caspase-3 were evaluated by immunoblotting. The results indicated that minocycline attenuated the number of apoptotic cells in both the cerebral cortex and lumbar spinal cord. Immunoblotting findings showed that the amounts of anti-apoptotic agents (Bcl-2 and HSP 70) were greater in the treatment groups than in the controls in both regions. Although minocycline did not change the level of caspase-3 at the doses used with morphine but the minocycline treated rats showed a significantly lower increase in caspase-3 activity than did in the control. In conclusion, minocycline decreased the number of TUNEL-positive cells and increased the amount of anti-apoptotic factors (Bcl-2 and HSP 70), but did not change the caspase-3 content. PMID:20711699

  5. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats

    PubMed Central

    Chavez, Julio R.; Ibancovichi, José A.; Sanchez-Aparicio, Pedro; Acevedo-Arcique, Carlos M.; Moran-Muñoz, Rafael; Recillas-Morales, Sergio

    2015-01-01

    Background It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC) of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC. Methods Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg), morphine (3 mg/kg), tramadol (10 mg/kg), acetaminophen (300 mg/kg) + morphine (3 mg/kg), and acetaminophen (300 mg/kg) + tramadol (10 mg/kg). Results The control and acetaminophen groups did not present statistically significant differences (p = 0.98). The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively. Conclusions The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane. PMID:26605541

  6. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions

    PubMed Central

    BARRETT, D. A.; BARKER, D. P.; RUTTER, N.; PAWULA, M.; SHAW, P. N.

    1996-01-01

    1The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants(24–41 weeks gestation) who were given a loading dose of 50 μg kg−1 or 200 μg kg−1 of diamorphine followed by an intravenous infusion of 15 μg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2Following both the 50 μg kg−1 or 200 μg kg−1 loading doses the mean steady-state plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1. 3M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1. 4M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half-life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half-life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1. 5No significant effect of the loading dose (50 μg kg−1 or 200 μg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7M3G:morphine and M6G:morphine steady-state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively. 8The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults. PMID:8799518

  7. Evoked release of methionine enkephalin from tolerant/dependent enteric ganglia: paradoxical dependence on morphine.

    PubMed

    Gintzler, A R; Chan, W C; Glass, J

    1987-04-01

    Experiments were performed in order to determine whether the state of tolerance to and dependence upon opiates is associated with changes in one or more of the characteristics of the electrically induced release of methionine enkephalin from enteric ganglia. Acute morphine pretreatment substantially reduces the magnitude of the evoked release of this peptide from opiate-naive ilea. However, the rate of the evoked release of enkephalin from morphine-pretreated, tolerant/dependent preparations is indistinguishable from that observed for untreated, naive ilea. Paradoxically, 15 min after acute in vitro withdrawal of morphine form such preparations, the presence of morphine appears to be prerequisite for the manifestation of electrically evoked release of methionine enkephalin. The evoked release of this peptide from ilea 60 min after withdrawal is no longer dependent upon morphine. Moreover, the magnitude of the increase in the rate of enkephalin release from these preparations is almost double that observed for opiate-naive ilea. These data indicate that the manifestation of opiate tolerance/dependence for the release of methionine enkephalin from enteric ganglia comprises several adaptive processes, the consequences of which can be observed at different stages of withdrawal. PMID:3470809

  8. Acute cadmium administration to rats exerts both immunosuppressive and proinflammatory effects in spleen.

    PubMed

    Demenesku, Jelena; Mirkov, Ivana; Ninkov, Marina; Popov Aleksandrov, Aleksandra; Zolotarevski, Lidija; Kataranovski, Dragan; Kataranovski, Milena

    2014-12-01

    Conflicting data (both suppression and augmentation as well as lack of the effect) exist in respect to cadmium (Cd) and splenic T cell-based immune cell activity. Spleen is also the site of innate immune responses but impact of Cd on this type of immunity has been less explored. In the present study the effects of acute Cd administration on basic aspects of both T cell-based and innate immune spleen cell activity were examined in rats. Intraperitoneal injection of 1mg of Cd/kg resulted in decrease in concanavalin A (ConA) induced proliferation which seems to be more related to altered spleen cells responsiveness to IL-2 than to apoptosis. Differential effects on proinflammatory T cell derived cytokines were observed (decreases of IFN-γ gene expression and ConA-stimulated production, but increases in IL-17 mRNA levels with no effect on concentrations of protein product). Reduction of IFN-γ production seemed not to rely on IL-4 and IL-10, but at least partly on nitric oxide (NO). Increased activity relevant for innate immunity (granulocyte and CD11b(+) cell accumulation in the spleen, inducible nitric oxide synthase/iNOS expression and NO production by spleen cells) was observed, but there was a decrease in respiratory burst (dihydrorhodamine/DHR oxidation and nitroblue tetrazolium/NBT reduction). Increases of TNF-α and IL-1β gene expression and IL-1β protein product were noted as well. Administration of 0.5mg Cd/kg resulted in less pronounced (ConA-induced proliferation) or lack of the effect (IFN-γ production) on spleen T cell activities and on innate activities (granulocyte accumulation, NO production) as well. However, increases of spleen cell respiratory burst activity and IL-1β production were observed. Effects of lower cadmium doses (5ppm and 50ppm) on several aspects of spleen cell immune activity were observed in intermediate period of exposure (30 days, oral intake) as well. Differential effects of Cd on immune activities of spleen cells might

  9. Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline.

    PubMed

    González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L; Monleón, Santiago; Vinader-Caerols, Concepción; Parra, Andrés

    2008-05-01

    The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline. PMID:18313125

  10. Outpatient pharmacotherapy and modes of administration for acute repetitive and prolonged seizures.

    PubMed

    McKee, Heather Ravvin; Abou-Khalil, Bassel

    2015-01-01

    Acute repetitive seizures (ARS) are a serious epilepsy phenomenon, generally described as closely grouped seizures over minutes to 2 days, representing an increase in seizure frequency compared with baseline. In some instances, ARS may not stop without treatment, and evolution into status epilepticus is a significant concern. Additionally, neuronal injury may occur after even brief repeated seizures. Given the substantial risks that may be involved with ARS, it is crucial to develop appropriate protocols for identification and management of this seizure phenomenon. This article focuses on pharmacotherapy and, in particular, different modes of administering medication for ARS in the outpatient setting. Our aim was to present a review of data from non-randomized and randomized, controlled trials to evaluate the efficacy, safety and tolerability of out-of-hospital ARS treatments. Several of the studies included patients with ARS, as well as patients with prolonged seizures. Prolonged seizures, or seizures lasting greater than 5 min, have similar risks and treatment options to those of ARS; therefore, this discussion also includes treatment trials and recommendations for prolonged seizures. All trials used benzodiazepines, a class of drugs that are ideal for the ARS and prolonged seizure populations because of their rapid onset of action and minimal adverse effects. Rectal diazepam is currently the only formulation approved by the US Food and Drug Administration (FDA) for out-of-hospital treatment. Oral benzodiazepines are appropriate only for mild ARS. Intramuscular diazepam autoinjection has shown success against ARS in clinical trials. Intranasal midazolam and diazepam are in testing. Other treatments have also been explored--specifically, buccal midazolam (approved in the European Union), sublingual lorazepam and intranasal lorazepam. PMID:25583219

  11. Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

    EPA Science Inventory

    Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

  12. Effect of Genistein on reproductive parameter and serum nitric oxide levels in morphine-treated mice

    PubMed Central

    Jalili, Cyrus; Ahmadi, Sharareh; Roshankhah, Shiva; Salahshoor, MohammadReza

    2016-01-01

    Background: The predominant phytoestrogen in soy and derived products is the isoflavone Genistein. Genistein has antioxidant properties. Morphine is a main psychoactive chemical in opium that can increase the generation of free radicals and therefore it could adversely affects the spermatogenesis. Objective: The main goal was to investigate whether the Genistein could protect morphine adverse effects on sperm cells viability, count, motility, and testis histology and testosterone hormone and nitric oxide in blood serum. Materials and Methods: In this study, various doses of Genistein (0, 1, 2, and 3 mg/kg) and Genistein plus morphine (0, 1, 2, and 3 mg/kg) were administered interaperitoneally to 48 male mice for 30 consequent days. These mice were randomly assigned to 8 groups (n=6) and sperm parameters (sperm cells viability, count, motility and morphology), testis weight and histology, testosterone hormone (ELISA method), FSH and LH hormones (immunoradiometry) and serum nitric oxide (griess assay) were analyzed and compared. Results: The results indicated that morphine administration significantly decreased testosterone (0.03 ng/mg) LH and FSH level, histological parameters, count, viability (55.3%), morphology and motility of sperm cells (1%), testis weight (0.08 gr) and increase nitric oxide compared to saline group (p=0.00). However, administration of Genistein and Genistein plus morphine significantly boosted motility, morphology, count, viability of sperm cells, seminiferous tubules diameter, germinal thickness, testosterone, LH and FSH while decrease nitric oxide level in all groups compared to morphine group (p<0.025). Conclusion: It seems that Genistein administration could increase the quality of spermatozoa and prevent morphine- induced adverse effects on sperm parameters. PMID:27200423

  13. Effect of morphine on /sup 3/H-thymidine incorporation in the subependyma of the rat: an autoradiographic study

    SciTech Connect

    Miller, C.R.; O'Steen, W.K.; Deadwyler, S.A.

    1982-06-20

    Following morphine treatment, an autoradiographic study investigated the uptake of /sup 3/H-thymidine by the subependymal cells in the rat brain. /sup 3/H-thymidine was administered subcutaneously to adult, male Sprague-Dawley rats 30 minutes after saline or morphine (19 mg/kg) injection. The animals were sacrified 1 hour after /sup 3/H-thymidine administration. In some experiments the opioid antagonist, naloxone, was given alone 45 minutes before /sup 3/H-thymidine or 125 minutes before morphine treatment. Three areas of the subependyma were evaluated in terms of the percentage labeled cells and number of grains per nucleus, and a dorsal-to-ventral gradiant was described. Morphine treatment significantly increased the number of /sup 3/H-thymidine labeled subependymal cells and number of grains/nucleus within labeled cells. Examination of the distribution of grains/nucleus showed that morphine-treated animals had significantly more cells labeled with 30 or more grains than did saline-injected controls. Prior administration of naloxone blocked the increased /sup 3/H-thymidine uptake in morphine-treated animals but had no significant influence on cell proliferation when administered alone. The data are discussed in terms of morphine's possible dual influence on mechanisms which enhance cell transition from G to S phase and/or which accelerate DNA synthesis once these cells have entered the S phase of cell replication.

  14. An isobolographic analysis of the antinociceptive effect of xylopic acid in combination with morphine or diclofenac

    PubMed Central

    Woode, Eric; Ameyaw, Elvis Ofori; Abotsi, Wonder Kofi Mensah; Boakye-Gyasi, Eric

    2015-01-01

    Background: A common practice of managing pain globally is the combination of analgesics and this is aimed at facilitating patient compliance, simplifying prescription, and improving efficacy without increasing adverse effects. Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders and xylopic acid (XA) present in the fruit extract have been shown to possess analgesic properties in animals. There is the likelihood of concomitant use of XA and the commonly used analgesics in traditional settings. This study, therefore, evaluated the pharmacologic interaction between XA/morphine and xylopic/diclofenac combinations. Methods: The formalin test and acetic acid writhing test were used to study the antinociceptive activity of XA, morphine, and diclofenac. The isobolographic analysis was used to study the antinociceptive interactions between XA co-administered with morphine or diclofenac. Results: Results obtained revealed that XA (10–100 mg/kg), morphine (1–10 mg/kg), and diclofenac (1–10 mg/kg) produced dose-related antinociception with different potencies in the formalin and acetic acid writhing tests. Isobolographic analysis of XA/morphine and XA/diclofenac combinations revealed potentiation of their antinociceptive effects. The degree of potentiation calculated as interaction index showed synergism for both combinations in all the nociceptive tests. Conclusion: In conclusion, the present study demonstrated synergism for the co-administration of XA with morphine or diclofenac. PMID:26692735

  15. Rewarding effects of ethanol combined with low doses of morphine through dopamine D1 receptors.

    PubMed

    Ise, Yuya; Mori, Tomohisa; Katayama, Shirou; Nagase, Hiroshi; Suzuki, Tsutomu

    2013-01-01

    This study investigated whether ethanol combined with low doses of morphine produces rewarding effects in rats. Ethanol (0.075-1.2 g/kg, intraperitoneal [i.p.]) alone did not induce place preference. A moderate dose (1 mg/kg, s.c.), but not a low dose (0.1 mg/kg), of morphine induced a significant place preference. The combination of ethanol (0.075-0.6 g/kg, i.p.) and 0.1 mg/kg of morphine, as well as low doses of morphine (0.03-0.1 mg/kg, subcutaneous [s.c.]) combined with ethanol (0.3 g/kg, i.p.), induced a significant place preference. The combined effect of ethanol and morphine was significantly attenuated by naloxone (0.3 mg/kg, s.c.), naltrindole (1.0 mg/kg, s.c.), or long-term administration of the dopamine D1 receptor antagonist SCH23390 (1.0 mg/kg/day, s.c.). These results suggest that the rewarding effect induced by ethanol and a low dose of morphine is mediated by activation of the central opioidergic and dopaminergic systems through dopamine D1 receptors. PMID:23470804

  16. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    SciTech Connect

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. )

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  17. Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels*

    PubMed Central

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Theresa R.; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-01-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an interorgan, interindividual, and interspecies basis. In both species, morphine was associated with decreased levels of Ki-67+ T-cell activation but with only minimal changes in overall T-cell counts, neutrophil counts, and NK cell counts. Although changes in T-cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent. PMID:22580588

  18. Effect of Topical Morphine on Cutaneous Leishmaniasis in an Animal Model: A Preliminary Report

    PubMed Central

    Ghaffarpasand, Fariborz; Akbarzadeh, Afsoon; Heiran, Hamid Reza; Karimi, Ali Asghar; Akbarzadeh, Armin; Ghobadifar, Mohamed Amin

    2016-01-01

    Background Pentavalent antimonials remain the choice of treatment for leishmaniasis, despite their toxicity, high cost, and difficult administration. As an alternative, morphine may induce the healing process of cutaneous leishmaniasis by its immunoregulatory characteristics. Objectives To study the effect of morphine on the wound-healing process of cutaneous leishmaniasis (CL) in a mouse model. Materials and Methods This was an experimental study in which 40 BALB/c mice (female, 6 - 8 weeks) were divided into four groups (each n = 10) who received either placebo alone (group 1), morphine ointment after parasite inoculation (group 2), morphine ointment after wound occurrence (group 3), or placebo after wound occurrence (group 4). Wound size was measured weekly for eight weeks. Results On the first day of treatment, the lesions measured ~1.5 mm in diameter. After eight weeks of treatment, the wound size was significantly smaller in the mice who received morphine ointment (4.81 ± 3.22 mm) compared to those who received placebo after parasite inoculation (8.95 ± 5.71 mm; P = 0.0001) or placebo after wound occurrence (P = 0.028). Conclusions The above data suggest that topical application of morphine accelerates the healing process of CL wounds. We are cautiously optimistic that the results of this study can be used clinically for potentiating CL wound-healing. PMID:27437123

  19. Proteomic analysis of rat prefrontal cortex in three phases of morphine-induced conditioned place preference.

    PubMed

    Yang, Liu; Sun, Zhong Sheng; Zhu, Yong-ping

    2007-06-01

    Morphological alterations of synapse are found after morphine administration, suggesting that regulation of synaptic plasticity may be one of the mechanisms of neuroadaptation in addiction. However, the molecular basis underlying the abnormal synapse morphological and physiological changes in the morphine-induced dependence, withdraw, and relapse is not well understood. As prefrontal cortex (PFC) is one of the most important brain regions, which provides executive control over drug use and is severely impaired in many addicts, systematic analysis of the biochemical and molecular alteration of synaptic fraction of PFC in morphine-induced neuroadaptation is necessary. In this study, differential protein expression profiling of synaptic fraction of rat PFC based on morphine-induced conditioned place preference (CPP) model was performed with two-dimensional gel electrophoresis (2-DE). Our results showed that a total of 80 proteins were differentially expressed by 2-DE analysis during three phases of CPP assay. Of them, 58 were further identified by mass spectrometry. These proteins were classified into multiple categories, such as energy metabolism, signal transduction, synaptic transmission, cytoskeletal proteins, chaperones, and local synaptic protein synthetic machinery according to their biological functions. Our study provides a global view of synaptic-related molecular networking in PFC under morphine-induced dependence, withdraw, and relapse, indicative of a concerted biological process in neuroadaptation under chronic morphine exposure. PMID:17444669

  20. Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent.

    PubMed

    Peregud, Danil I; Yakovlev, Alexander A; Stepanichev, Mikhail Yu; Onufriev, Mikhail V; Panchenko, Leonid F; Gulyaeva, Natalia V

    2016-08-01

    Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10-100 mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect Trk

  1. The role of spinal nitric oxide and glutamate in nociceptive behaviour evoked by high-dose intrathecal morphine in rats.

    PubMed

    Watanabe, Chizuko; Sakurada, Tsukasa; Okuda, Kazuhiro; Sakurada, Chikai; Ando, Ryuichiro; Sakurada, Shinobu

    2003-12-01

    Injection of high-dose of morphine into the spinal lumbar intrathecal (i.t.) space of rats elicits a nociceptive behavioural syndrome characterized by periodic bouts of spontaneous agitation and severe vocalization. The induced behavioural response such as vocalization and agitation was observed dose-dependently by i.t. administration of morphine (125-500 nmol). Pretreatment with naloxone (s.c. and i.t.), an opioid receptor antagonist, failed to reverse the morphine-induced behavioural response. The excitatory effect of morphine was inhibited dose-dependently by pretreatment with 3-((+)2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and MK-801, a non-competitive NMDA receptor antagonist. The non-selective nitric oxide (NO) synthase inhibitor N(G)-nitro L-arginine methyl ester (L-NAME) inhibited dose-dependently the behavioural response to high-dose i.t. morphine (500 nmol), whereas D-NAME was without affecting the response to high-dose i.t. morphine. In the present study, we measured NO metabolites (nitrite/nitrate) in the extracellular fluid of rat dorsal spinal cord using in vivo microdialysis. The i.t. injection of morphine (500 nmol) evoked significant increases in NO metabolites and glutamate from the spinal cord. Not only NO metabolites but also glutamate released by high-dose morphine were reduced significantly by pretreatment with L-NAME (400 nmol). Pretreatment with CPP and MK-801 showed a significant reduction of the NO metabolites and glutamate levels elevated by high-dose i.t. morphine. These results suggest that the excitatory action of high-dose i.t. morphine may be mediated by an NMDA-NO cascade in the spinal cord. PMID:14659510

  2. Chronic Morphine Alters the Presynaptic Protein Profile: Identification of Novel Molecular Targets Using Proteomics and Network Analysis

    PubMed Central

    Abul-Husn, Noura S.; Annangudi, Suresh P.; Ma'ayan, Avi; Ramos-Ortolaza, Dinah L.; Stockton, Steven D.; Gomes, Ivone; Sweedler, Jonathan V.; Devi, Lakshmi A.

    2011-01-01

    Opiates produce significant and persistent changes in synaptic transmission; knowledge of the proteins involved in these changes may help to understand the molecular mechanisms underlying opiate dependence. Using an integrated quantitative proteomics and systems biology approach, we explored changes in the presynaptic protein profile following a paradigm of chronic morphine administration that leads to the development of dependence. For this, we isolated presynaptic fractions from the striata of rats treated with saline or escalating doses of morphine, and analyzed the proteins in these fractions using differential isotopic labeling. We identified 30 proteins that were significantly altered by morphine and integrated them into a protein-protein interaction (PPI) network representing potential morphine-regulated protein complexes. Graph theory-based analysis of this network revealed clusters of densely connected and functionally related morphine-regulated clusters of proteins. One of the clusters contained molecular chaperones thought to be involved in regulation of neurotransmission. Within this cluster, cysteine-string protein (CSP) and the heat shock protein Hsc70 were downregulated by morphine. Interestingly, Hsp90, a heat shock protein that normally interacts with CSP and Hsc70, was upregulated by morphine. Moreover, treatment with the selective Hsp90 inhibitor, geldanamycin, decreased the somatic signs of naloxone-precipitated morphine withdrawal, suggesting that Hsp90 upregulation at the presynapse plays a role in the expression of morphine dependence. Thus, integration of proteomics, network analysis, and behavioral studies has provided a greater understanding of morphine-induced alterations in synaptic composition, and identified a potential novel therapeutic target for opiate dependence. PMID:22043286

  3. Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance.

    PubMed

    Shavit, Y; Terman, G W; Lewis, J W; Zane, C J; Gale, R P; Liebeskind, J C

    1986-05-01

    Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats. PMID:3011211

  4. Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

    PubMed

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2016-02-01

    Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL. PMID:26708494

  5. Acute Administration of n-3 Rich Triglyceride Emulsions Provides Cardioprotection in Murine Models after Ischemia-Reperfusion

    PubMed Central

    Zirpoli, Hylde; Abdillahi, Mariane; Quadri, Nosirudeen; Ananthakrishnan, Radha; Wang, Lingjie; Rosario, Rosa; Zhu, Zhengbin; Deckelbaum, Richard J.; Ramasamy, Ravichandran

    2015-01-01

    Dietary n-3 fatty acids (FAs) may reduce cardiovascular disease risk. We questioned whether acute administration of n-3 rich triglyceride (TG) emulsions could preserve cardiac function and decrease injury after ischemia/reperfusion (I/R) insult. We used two different experimental models: in vivo, C57BL/6 mice were exposed to acute occlusion of the left anterior descending coronary artery (LAD), and ex-vivo, C57BL/6 murine hearts were perfused using Langendorff technique (LT). In the LAD model, mice treated with n-3 TG emulsion (1.5g/kg body weight), immediately after ischemia and 1h later during reperfusion, significantly reduced infarct size and maintained cardiac function (p<0.05). In the LT model, administration of n-3 TG emulsion (300mgTG/100ml) during reperfusion significantly improved functional recovery (p<0.05). In both models, lactate dehydrogenase (LDH) levels, as a marker of injury, were significantly reduced by n-3 TG emulsion. To investigate the mechanisms by which n-3 FAs protects hearts from I/R injury, we investigated changes in key pathways linked to cardioprotection. In the ex-vivo model, we showed that n-3 FAs increased phosphorylation of AKT and GSK3β proteins (p<0.05). Acute n-3 TG emulsion treatment also increased Bcl-2 protein level and reduced an autophagy marker, Beclin-1 (p<0.05). Additionally, cardioprotection by n-3 TG emulsion was linked to changes in PPARγ protein expression (p<0.05). Rosiglitazone and p-AKT inhibitor counteracted the positive effect of n-3 TG; GSK3β inhibitor plus n-3 TG significantly inhibited LDH release. We conclude that acute n-3 TG injection during reperfusion provides cardioprotection. This may prove to be a novel acute adjunctive reperfusion therapy after treating patients with myocardial infarction. PMID:25559887

  6. Effect of acute and chronic administration of L-tyrosine on nerve growth factor levels in rat brain.

    PubMed

    Ferreira, Gabriela K; Jeremias, Isabela C; Scaini, Giselli; Carvalho-Silva, Milena; Gomes, Lara M; Furlanetto, Camila B; Morais, Meline O; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2013-08-01

    Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Neurological manifestations are variable and some patients are developmentally normal, while others show different degrees of developmental retardation. Considering that current data do not eliminate the possibility that elevated levels of tyrosine and/or its derivatives may have noxious effects on central nervous system development in some patients, the present study evaluated nerve growth factor (NGF) levels in hippocampus, striatum and posterior cortex of young rats. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal administration of L-tyrosine (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); the rats were killed 12 h after the last injection. NGF levels were then evaluated. Our findings showed that acute administration of L-tyrosine decreased NGF levels in striatum of 10-day-old rats. In the 30-day-old rats, NGF levels were decreased in hippocampus and posterior cortex. On the other hand, chronic administration of L-tyrosine increased NGF levels in posterior cortex. Decreased NGF may impair growth, differentiation, survival and maintenance of neurons. PMID:23690230

  7. Social influences on morphine sensitization in adolescent females.

    PubMed

    Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-08-01

    We recently observed that social interactions influence morphine responsiveness in adolescent males. Given sex-related differences in both social interactions and responses to morphine, the present study examines social influences on morphine sensitization in adolescent female mice. Four experimental groups were examined: (1) morphine-treated mice (twice daily, 10-40 mg/kg, s.c.) housed physically and visually separated from saline-treated mice ('morphine only'), (2) morphine-treated mice housed together with saline-treated mice ('morphine cage-mates (of saline)'), (3) saline-treated mice housed together with morphine-treated mice ('saline cage-mates (of morphine)'), and (4) saline-treated mice housed physically and visually separated from morphine-treated mice ('saline only'). Following the treatment period, mice were tested individually for their locomotor response to 20 mg/kg morphine (s.c.). There were no significant differences in morphine-induced hyper-locomotion between saline only and saline cage-mates (of morphine) female adolescent mice. Notably, morphine only mice exhibited significantly greater morphine sensitization as compared to morphine cage-mates (of saline). Thus, this study demonstrates social influences on morphine sensitization in adolescent females. Drug use during early adolescence is a key predictor of later drug abuse and dependence during adulthood. Thus, understanding the specific vulnerabilities to drug use in this age group may represent a first step in helping develop more effective treatment programs. PMID:20456874

  8. Effect of acute administration of cadmium on the disposition of copper, zinc, and iron in the rat

    SciTech Connect

    Ashby, S.L.; King, L.J.; Parke, D.V.W.

    1980-02-01

    Acute administration of subcutaneous doses of cadmium (0.1 to 1.5 mg/kg) to male rats results in high plasma concentrations of copper 24 hr after treatment. In contrast, plasma zinc and iron levels were markedly reduced. The magnitude and significance of the changes in plasma metal ion concentrations were dependent upon the dose of cadmium administered. Liver copper levels were slightly but not significantly increased, but circulating ceruloplasmin levels increased as the total plasma copper increased. Biliary excretion of copper was markedly inhibited after cadmium administration (subcutaneous and oral) and the degree of inhibition was directly related to the dose. Simultaneous parenteral administration of zinc did not counteract this effect. These results suggest that cadmium blocks the excretion of copper into the bile leading to an accumulation of copper in the liver, which in turn, stimulates the synthesis of ceruloplasmin. The mechanisms by which cadmium may inhibit biliary copper excretion are discussed.

  9. Absorption of morphine from a slow-release emulsion used to induce morphine dependence in rats.

    PubMed

    Salem, A; Hope, W

    1998-10-01

    This study was performed to measure absorption of morphine from the injection site following treatment of rats with slow-release emulsions formulated with morphine hydrochloride and morphine base. Samples of emulsion were collected from the injection site of halothane anesthetized animals at 24 and 48 h following emulsion treatment and concentrations of morphine remaining in the emulsion were analyzed using high-performance liquid chromatography (HPLC). In another group of morphine-treated rats, at times equivalent to collecting samples of emulsion, the intensity of naloxone-precipitated withdrawal behaviors was monitored. Both morphine base- and hydrochloride-containing emulsions induced a high degree of physical dependence in animals treated over 48 h. Release of morphine from emulsions containing morphine base was slower than that from the hydrochloride formulations. In the 24-h morphine base-treated animals, approximately 45% was absorbed from the injection site as opposed to 99% in the 24-h morphine hydrochloride-treated animals. These results suggest that morphine base containing emulsions provide a more sustained exposure to the opioid. PMID:10334632

  10. Dopamine and 5-HT supersensitivity in nonorganic central pain and in morphine abstinence: fortuitous or renal analogy?

    PubMed

    Sicuteri, F; Anselmi, B; Del Bianco, P L

    1980-01-01

    Unexplained pain, such as central panalgesia, might be the most common clinical expression of a deficiency, central in nature, of the endorphin system. Acute natural opioid deficiency is comparable to morphine withdrawal in addicts characterized by vegetative, psychic disorder and the appearance of pain. An impressive supersensitivity (up to 1000 fold) to dopamine and 5-HT of the smooth muscle (hand dorsal vein: venotest) is detected both in central panalgesia sufferers and in addicts during spontaneous (withdrawal) or pharmacological (naloxone) abstinence. A 5-HT and dopamine supersensitivity, of less intensity, however, (10-30 fold), is found during migraine attacks: on these occasions, morphine-like factors in CSF appear reduced or undetectable, reinforcing the chemical analogy between morphine abstinence and migraine attacks. In the present study, evidence of opiate receptors in the human vein is also provided: 5-HT venospasms, inhibited by morphine, promptly emerge when naloxone is inoculated locally. PMID:7395606

  11. Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

    PubMed Central

    Elhabazi, K; Trigo, JM; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, JJ; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

    2012-01-01

    BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. PMID:21718302

  12. Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

    PubMed

    Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

    2014-07-15

    The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. PMID:24755308

  13. Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: a study of GIRK knockout mice

    PubMed Central

    Torrecilla, Maria; Quillinan, Nidia; Williams, John T.; Wickman, Kevin

    2008-01-01

    While the acute inhibitory effect of opioids on locus coeruleus (LC) neurons is mediated primarily by the activation of G protein-gated inwardly-rectifying K+ (GIRK) channels, the 3′-5′-cyclic adenosine monophosphate (cAMP)-system has been implicated in the effects of chronic morphine exposure. Presently, the impact of chronic morphine treatment on GIRK-dependent and GIRK-independent mechanisms underlying the opioid-induced inhibition of LC neurons is unclear. Here, opioid-induced postsynaptic inhibition was studied in LC neurons from wild-type and GIRK2/GIRK3-/- mice at baseline and following chronic morphine treatment. The postsynaptic inhibition of LC neurons caused by the opioid agonist [Met]5 enkephalin (ME) was unaffected by chronic morphine treatment in mice of both genotypes. Furthermore, chronic morphine treatment had no effect on the forskolin augmentation of the ME-induced current in wild-type LC neurons, and only a minor effect on the ME-induced current in LC neurons from GIRK2/GIRK3-/- mice. Chronic morphine treatment did, however, lead to an increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the LC. Interestingly, while forskolin augmented the EPSC frequency similarly in untreated and morphine-treated wild-type mice, as well as untreated GIRK2/GIRK3-/- mice, it failed to increase the frequency of EPSCs in morphine-treated GIRK2/GIRK3-/- mice. Altogether, the findings suggest that chronic morphine treatment exerts little impact on ion channels and signaling pathways that mediate the postsynaptic inhibitory effects of opioids, but does enhance excitatory neurotransmission in the mouse LC. PMID:18702733

  14. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide

    PubMed Central

    Parvardeh, Siavash; Moghimi, Mahsa; Eslami, Pegah; Masoudi, Alireza

    2016-01-01

    Objective(s): Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. α-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since α-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of α-terpineol on morphine-induced dependence and tolerance in mice. Materials and Methods: The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of α-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used. Results: Administration of α-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, α-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of α-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of α-terpineol on dependence and tolerance to morphine. Conclusion: These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production. PMID:27081466

  15. The effect of chronic morphine or methadone exposure and withdrawal on clock gene expression in the rat suprachiasmatic nucleus and AA-NAT activity in the pineal gland.

    PubMed

    Pačesová, D; Novotný, J; Bendová, Z

    2016-07-18

    The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine. PMID:27070740

  16. Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α₂A-adrenoceptor.

    PubMed

    Nakagawa, T; Nagayasu, K; Nishitani, N; Shirakawa, H; Sekiguchi, K; Ikarashi, Y; Kase, Y; Kaneko, S

    2012-12-27

    Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18β-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade. PMID:23069764

  17. Delay of Morphine Tolerance by Palmitoylethanolamide

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Corti, Francesca; Micheli, Laura; Zanardelli, Matteo; Ghelardini, Carla

    2015-01-01

    In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1 PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1 intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested. PMID:25874232

  18. Synthetic substances with morphine-like effect

    PubMed Central

    Braenden, Olav J.; Eddy, Nathan B.; Halbach, H.

    1955-01-01

    For morphine-, morphinan-, pethidine-, methadone-, and dithienyl-butenylamine groups of analgesic compounds a systematic survey is given of how analgesic activity is quantitatively affected by alteration of the chemical constitution. Features common to the structural formulae of substances with morphine-like analgesic effect are pointed out. ImagesFIG. 1FIG. 1(Contd.) PMID:13284565

  19. Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats.

    PubMed

    Macedo, Levy W; Cararo, José H; Maravai, Soliany G; Gonçalves, Cinara L; Oliveira, Giovanna M T; Kist, Luiza W; Guerra Martinez, Camila; Kurtenbach, Eleonora; Bogo, Maurício R; Hipkiss, Alan R; Streck, Emilio L; Schuck, Patrícia F; Ferreira, Gustavo C

    2016-10-01

    Carnosine (β-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-γ coactivator 1-α (Ppargc1α), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders. PMID:26476839

  20. Intrathecal morphine for post-thoracotomy pain.

    PubMed

    Gray, J R; Fromme, G A; Nauss, L A; Wang, J K; Ilstrup, D M

    1986-08-01

    We wished to investigate possible differences in the duration of postoperative analgesia and the incidence of respiratory depression after the intrathecal injection in the lumbar area of 10 micrograms/kg morphine in hypobaric and hyperbaric solution for relief of post-thoracotomy pain. Twenty-nine patients received morphine plus dextrose (hyperbaric) and 21 received morphine in preservative-free normal saline. The duration of analgesia was longer with the morphine in the normal saline group than in the hyperbaric group (P less than 0.04). One patient developed delayed respiratory depression. Our data support the use of morphine in normal saline mixtures for greater duration of analgesia after thoracic operations. PMID:3755305

  1. Suppressive effects of rosa damascena essential oil on naloxone- precipitated morphine withdrawal signs in male mice.

    PubMed

    Abbasi Maleki, Navid; Abbasi Maleki, Saeid; Bekhradi, Reza

    2013-01-01

    This research was done to test the effect of Rosa damascena essential oil on withdrawal signs of naloxone-precipitated morphine in male mice. Morphine dependence was induced by injection (IP) three times daily at doses of 50, 50 and 75 mg/kg, respectively, for 3 days. On day 4, after the last administration of morphine, Rosa damascena essential oil was administered at different concentrations (5, 2 and 40%, IP) 30 min before administration of naloxone (5 mg/kg, IP). The following actions were taken as signs of withdrawal and records taken for jumping as a number and scores of 0 to 3 were given for incidences of grooming, teeth chattering, rearing, writing, diarrhea, wet dog shakes and climbing during a 30 min period. Results showed that different concentrations of Rosa damascena essential oil significantly reduced signs of morphine withdrawal compared to the control group in terms of number of jumps (p < 0.05 and p < 0.01), grooming, teeth chattering, rearing, climbing, wet dog shakes and writhing, but not for diarrhea (p < 0.05). In conclusion it seems that GABAergic activity induced by flavonoids from Rosa damascena essential oil can alleviate signs of morphine withdrawal, but further studies need to be done to better understand this mechanism. PMID:24250642

  2. Naloxone inhibits and morphine potentiates the adrenal steroidogenic response to ACTH

    NASA Technical Reports Server (NTRS)

    Heybach, J. P.; Vernikos, J.

    1981-01-01

    The administration of morphine to hypophysectomized rats potentiated the steroidogenic response of the adrenal cortex to exogenous adrenocorticotrophic hormone (ACTH) in a dose-dependent fashion. Conversely, the opiate antagonist naloxone inhibited the adrenal response to ACTH. Naloxone pretreatment also antagonized the potentiating effect of morphine on ACTH-induced steroidogenesis in a dose-dependent manner. Neither morphine nor naloxone, administered to hypophysectomized rats, had any direct effect on adrenal steroidogenesis. These adrenal actions were stereospecific since neither the (+)-stereoisomer of morphine, nor that or naloxone, had any effect on the adrenal response to ACTH. The administration of human beta-endorphin to hypophysectomized rats had no effect on the adrenal corticosterone concentration nor did it alter the response of the adrenal gland to ACTH. These results indicate that morphine can potentiate the action of ACTH on the adrenal by a direct, stereospecific, dose-dependent mechanism that is prevented by naloxone pretreatment and which may involve competition for ACTH receptors on the corticosterone-secreting cells of the adrenal cortex.

  3. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  4. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  5. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  6. Small intestinal amyogenesia and dysmyogenesia induced by morphine and loperamide.

    PubMed

    Sarna, S K; Otterson, M F

    1990-02-01

    We studied the effects of morphine and loperamide on small bowel myoelectric and contractile activity in 12 conscious dogs. After initially producing premature migrating myoelectric complexes, both substances destabilized and obliterated electrical control activity (ECA). The obliteration of ECA occurred mainly in the proximal half of the small intestine. During ECA obliteration, the base line was almost flat at the usual amplification. At higher amplification, the base line exhibited irregular low level fluctuations that could not be related to electrical response activity (ERA) bursts or contractions. The mean time lag for obliteration of ECA in the proximal small intestine decreased at higher doses of morphine infusion. During the destabilization and obliteration of ECA, contractions and ERA bursts occurred in unusual patterns. The ERA bursts and contractions were generally discoordinated. However, in the proximal small intestine some contractions migrated rapidly and uninterrupted at 32 +/- 7 cm/s over long distances (124 +/- 24 cm). ECA destabilization and obliteration were reversed in approximately 15-30 min after the ingestion of a meal or intravenous administration of atropine, hexamethonium, or naloxone. We conclude that during the absence or destabilization of ECA, the ERA bursts and contractions occur in an uncontrolled manner. These two states were called "amyogenesia" and "dysmyogenesia," respectively. The unusual patterns of contractions during small intestinal amyogenesia and dysmyogenesia may be one of the factors in delayed intestinal transit produced by morphine and loperamide. PMID:1968317

  7. Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice.

    PubMed

    Chefer, Vladimir I; Kieffer, Brigitte L; Shippenberg, Toni S

    2003-10-01

    Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors. Locomotor activity was assessed in these same animals. No difference between genotypes in basal dialysate DA levels was seen. No net flux studies revealed significant decreases in the DA extraction fraction in both MOR- and DOR-knockout mice, indicating decreased basal DA uptake in both genotypes. Extracellular DA, however, was unchanged. Because extracellular neurotransmitter levels are determined by the dynamics of both release and uptake, these findings provide suggestive evidence that basal DA release is decreased in mutant mice. Systemic administration of morphine significantly increased locomotor activity and dialysate DA levels in wild-type mice. MOR-knockout mice failed to exhibit a behavioural response to morphine. The ability of morphine to increase DA levels, however, was reduced but not prevented. No alteration in the effects of morphine was observed in DOR-knockout mice. These data provide genetic evidence for the existence of tonically active MOR and DOR systems that modulate basal DA neurotransmission in the NAc. Furthermore, they demonstrate that in contrast to the locomotor-activating effects of morphine, a small component of morphine-evoked DA release occurs independently of MOR activation. PMID:14622224

  8. Drug discrimination in pigeons trained to discriminate among morphine, U50488, a combination of these drugs, and saline.

    PubMed

    Wessinger, William D; Li, Mi; McMillan, Donald E

    2011-09-01

    This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of μ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (μ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule. After training, correct-key responding averaged 94.4 (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50488. Combining high doses of morphine with low doses of U50488 produced responding on the morphine key and combining high doses of U50488 with low doses of morphine produced responding on the U50488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50488 key. The four-choice procedure under the FR schedule has the potential for determining the discriminative stimulus effects of mixed agonists. PMID:21836460

  9. Differential desensitization of mu- and delta- opioid receptors in selected neural pathways following chronic morphine treatment.

    PubMed Central

    Noble, F.; Cox, B. M.

    1996-01-01

    1. Morphine produces a plethora of pharmacological effects and its chronic administration induces several side-effects. The cellular mechanisms by which opiates induce these side-effects are not fully understood. Several studies suggest that regulation of adenylyl cyclase activity by opioids and other transmitters plays an important role in the control of neural function. 2. The aim of this study was to evaluate desensitization of mu- and delta- opioid receptors, defined as a reduced ability of opioid agonists to inhibit adenylyl cyclase activity, in four different brain structures known to be involved in opiate drug actions: caudate putamen, nucleus accumbens, thalamus and periaqueductal gray (PAG). Opiate regulation of adenylyl cyclase in these regions has been studied in control and morphine-dependent rats. 3. The chronic morphine treatment used in the present study (subcutaneous administration of 15.4 mg morphine/rat/day for 6 days via osmotic pump) induced significant physical dependence as indicated by naloxone-precipitated withdrawal symptoms. 4. Basal adenylyl cyclase in the four brain regions was not modified by this chronic morphine treatment. In the PAG and the thalamus, a desensitization of mu- and delta-opioid receptors was observed, characterized by a reduced ability of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO; mu), Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; delta) and [D-Ala2]-deltorphin-II (DT-II; delta) to inhibit adenylyl cyclase, activity following chronic morphine treatment. 5. The opioid receptor desensitization in PAG and thalamus appeared to be heterologous since the metabotropic glutamate receptor agonists, L-AP4 and glutamate, and the 5-hydroxytryptamine (5-HT)1A receptor agonist, R(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), also showed reduced inhibition of adenylyl cyclase activity following chronic morphine treatment. 6. In the nucleus accumbens and the caudate putamen, desensitization of delta-opioid receptor

  10. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.

    PubMed

    Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli; Mathews, Lisa; Koehn, Brent H; Dwyer, Gaelen K; Lott, Jeremy M; Uhl, Franziska M; Pfeifer, Dietmar; Feser, Colby J; Smith, Michelle J; Liu, Quan; Zeiser, Robert; Blazar, Bruce R; Turnquist, Hēth R

    2016-07-21

    During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation. PMID:27222477

  11. Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus.

    PubMed

    Scaini, Giselli; Mello-Santos, Lis Mairá; Furlanetto, Camila B; Jeremias, Isabela C; Mina, Francielle; Schuck, Patrícia F; Ferreira, Gustavo C; Kist, Luiza W; Pereira, Talita C B; Bogo, Maurício R; Streck, Emilio L

    2013-12-01

    Maple syrup urine disease (MSUD) is a neurometabolic disorder caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase leading to accumulation of the branched-chain amino acids (BCAA) and their corresponding branched-chain α-keto acids. In this study, we examined the effects of acute and chronic administration of BCAA on protein levels and mRNA expression of nerve growth factor (NGF) considering that patients with MSUD present neurological dysfunction and cognitive impairment. Considering previous observations, it is suggested that oxidative stress may be involved in the pathophysiology of the neurological dysfunction of MSUD. We also investigated the influence of antioxidant treatment (N-acetylcysteine and deferoxamine) in order to verify the influence of oxidative stress in the modulation of NGF levels. Our results demonstrated decreased protein levels of NGF in the hippocampus after acute and chronic administration of BCAA. In addition, we showed a significant decrease in the expression of ngf in the hippocampus only following acute administration in 10-day-old rats. Interestingly, antioxidant treatment was able to prevent the decrease in NGF levels by increasing ngf expression. In conclusion, the results suggest that BCAA is involved in the regulation of NGF in the developing rat. Thus, it is possible that alteration of neurotrophin levels during brain maturation could be of pivotal importance in the impairment of cognition provoked by BCAA. Moreover, the decrease in NGF levels was prevented by antioxidant treatment, reinforcing that the hypothesis of oxidative stress can be an important pathophysiological mechanism underlying the brain damage observed in MSUD. PMID:23559405

  12. D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

    PubMed

    Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

    2016-10-01

    The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine. PMID:27374160

  13. Protocol: does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI)

    PubMed Central

    2013-01-01

    Background Whilst advances in reperfusion therapies have reduced early mortality from acute myocardial infarction, heart failure remains a common complication, and may develop very early or long after the acute event. Reperfusion itself leads to further tissue damage, a process described as ischaemia-reperfusion-injury (IRI), which contributes up to 50% of the final infarct size. In experimental models nitrite administration potently protects against IRI in several organs, including the heart. In the current study we investigate whether intravenous sodium nitrite administration immediately prior to percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction will reduce myocardial infarct size. This is a phase II, randomised, placebo-controlled, double-blinded and multicentre trial. Methods and outcomes The aim of this trial is to determine whether a 5 minute systemic injection of sodium nitrite, administered immediately before opening of the infarct related artery, results in significant reduction of IRI in patients with first acute ST elevation myocardial infarction (MI). The primary clinical end point is the difference in infarct size between sodium nitrite and placebo groups measured using cardiovascular magnetic resonance imaging (CMR) performed at 6–8 days following the AMI and corrected for area at risk (AAR) using the endocardial surface area technique. Secondary end points include (i) plasma creatine kinase and Troponin I measured in blood samples taken pre-injection of the study medication and over the following 72 hours; (ii) infarct size at six months; (iii) Infarct size corrected for AAR measured at 6–8 days using T2 weighted triple inversion recovery (T2-W SPAIR or STIR) CMR imaging; (iv) Left ventricular (LV) ejection fraction measured by CMR at 6–8 days and six months following injection of the study medication; and (v) LV end systolic volume index at 6–8 days and six months. Funding, ethics and

  14. P2Y12 Receptor Antagonists and Morphine: A Dangerous Liaison?

    PubMed

    Giannopoulos, Georgios; Deftereos, Spyridon; Kolokathis, Fotios; Xanthopoulou, Ioanna; Lekakis, John; Alexopoulos, Dimitrios

    2016-09-01

    P2Y12 receptor antagonists, concurrently administered with aspirin in what has come to be commonly called dual antiplatelet therapy, are a mainstay of treatment for patients with acute coronary syndromes. Morphine, on the contrary, is a commonly used drug in the acute phase of acute coronary syndromes to relieve pain-with the added potential benefit of attenuating acutely raised sympathetic tone. In current guidelines, though, morphine is recommended with decreasing strength of recommendation. One reason is that it raises concern regarding the potentially significant interaction with antiplatelet agents, leading to impaired inhibition of platelet activation. In any case, it is still considered a mandatory part of the inventory of available medications in prehospital acute myocardial infarction management. The goal of the present review is to present published evidence on morphine and its potential interactions with P2Y12 receptor antagonists, as well as on the central issue of whether such interactions may underlie clinically significant effects on patient outcomes. PMID:27586412

  15. HINDBRAIN AND CRANIAL NERVE DYSMORPHOGENESIS RESULT FROM ACUTE MATERNAL ETHANOL ADMINISTRATION

    EPA Science Inventory

    Acute exposure of mouse embryos to ethanol during stages of hindbrain segmentation results in excessive cell death in specific cell populations. This study details the ethanol-induced cell loss and defines the subsequent effects of this early insult on rhombomere and cranial ner...

  16. Comparison of the antinociceptive effect of systemic versus intrathecal magnesium sulphate on spinal morphine analgesia.

    PubMed

    Messeha, Medhat M; Boshra, Vivian

    2016-03-01

    The aim of this work was to compare the possible antinociceptive effect of the intravenous (IV) versus the intrathecal (IT) administration of magnesium sulphate prior to spinal morphine analgesia. This research was conducted in two sets: First; experimentally, to compare the antinociceptive effect of IT magnesium sulphate (375 μg/rat) versus IP magnesium sulphate 100 mg/kg), prior to IT morphine (10 μg/rat). Pain was assessed using Randall-Selitto testing, the hot-plate, and formalin tests. A non-significant difference in the nociceptive threshold was observed between IT and IP magnesium sulphate administration prior to IT morphine in rats. Second: clinically, in patients undergoing orthopedic surgery, who received either an IT mixture of 1 mg of morphine with 3 mL hyperbaric 0.5% bupivacaine, an IT mixture of morphine with bupivacaine and 50 mg of magnesium sulphate, or an IT mixture of morphine bupivacaine plus IV 20 mg/kg of magnesium sulphate as a loading dose over 15 min prior to surgery, followed by infusion at a rate of 10 mg/kg/h. Pain was evaluated using a visual analog pain scale (VAS) score at one hour, 6 h and 12 h postoperatively. The use of IT or IV magnesium sulphate, in addition to the spinal morphine caused a significant decrease in the VAS score in the 6(th) and 12(th) post-operative hours with a non-significant difference between both routes. In conclusion the efficacy of systemic magnesium sulphate to potentiate the analgesic effect of intrathecal morphine is a promising and attractive route of choice for postoperative pain relief during spinal anesthesia. Opioid analgesia could be prolonged and the incidence of motor paralysis, common with the intrathecal route of magnesium sulphate administration, reduced. PMID:27160490

  17. Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice*

    PubMed Central

    Karami, Reza; Hosseini, Mahmoud; Khodabandehloo, Fatimeh; Khatami, Leila; Taiarani, Zahra

    2011-01-01

    Objective: The roles of gonadal hormones and nitric oxide (NO) on the analgesic effects of morphine, tolerance to morphine, and their interactions have been widely investigated. In the present study, the effect of L-arginine (an NO precursor) on morphine tolerance in sham and ovariectomized (OVX) female mice was investigated. Methods: Forty mice were divided into sham and OVX groups. On the first day, a hot plate test ((55±0.2) °C; cut-off 30 s) was carried out as a base record 15 min before injection of morphine (10 mg/kg, subcutaneously (s.c.)) and was repeated every 15 min after injection. The sham group was then divided into two subgroups: sham-tolerance-L-arginine (Sham-Tol-LA) and sham-tolerance-saline (Sham-Tol-Sal) which received either L-arginine 50 mg/kg (intraperitoneally (i.p.)) or saline 10 ml/kg (i.p.), respectively, three times in a day for three consecutive days. Morphine tolerance was induced in animals by injecting 30 mg/kg morphine (s.c.) three times/day for three days. This treatment was also used for OVX subgroups. On the fifth day, the hot plate test was repeated. The analgesic effect of morphine was calculated as the maximal percent effect (MPE). The results were compared using repeated measure analysis of variance (ANOVA). Results: There was no significant difference in MPE between the OVX and sham groups. The MPEs in both the Sham-Tol-Sal and OVX-Tol-Sal groups were lower than those in both the sham and OVX groups (P<0.01). The MPE in the OVX-Tol-Sal group was greater than that in the Sham-Tol-Sal group (P<0.01). The MPE in the Sham-Tol-LA group was higher than that in the Sham-Tol-Sal group (P<0.01). However, there was no significant difference between the Sham-Tol-LA and sham groups or between the OVX-Tol-LA and OVX-Tol-Sal groups. Conclusions: The results of the present study showed that repeated administration of morphine causes tolerance to the analgesic effect of morphine. L-Arginine could prevent tolerance to morphine but its

  18. Acute and Chronic Alcohol Administration: Effects on Performance of Zebrafish in a Latent Learning Task

    PubMed Central

    Luchiari, Ana C; Salajan, Diana C; Gerlai, Robert

    2015-01-01

    Alcohol abuse is a major medical problem. Zebrafish have been proposed to model alcohol related human disorders. Alcohol impairs learning and memory. Here, we analyze the effects of alcohol on performance of zebrafish in a recently developed latent learning paradigm. We employ a 2 × 3 × 2 experimental design (chronic × acute alcohol treatment × path blocked). The latent learning task had two phases: one, 30 min long exploration trials (16 days, 1 trial/day) with left or right path of a complex maze blocked, and two, a subsequent probe trial with all paths open leading to a goal box that now contained stimulus fish. During the 16 days each fish received one of two chronic treatments: freshwater or 0.50% (vol/vol%) alcohol. Subsequently, fish were immersed for 1h in one of the following solutions: 0.00 (freshwater), 0.50 or 1.00% alcohol, the acute challange. Behavior of fish was recorded during the probe trial that commenced immediately after the acute treatment. Path choices, latency to leave the start box and to enter the goal box, time spent in the goal box, distance travelled, and duration of freezing were quantified. We found that acute exposure to 1.00% alcohol after chronic freshwater disrupted learning performance, so did exposure to freshwater after chronic alcohol treatment (withdrawal). We also found exposure to chronic alcohol to diminish the effect of subsequent acute alcohol suggesting development of tolerance. Our results demonstrate that analysis of learning performance of zebrafish allows detection of alcohol-induced functional changes. The simplicity and scalability of the employed task also imply the utility of the zebrafish in high throughput drug screens. PMID:25557800

  19. Acute alcohol exposure, acidemia or glutamine administration impacts amino acid homeostasis in ovine maternal and fetal plasma

    PubMed Central

    Washburn, Shannon E.; Sawant, Onkar B.; Lunde, Emilie R.; Wu, Guoyao; Cudd, Timothy A.

    2013-01-01

    Fetal alcohol syndrome (FAS) is a significant problem in human reproductive medicine. Maternal alcohol administration alters maternal amino acid homeostasis and results in acidemia in both mother and fetus, causing fetal growth restriction. We hypothesized that administration of glutamine, which increases renal ammoniagenesis to regulate acid-base balance, may provide an intervention strategy. This hypothesis was tested using sheep as an animal model. On day 115 of gestation, ewes were anesthetized and aseptic surgery was performed to insert catheters into the fetal abdominal aorta as well as the maternal abdominal aorta and vena cava. On day 128 of gestation, ewes received intravenous administration of saline, alcohol [1.75 g/kg body weight (BW)/h], a bolus of 30 mg glutamine/kg BW, alcohol + a bolus of 30 mg glutamine/kg BW, a bolus of 100 mg glutamine/kg BW, alcohol + a bolus of 100 mg glutamine/kg BW, or received CO2 administration to induce acidemia independent of alcohol. Blood samples were obtained simultaneously from the mother and the fetus at times 0 and 60 min (the time of peak blood alcohol concentration) of the study. Administration of alcohol to pregnant ewes led to a reduction in concentrations of glutamine and related amino acids in plasma by 21–30%. An acute administration of glutamine to ewes, concurrent with alcohol administration, improved the profile of most amino acids (including citrulline and arginine) in maternal and fetal plasma. We suggest that glutamine may have a protective effect against alcohol-induced metabolic disorders and FAS in the ovine model. PMID:23315157

  20. Effect of acute transdermal estrogen administration on basal, mental stress and cold pressor-induced sympathetic responses in postmenopausal women.

    PubMed

    Sofowora, Gbemiga G; Singh, Iqbal; He, Huai B; Wood, Alastair J J; Stein, C Michael

    2005-06-01

    Administration of estrogen has vascular effects through poorly defined mechanisms that may include sympathetic withdrawal. To define the effects of acute estrogen administration on sympathetic responses, nineteen healthy postmenopausal women (age 54+/-2 years) were studied after application of a placebo or estrogen patch for 36 hours, in random order. A p-value, adjusted for multiple comparisons, of <0.017 was used to determine statistical significance. Heart rate, blood pressure, and norepinephrine spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Estrogen did not attenuate basal or stimulated hemodynamic responses significantly. The increase in mean arterial pressure after the Stroop test (5.9+/-1.2mm/ Hg on placebo vs 6.1+/-1.6mm/Hg on estrogen, p=0.9) and after the cold pressor test (12.6+/-2.4mm/Hg on placebo vs 13.0+/-2.2 mm/Hg on estrogen, p=0.8) did not differ. Basal, mental stress and cold pressor-stimulated norepinephrine spillover were not significantly affected by short-term estrogen administration. Norepinephrine spillover tended to be higher after estrogen (1296.2+/-238 ng/min) than placebo (832.5+/-129 ng/min) (p=0.02) at baseline and after the Stroop test (1881.1+/-330 ng/min vs 1014.6+/-249 ng/min) (p=0.02). Acute transdermal estrogen administration did not attenuate norepinephrine spillover or sympathetically mediated hemodynamic responses. PMID:15944868

  1. The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat

    PubMed Central

    Paterson, Neil E.; Semenova, Svetlana; Markou, Athina

    2008-01-01

    Rationale Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence. Objectives To evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats. Methods A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic minipumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via minipump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing minipumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure. Results Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding. Conclusions The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal, and may alter the rewarding effects of nicotine and food. PMID:18438738

  2. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

    PubMed

    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression. PMID:26789010

  3. Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study

    PubMed Central

    Grach, Michael; Massalha, Wattan; Pud, Dorit; Adler, Rivka; Eisenberg, Elon

    2004-01-01

    Aims The coadministration of subantinociceptive doses of oxycodone with morphine has recently been shown to result in a synergistic antinociceptive effect in rats. The present study was aimed to investigate the possibility that coadministration of morphine and oxycodone can produce a similar synergistic effect in humans exposed to an experimental model of cold pressor test (CPT). Methods The enriched enrolment design was used to exclude ‘stoic’ and ‘placebo responders’ in a single-blind fashion. ‘Nonstoic’, placebo ‘nonresponder’ female volunteers (n = 30) were randomly assigned to receive 0.5 mg kg−1 oral morphine sulphate, 0.5 mg kg−1 oral oxycodone hydrochloride, and the combination of 0.25 mg kg−1 morphine sulphate with 0.25 mg kg−1 oxycodone hydrochloride, 1 week apart from each other, in a double-blind crossover design. Latency to pain onset (threshold), pain intensity (VAS), and pain tolerance (time until removal of the hand from the water) were measured six times over a 3-h period, subsequent to the administration of each medication, and were used to assess their antinociceptive effect. Results The combination produced a significantly higher effect on latency to pain onset than that of morphine alone [difference in mean postbaseline value 2.2; 95% confidence interval (CI) 0.48, 3.9; P = 0.01] but the effect was nonsignificantly smaller that that of oxycodone alone. Similarly, the effect of the combination on pain tolerance was significantly larger than that of morphine alone (combination difference 8.4; 95% CI 2.5, 14.3; P = 0.007), whereas oxycodone alone caused a nonsignificantly larger effect than that of the combination treatment. Comparisons of pain magnitude failed to show any significant differences between the three treatments. Conclusions These results indicate that at the doses tested, morphine and oxycodone do not produce synergistic antinociceptive effects in healthy humans exposed to the CPT. PMID:15327582

  4. Long-term behavioral effects in a rat model of prolonged postnatal morphine exposure.

    PubMed

    Craig, Michael M; Bajic, Dusica

    2015-10-01

    Prolonged morphine treatment in neonatal pediatric populations is associated with a high incidence of opioid tolerance and dependence. Despite the clinical relevance of this problem, our knowledge of long-term consequences is sparse. The main objective of this study was to investigate whether prolonged morphine administration in a neonatal rat is associated with long-term behavioral changes in adulthood. Newborn animals received either morphine (10 mg/kg) or equal volume of saline subcutaneously twice daily for the first 2 weeks of life. Morphine-treated animals underwent 10 days of morphine weaning to reduce the potential for observable physical signs of withdrawal. Animals were subjected to nonstressful testing (locomotor activity recording and a novel-object recognition test) at a young age (Postnatal Days [PDs] 27-31) or later in adulthood (PDs 55-56), as well as stressful testing (calibrated forceps test, hot plate test, and forced swim test) only in adulthood. Analysis revealed that prolonged neonatal morphine exposure resulted in decreased thermal but not mechanical threshold. Importantly, no differences were found for total locomotor activity (proxy of drug reward/reinforcement behavior), individual forced swim test behaviors (proxy of affective processing), or novel-object recognition test. Performance on the novel-object recognition test was compromised in the morphine-treated group at the young age, but the effect disappeared in adulthood. These novel results provide insight into the long-term consequences of opioid treatment during an early developmental period and suggest long-term neuroplastic differences in sensory processing related to thermal stimuli. PMID:26214209

  5. Divergent Effect of Dezocine, Morphine and Sufentanil on Intestinal Motor Function in Rats

    PubMed Central

    Bian, Xiaocui; Zhou, Renlong; Yang, Yuting; Li, Peiying; Hang, Yannan; Hu, Youmin; Yang, Liqun; Wen, Daxiang

    2015-01-01

    Background: Opioid induced bowel dysfunction is the most common side effect of preoperatively administrated morphine, fentanyl and its derivative. However, the influence of dezocine on intestinal mobility is rarely reported. This study was designed to investigate the effects of dezocine, morphine and sufentanil on both intestinal smooth muscle contraction and propulsion in rats. Methods: Contractile tension and frequency of isolated rat small intestine smooth muscle were measured using tension transducer after incubation with different concentrations of dezocine, morphine and sufentanil. The propulsive rate of methylene blue in rat intestinal tract was measured 30 minutes after intraperitoneal injection of morphine, sufentanil and dezocine. Percent of change in contractile tension and contraction frequency compared to baseline level were calculated to evaluate muscle contraction. Propulsive rate of methylene blue was calculated as the percentage of methylene blue moving distance in intestinal tract compared to the length of the small intestine. Results: Morphine and sufentanil significantly increased the contractile tension of isolated small intestine smooth muscle at high doses. The contraction frequency did not change significantly among the 3 tested doses. Increasing the dose of dezocine from 1.7 mg.L-1 to 10.2 mg.L-1 did not change either the contractile tension or the contraction frequency. The propulsive rate of methylene blue in intestinal tract was significantly decreased after the treatment with morphine, sufentanil and dezocine (45.6%, 43.7%, and 42.1% respectively) compared to control group(57.1%), while the difference among the 3 drug groups were not significant. Conclusion: Morphine and sufentanil may dose dependently increase the contractile tension and contraction ability of isolated rat small intestine smooth muscle, while dezocine has no significant effect on intestine smooth muscle contraction. However, all these opioids might impair small

  6. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    SciTech Connect

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  7. Can personality traits and gender predict the response to morphine? An experimental cold pain study.

    PubMed

    Pud, Dorit; Yarnitsky, David; Sprecher, Elliot; Rogowski, Zeev; Adler, Rivka; Eisenberg, Elon

    2006-02-01

    The aim of the present study was to examine the possible role of personality traits, in accordance with Cloninger's theory, and gender, in the variability of responsiveness to opioids. Specifically, it was intended to test whether or not the three personality dimensions - harm avoidance (HA), reward dependence (RD) and novelty seeking (NS) - as suggested by Cloninger, can predict inter-personal differences in responsiveness to morphine after exposure to experimental cold pain. Thirty-four healthy volunteers (15 females, 19 males) were given the cold pressor test (CPT). Pain threshold, tolerance, and magnitude (VAS) were measured before and after (six measures, 30 min apart) the administration of either 0.5 mg/kg oral morphine sulphate (n=21) or 0.33 mg/kg oral active placebo (diphenhydramine) (n=13) in a randomized, double blind design. Assessment of the three personality traits, according to Cloninger's Tridimensional Personality Questionnaire, was performed before the CPT. A high HA score (but not RD, NS, or baseline values of the three pain parameters) predicted a significantly larger pain relief following the administration of morphine sulphate (but not of the placebo). Women exhibited a larger response in response to both treatments, as indicated by a significantly increased threshold and tolerance following morphine sulphate as well as significantly increased tolerance and decreased magnitude following placebo administration. The present study confirms the existence of individual differences in response to analgesic treatment. It suggests that high HA personality trait is associated with better responsiveness to morphine treatment, and that females respond better than men to both morphine and placebo. PMID:16310713

  8. Effects of acute or chronic administration of novel 3,4-dimethoxyphenylethylamine derivates on anxiety-like behavior

    PubMed Central

    Fedotova, Julia; Barishpolec, Victoria; Zulli, Anthony; Büsselberg, Dietrich; Gaspar, Ludovit; Kruzliak, Peter

    2015-01-01

    Novel anxiolytic medications are necessary to broaden treatment therapy. Thus, the aim of the present study was to compare the clinically effective anxiolytic, diazepam with the novel 3,4-dimethoxyphenylethylamine derivates. The novel 3,4-dimethoxyphenylethylamine derivates (PK, 0.1, 1.0, 10.0 mg/kg, i.p.) and diazepam (1.0 mg/kg) were injected acutely or chronically in animals subjected to the black-white model and the open field test. The acute administration of PK-2122 (0.1 mg/kg, i.p.) exerted anxiogenic-like effect, while in the middle or high doses PK-2122 exerted anxiolytic-like effect compared with the control group (p<0.05). The repeated treatment with PK-2111 was followed by anxiolytic-like effect in doses of 0.1 or 1.0 mg/kg which was more significant compared not only with control group, but with comparison to group treated with diazepam (p<0.05). Chronic treatment with PK-2123 or PK-2122 in all tested doses produced anxiolytic-like effect (p<0.05), compared with control group and diazepam group. These results demonstrate that PK-2126, but not PK-2122, is dose independent and may be effective in experimental model of anxiety in rats when administered acutely or repeatedly. PMID:26807191

  9. Photoaffinity labeling of opioid receptor with morphine-7,8-oxide (morphine epoxide)

    SciTech Connect

    Takayanagi, I.; Shibata, R.; Miyata, N.; Hirobe, M.

    1982-05-01

    The opioid receptor mediating inhibitory action of morphine in the electrically stimulated guinea pig ileum was irreversibly photoinactivated by morphine epoxide (3 X 10(-6) M). Morphine epoxide (up to 3 X 10(-5) M) did not influence the responses of rat vas deferens (epsilon-receptor) or rabbit vas deferens (kappa-receptor) to electrical stimulation. Effective concentrations of morphine epoxide were much lower in the guinea pig ileum (mu-receptor) than in the mouse vas deference (delta-receptor). The inhibitory action of (Met)-enkephalin on the twitch responses of the rat vas deferens and mouse vas deferens to electrical stimulation were not influenced after irradiation in the presence of morphine epoxide (3 X 10(-6) M). Therefore, morphine epoxide is probably a useful probe for photoaffinity labeling of the mu-receptor in vitro.

  10. The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice.

    PubMed

    Blagaic, Alenka Boban; Blagaic, Vladimir; Romic, Zeljko; Sikiric, Predrag

    2004-09-24

    The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.1419), which was promising in inflammatory bowel disease (PL-10, PLD-116, PL-14736, Pliva) trials, protects against both acute and chronic alcohol-induced lesions in stomach and liver, but also, given peripherally, affects various centrally mediated disturbances. Now, in male NMRI mice BPC 157 (10 pg intraperitoneally, 10 ng and 10 microg, intraperitoneally or intragastrically) (i) strongly opposed acute alcohol (4 g/kg intraperitoneally) intoxication (i.e., quickly produced and sustained anesthesia, hypothermia, increased ethanol blood values, 25% fatality, 90-min assessment period) given before or after ethanol, and (ii) when given after abrupt cessation of ethanol (at 0 or 3 or 7 h withdrawal time), attenuated withdrawal (assessed through 24 hours) after 20%-alcohol drinking (7.6 g/kg) through 13 days, with provocation on the 14th day. PMID:15381050

  11. Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

    PubMed

    Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah

    2016-04-01

    This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats. PMID:26397757

  12. [Need of risk reevaluation in morphine dependence in pain patients].

    PubMed

    Boureau, F; Luu, M; Koskas-Sergent, A S; Doubrere, J F

    1992-11-01

    It is commonly recognized than opioids analgesics have an major place in the treatment of pain. In spite of guidelines, opioids drugs remain underutilized in chronic cancer pain and acute severe pain. Among the possible factors, involved in the insufficient use of opioids drugs, is the fear (opiophoby) of physicians, nurses, patients and family to induce or to maintain an addiction. This review examines the potential of iatrogenic addiction. We will examined the place of morphine-like drugs in the treatment of severe acute pain and chronic cancer pain, the definition of dependency in pain patients, the assessment of the dependency potential in patients treated for pain. Available studies indicate that iatrogenic addiction is quite scarce and that the risk for a major tolerance is very small. Further studies will be necessary, since opioids analgesics may also be useful in some non-cancer chronic pain. PMID:1363796

  13. Acute Administration of Branched-Chain Amino Acids Increases the Pro-BDNF/Total-BDNF Ratio in the Rat Brain.

    PubMed

    Scaini, Giselli; Morais, Meline O S; Furlanetto, Camila B; Kist, Luiza W; Pereira, Talita C B; Schuck, Patrícia F; Ferreira, Gustavo C; Pasquali, Matheus A B; Gelain, Daniel P; Moreira, José Cláudio F; Bogo, Maurício R; Streck, Emilio L

    2015-05-01

    Maple syrup urine disease (MSUD) is caused by an inborn error in metabolism resulting from a deficiency in the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. High levels of BCAAs are associated with neurological dysfunction and the role of pro- and mature brain-derived neurotrophic factor (BDNF) in the neurological dysfunction of MSUD is still unclear. Thus, in the present study we investigated the effect of an acute BCAA pool administration on BDNF levels and on the pro-BDNF cleavage-related proteins S100A10 and tissue plasminogen activator (tPA) in rat brains. Our results demonstrated that acute Hyper-BCAA (H-BCAA) exposure during the early postnatal period increases pro-BDNF and total-BDNF levels in the hippocampus and striatum. Moreover, tPA levels were significantly decreased, without modifications in the tPA transcript levels in the hippocampus and striatum. On the other hand, the S100A10 mRNA and S100A10 protein levels were not changed in the hippocampus and striatum. In the 30-day-old rats, we observed increased pro-BDNF, total-BDNF and tPA levels only in the striatum, whereas the tPA and S100A10 mRNA expression and the immunocontent of S100A10 were not altered. In conclusion, we demonstrated that acute H-BCAA administration increases the pro-BDNF/total-BDNF ratio and decreases the tPA levels in animals, suggesting that the BCAA effect may depend, at least in part, on changes in BDNF post-translational processing. PMID:25681161

  14. Single and Repeated Ultra-Rapid Detoxification Prevents Cognitive Impairment in Morphine Addicted Rats: A Privilege for Single Detoxification

    PubMed Central

    Ghamati, Leila; Hajali, Vahid; Sheibani, Vahid; Esmaeilpour, Khadijeh; Sepehri, Gholamreza; Shojaee, Mojtaba

    2014-01-01

    Background Opioids have been shown to affect learning and memory processes. Different protocols of morphine withdrawal can substantially vary in their success to prevent opioid induced impairments of cognitive performance. In the present study, we report the effects of single and repetitive ultra-rapid detoxification (URD) on spatial learning and memory in morphine addicted rats. Methods Morphine (10 mg/kg) was intraperitoneally (IP) injected in male rats once a day over one week and after which they were detoxified with naloxone administration under anesthesia. For the repetitive procedure, a second one week morphine treatment with a second subsequent detoxification was performed. Control groups received an equivalent volume of saline injections. Spatial learning and memory was evaluated using the Morris water maze (MWM) task. Findings Both protocols of morphine administration resulted in a severe spatial memory impairment that could be significantly prevented by both single and repetitive URD. However, memory abilities in animals treated with repetitive URD were still significantly lower than in animals of the corresponding control group. Alterations in motor activity or sensory-motor coordination between morphine treated and control animals could be ruled out by comparing swimming speed and visible platform performances that were not different between groups. Thus, URD and, specifically single URD, can prevent the spatial memory impairments in addicted rats. Conclusion As opioid addiction is an extending and serious concern in many societies, these findings may have clinical values and therapeutic implications for patients who experience multiple opioid relapses. PMID:25140218

  15. Naloxone inhibits and morphine potentiates. The adrenal steroidogenic response to ACTH

    NASA Technical Reports Server (NTRS)

    Heybach, J. P.; Vernikos, J.

    1980-01-01

    The adrenal actions were stereospecific since neither the positve stereoisomer of morphine, nor that of naloxone, had any effect on the adrenal response to exogenous adrenocorticotrophic hormone (ACTH). The administration of human beta endorphin to phyophysectomized rats had no effect on the adrenal corticosterone concentration nor did it alter the response of the adrenal gland to ACTH. These results indicate that morphine can potentiate the action of ACTH on the adrenal by a direct, stereospecific, dose dependent mechanism that is prevented by naloxone pretreatment and which may involve competition for ACTH receptors on the corticosterone secreting cells of the adrenal cortex.

  16. Influence of morphine on respiratory activities of phrenic and hypoglossal nerves in cats.

    PubMed

    Bartlett, D; St John, W M

    1986-06-01

    Anesthetic and sedative drugs have been found to diminish the respiratory motor activity of the hypoglossal nerve more than that of the phrenic nerve. This differential depression of motor activity to the upper airway may contribute to the exacerbation of obstructive sleep apnea by sedative drugs. To determine whether morphine has a similar selective action, we recorded phrenic and hypoglossal nerve activities before and after morphine administration in decerebrate, vagotomized cats, paralyzed with gallamine. Morphine diminished the activities of both nerves in most animals, but the responses were highly variable, and no consistent pattern of differential depression was apparent. The variability of the results may reflect the complex nature of opiate actions on the control of breathing. PMID:3738255

  17. Effects of Met-enkephalin on body temperature of normal and morphine-tolerant rats.

    PubMed

    Ferri, S; Arrigo Reina, R; Santagostino, A; Scoto, G M; Spadaro, C

    1978-07-19

    The endogenous opioid met-enkephalin intraventricularly adminstered to the rat at the dose of 100 microgram raised rectal temperature, whereas 400 microgram of the pentapeptide caused a diphasic effect, i.e., hypothermia followed by hyperthermia. Met-enkephalin was ineffective when administered i.p. The effects on temperature were substantially similar to those elicited, for both routes of administration, by morphine, which may either raise or lower rat temperature depending on the dose. More naloxone was required to antagonize thermic effects of met-enkephalin than morphine. Finally, there was a lack of effects on temperature for met-enkephalin centrally administered to morphine-tolerant animals, thus providing further evidence, in vivo, of cross tolerance between opiates and naturally occurring ligands of opiate receptors. PMID:98798

  18. Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore

    PubMed Central

    Dorsch, Marianne; Behmenburg, Friederike; Raible, Miriam; Blase, Dominic; Grievink, Hilbert; Hollmann, Markus W.; Heinen, André; Huhn, Ragnar

    2016-01-01

    Background Morphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway. Methods Male Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition. Results Morphine reduced infarct size from 64±5% to 39±9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64±9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61±10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64±5%; P>0.05 vs. Con). In isolated

  19. Anti-CD40 antibody and toll-like receptor 3 ligand restore dendritic cell-mediated anti-tumor immunity suppressed by morphine

    PubMed Central

    Chang, Ming-Cheng; Chen, Yu-Li; Chiang, Ying-Cheng; Cheng, Ya-Jung; Jen, Yu-Wei; Chen, Chi-An; Cheng, Wen-Fang; Sun, Wei-Zen

    2016-01-01

    The influence of morphine on host immunity and the underlying mechanism are still unclear. In the current study, we investigated the influence of morphine on dendritic cells (DCs), its possible mechanism of action, and the molecules that could reverse these effects. Morphine suppressed DC maturation, antigen presenting abilities, and the ability to activate antigen-specific CD8+ T cells. Morphine-treated DCs also secreted higher concentrations of IL-10, but lower IL-6 and TNF-α. Morphine-treated DCs showed decreased ERK1/2 phosphorylation and reduced p38 dephosphorylation. The in vivo administration of immuno-modulators, anti-CD40 Ab and TLR3 ligand-poly(I:C), enhanced antigen-specific immunity, promoted the anti-tumor effects, and prolonged the survival of morphine-treated, tumor-bearing mice by promoting the maturation and function of BMM-derived DCs by enhancing ERK1/2 phosphorylation and p38 dephosphorylation. We concluded that morphine can inhibit DC-mediated anti-tumor immunity by suppressing DC maturation and function. Immuno-modulators, such as anti-CD40 Abs and TLR agonists, can restore the DC-mediated anti-tumor immunity. Use of immuno-modulators could serve as a useful approach to overcome the immunocompromised state generated by morphine. PMID:27186393

  20. Anti-nociceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice.

    PubMed

    Hosseinzadeh, H; Moallem, S A; Moshiri, M; Sarnavazi, M S; Etemad, L

    2012-07-01

    In this study, the anti-nociceptive and anti-inflammatory effects of cyanocobalamin (Vit B12) against acute and chronic pain and inflammation were evaluated in mice. Vit B12 (0.87, 1 and 1.77 mg/kg) were injected intraperitoneally. The anti-nociceptive effects against acute pain were examined using hot-plate and writhing tests. The chronic pain was examined 14 days after sciatic nerve ligation using the hot-plate test. Morphine (10 mg/kg) was used as a positive control. Anti-inflammatory effects of Vit B12 against acute and chronic inflammation were assessed using xylene-induced edema in ears and granuloma caused by compressed cotton implantation, respectively. In these tests, sodium diclofenac (15 mg/kg) was used as a positive control. Vit B12 showed a dose related effect in acute anti-nociceptive test and increased the anti-nociceptive effect of morphine in chronic treatment. Vit B12 demonstrated an anti-nociceptive effect in chronic studies as single or continues daily treatment and increased significantly the anti-nociceptive effect of morphine. All doses of Vit B12 significantly decreased xylene-induced ear edema. Maximum anti-inflammatory effect (37.5%) was obtained at dose of 1 mg/kg. In chronic inflammation, Vit B12 significantly decreased granuloma formation in mice. In conclusion our work presents some experimental evidence supporting the administration of cyanocobalamin in controlling acute and chronic neuropathic pain. Cyanocobalamin may have anti-inflammatory effect. It may reduce tolerance to anti-nociceptive effect of morphine as well. PMID:22588629

  1. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    PubMed

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. PMID:25820086

  2. A Single-Dose Intra-Articular Morphine plus Bupivacaine versus Morphine Alone following Knee Arthroscopy: A Systematic Review and Meta-Analysis

    PubMed Central

    Wang, Yi-lun; Li, Yu-sheng; Wei, Jie; Li, Hui; Yang, Tuo; Yang, Tu-bao; Lei, Guang-hua

    2015-01-01

    Objectives The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing arthroscopic knee surgery. Methods Randomized controlled trials comparing a combination of morphine and bupivacaine with morphine alone injected intra-articularly in the management of pain after knee arthrocopic surgery were retrieved (up to August 10, 2014) from MEDLINE, the Cochrane Library and Embase databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95% confidence intervals (CIs) were calculated using RevMan statistical software. Results Thirteen randomized controlled trials were included. Statistically significant differences were observed with regard to the VAS values during the immediate period (0-2h) (WMD -1.16; 95% CI -2.01 to -0.31; p = 0.007) and the time to first request for rescue analgesia (WMD = 2.05; 95% CI 0.19 to 3.92; p = 0.03). However, there was no significant difference in the VAS pain score during the early period (2-6h) (WMD -0.36; 95% CI -1.13 to 0.41; p = 0.35), the late period (6-48h) (WMD 0.11; 95% CI -0.40 to 0.63; p = 0.67), and the number of patients requiring supplementary analgesia (RR = 0.78; 95% CI 0.57 to 1.05; p = 0.10). In addition, systematic review showed that intra-articular morphine plus bupivacaine would not increase the incidence of adverse effects compared with morphine alone. Conclusion The present study suggested that the administration of single-dose intra-articular morphine plus bupivacaine provided better pain relief during the immediate period (0-2h), and lengthened the time interval before the first request for analgesic rescue without increasing the short-term side effects when compared with morphine alone. Level of Evidence Level I, meta-analysis of Level I studies. PMID:26474401

  3. Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats.

    PubMed

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I-III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α , and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I-III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α , and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  4. Impairment of Electron Transfer Chain Induced by Acute Carnosine Administration in Skeletal Muscle of Young Rats

    PubMed Central

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I–III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α, and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I–III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α, and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  5. Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice.

    PubMed

    Waxman, Amanda R; Arout, Caroline; Caldwell, Megan; Dahan, Albert; Kest, Benjamin

    2009-10-01

    Although mu-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used mu-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking mu, delta, and kappa opioid receptors. For both groups, an acute fentanyl bolus dose (0.25mg/kg, s.c.) and continuous fentanyl infusion (cumulative daily dose: 10mg/kg) did not cause analgesia at any time. Instead, fentanyl significantly decreased withdrawal latencies relative to pre-drug values for the next 15-60 min and for six days, respectively. MK-801 blocked and reversed hyperalgesia caused by the acute injection and continuous infusion of fentanyl, respectively, in naltrexone-treated CD-1 mice, indicating the contribution of NMDA receptors to fentanyl hyperalgesia. These data show that the synthetic opioid fentanyl causes hyperalgesia independently of prior or concurrent opioid receptor activity or analgesia. Since the biotransformation of fentanyl does not yield any known pronociceptive metabolites, these data challenge assumptions regarding the role of neuroexcitatory metabolites in opioid-induced hyperalgesia. PMID:19559072

  6. Secondary adrenal insufficiency after glucocorticosteroid administration in acute spinal cord injury: A case report

    PubMed Central

    Yang, Huiqing; Trbovich, Michelle; Harrow, Jeffrey

    2014-01-01

    Context/background A 61-year-old female with cervical stenosis underwent an elective cervical laminectomy with post-op worsening upper extremity weakness. Over the first 3 weeks post-op, she received two separate courses of intravenous steroids. Two days after cessation of steroids, she presented with non-specific symptoms of adrenal insufficiency (AI). Initial formal diagnostic tests of random cortisol level and 250 µg cosyntropin challenge were non-diagnostic; however, symptoms resolved with the initiation of empiric treatment with hydrocortisone. Ten days later, repeat cosyntropin (adrenocortocotropic hormone stimulation) test confirmed the diagnosis of AI. Findings AI is a potentially life-threatening complication of acute spinal cord injury (ASCI), especially in those receiving steroids acutely. Only three cases have been reported to date of AI occurring in ASCI after steroid treatment. The presenting symptoms can be non-specific (as in this patient) and easily confused with other common sequelae of ASCI such as orthostasis and diffuse weakness. The 250 µg cosyntropin simulation test may not the most sensitive test to diagnose AI in ASCI. Conclusion The non-specific presentations and variability of diagnosis criteria make diagnosis more difficult. One microgram cosyntropin simulation test may be more sensitive than higher dose. Clinicians should be aware that AI can be a potential life-threatening complication of ASCI post-steroid treatment. Prompt diagnosis and treatment can reverse symptoms and minimize mortality. PMID:24969098

  7. Morphine

    MedlinePlus

    ... breathing problems or other serious, life-threatening side effects. Tell your doctor if you are taking or plan to take any of the following medications: cimetidine (Tagamet); other narcotic pain medications; medications for anxiety, seizures, depression, mental illness, or nausea; muscle relaxants; ...

  8. An unusual cause of chest pain: Acute coronary syndrome following administration of ergotamine tartrate.

    PubMed

    Okutucu, Sercan; Karakulak, Ugur Nadir; Kabakcı, Giray; Aytemir, Kudret

    2012-01-01

    For many years, ergotamine has been used for the acute treatment of migraine. Ergotamine may produce coronary vasospasm, which is often associated with ischemic electrocardiography changes and angina pectoris. A 62-year-old woman who was admitted to the emergency department because of chest pain is described. She had a history of severe migraine attacks and started to use ergotamine tartrate 0.75 mg daily the day before. Electrocardiography revealed sinus tachycardia with left anterior hemiblock and T wave inversion in the precordial leads. Cardiac biomarker levels were elevated. After discontinuation of the drug and initiation of vasodilator treatment, her chest pain resolved. Patients with migraine may have an underlying vasospastic disorder predisposing them to coronary artery spasm. Physicians should be alerted to potential cardiac vasospastic effects of low-dose ergotamine in the treatment of migraine. PMID:23204901

  9. Reconstruction of the anterior cruciate ligament: comparison of analgesia using intrathecal morphine, intra-articular morphine and intra-articular levobupivacaine☆

    PubMed Central

    Pinheiro, Leandro Queiroz; Neri Junior, Edmundo; Fernandes, Reginaldo Mendonça; Cardozo, Rodrigo Tavares; Rezende, Priscila Rodrigues

    2015-01-01

    Objective To compare the analgesic effect of intra-articular administration of morphine and levobupivacaine (separately or in combination) with intrathecal administration of morphine in patients undergoing anterior cruciate ligament (ACL) reconstruction using autologous grafts from the patellar tendon. Methods This was a retrospective analysis on data gathered from the medical files of 60 patients aged 20 to 50 years who underwent knee video arthroscopy for ACL reconstruction. The patients were divided into four groups of 15 individuals (A, B, C and D) according to the agent administered into the joint and around the incision: 20 mL of saline solution with 5 mg of morphine in A; 20 mL of 0.5% levobupivacaine solution in B; 10 mL of solution with 2.5 mg of morphine plus 10 mL of 0.5% levobupivacaine solution in C; and morphine administered intrathecally in D. Results All the groups presented low pain scores during the first 12 h after the surgery. Groups B and C presented significantly greater pain scores than shown by group D (control), 24 h after the surgery. There was no statistical difference in pain scores between group A and group D. Conclusion The patients in group A presented analgesia comparable to that of the patients in group D, whereas the procedure of group C was no capable of reproducing the analgesic effect observed in group D, as observed 24 h after the surgery. Further studies are needed in order to show the exact mechanism of action, along with the ideal dose and concentration for applying opioids to joints. PMID:26229934

  10. Acute and chronic caffeine administration increases physical activity in sedentary adults.

    PubMed

    Schrader, Patrick; Panek, Leah M; Temple, Jennifer L

    2013-06-01

    Caffeine is a commonly used stimulant thought to have ergogenic properties. Most studies on the ergogenic effects of caffeine have been conducted in athletes. The purpose of this study was to test the hypothesis that caffeine reduces ratings of perceived exertion and increases liking of physical activity in sedentary adults. Participants completed treadmill walking at 60% to 70% of their maximal heart rate at baseline and for 6 subsequent visits, during which half of the participants were given caffeine (3 mg/kg) and half given placebo in a sports drink vehicle. To investigate the potential synergistic effects of acute and chronic caffeine on self-determined exercise duration, participants were rerandomized to either the same or different condition for the last visit, creating 4 chronic/acute treatment groups (placebo/placebo, placebo/caffeine, caffeine/placebo, caffeine/caffeine). Participants rated how much they liked the activity and perceived exertion at each visit. There was a main effect of time on liking of physical activity, with liking increasing over time and an interaction of sex and caffeine treatment on liking, with liking of activity increasing in female participants treated with caffeine, but not with placebo. There was no effect of caffeine on ratings of perceived exertion. Individuals who received caffeine on the final test day exercised for significantly longer than those who received placebo. These data suggest that repeated exposure to physical activity significantly increases liking of exercise and reduces ratings of perceived exertion and that caffeine does little to further modify these effects. PMID:23746561

  11. Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice.

    PubMed

    Cometa, Maria Francesca; Buratti, Franca Maria; Fortuna, Stefano; Lorenzini, Paola; Volpe, Maria Teresa; Parisi, Laura; Testai, Emanuela; Meneguz, Annarita

    2007-05-01

    Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects. PMID:17382447

  12. Effects of Intracoronary Administration of Autologous Adipose Tissue-Derived Stem Cells on Acute Myocardial Infarction in a Porcine Model

    PubMed Central

    Lee, Hye Won; Park, Jong Ha; Kim, Bo Won; Ahn, Jinhee; Kim, Jin Hee; Park, Jin Sup; Oh, Jun-Hyok; Choi, Jung Hyun; Cha, Kwang Soo; Hong, Taek Jong; Park, Tae Sik; Kim, Sang-Pil; Song, Seunghwan; Kim, Ji Yeon; Park, Mi Hwa; Jung, Jin Sup

    2015-01-01

    Purpose Adipose-derived stem cells (ADSCs) are known to be potentially effective in regeneration of damaged tissue. We aimed to assess the effectiveness of intracoronary administration of ADSCs in reducing the infarction area and improving function after acute transmural myocardial infarction (MI) in a porcine model. Materials and Methods ADSCs were obtained from each pig's abdominal subcutaneous fat tissue by simple liposuction. After 3 passages of 14-days culture, 2 million ADSCs were injected into the coronary artery 30 min after acute transmural MI. At baseline and 4 weeks after the ADSC injection, 99mTc methoxyisobutylisonitrile-single photon emission computed tomography (MIBI-SPECT) was performed to evaluate the left ventricular volume, left ventricular ejection fraction (LVEF; %), and perfusion defects as well as the myocardial salvage (%) and salvage index. At 4 weeks, each pig was sacrificed, and the heart was extracted and dissected. Gross and microscopic analyses with specific immunohistochemistry staining were then performed. Results Analysis showed improvement in the perfusion defect, but not in the LVEF in the ADSC group (n=14), compared with the control group (n=14) (perfusion defect, -13.0±10.0 vs. -2.6±12.0, p=0.019; LVEF, -8.0±15.4 vs. -15.9±14.8, p=0.181). There was a tendency of reducing left ventricular volume in ADSC group. The ADSCs identified by stromal cell-derived factor-1 (SDF-1) staining were well co-localized by von Willebrand factor and Troponin T staining. Conclusion Intracoronary injection of cultured ADSCs improved myocardial perfusion in this porcine acute transmural MI model. PMID:26446632

  13. Relation between respiratory function and pulmonary hemodynamics before and after intravenous administration of furosemide in acute myocardial infarction.

    PubMed

    Rolla, G; Bucca, C; Sclavo, M; Borello, G; Bellone, E

    1981-01-01

    Static lung volumes, flow volume curve in air and in a helium-oxygen mixture, PaO2 and pulmonary vascular pressures were measured in 16 patients 2 weeks after uncomplicated acute myocardial infarction and repeated 2 h after furosemide 40 mg i.v. administration. The patients with wedge pressure (WP) greater than 18 mm Hg had significantly lower values of FEV1, FEV1/VC%, MEF40 and MEF 25 in comparison with the patients with WE less than 18 mm Hg. A negative correlation was found between both PAP and WP and MEF25 values (p less than 0.001). After furosemide respiratory function tests improved only in patients with a good hemodynamic response to the drug. PaO2 did not change significantly. Airflow response to helium seemed to be a useful test for determining the site of major bronchial compression. PMID:7313341

  14. Acute administration of cocaine reduces metabotropic glutamate receptor 8 protein expression in the rat striatum in vivo

    PubMed Central

    Zhang, Guo-Chi; Vu, Khang; Parelkar, Nikhil K; Mao, Li-Min; Stanford, Ian M.; Fibuch, Eugene E.; Wang, John Q.

    2009-01-01

    Metabotropic glutamate receptors (mGluRs) are densely expressed in the limbic system of mammalian brain. Increasing evidence suggests a critical role of mGluRs in the pathogenesis of various mental illnesses, including drug abuse and addiction. In this study, we investigated the effect of psychostimulant cocaine on protein expression of a specific mGluR subtype, mGluR8, in the rat forebrain in vivo. A rabbit antibody against the extracellular N-terminus of mGluR8 was developed to detect changes in mGluR8 proteins in immunoblot assays. With this antibody, we found that acute systemic injection of cocaine reduced mGluR8 protein levels in the striatum. The reduction of mGluR8 proteins was rapid and transient as it was induced 25 min after cocaine injection and returned to the normal level by 6 h. No significant change in mGluR8 protein levels in the prefrontal cortex and the hippocampus was observed following cocaine administration. These data demonstrate that protein expression of mGluR8 is subject to the modulation by dopamine stimulation. Acute exposure to cocaine results in a dynamic and region-specific downregulation of mGluR8 expression in the striatum. PMID:19010389

  15. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9.

    PubMed

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  16. Excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone in the urine of rats following acute and chronic administration of ethanol.

    PubMed

    Moser, J; Bagchi, D; Akubue, P I; Stohs, S J

    1993-05-01

    Recent studies have shown that xenobiotics which induce oxidative stress result in an increased production and excretion of acetaldehyde (ACT), formaldehyde (FA), acetone (ACON) and malondialdehyde (MDA) in the urine of rats. We have therefore examined the effect of acute and chronic ethanol administration on the excretion of these four lipid metabolites in female Sprague-Dawley rats. Urine samples were collected over dry ice for 6 hr time periods. Aliquots of urine were derivatized with 2,4-dinitrophenylhydrazine HCl, and extracted with n-pentane. High pressure lipid chromatogrpahy (HPLC) was used to quantitate and the hydrazones of the four lipid metabolite products. Following a single, oral, acute dose of 5 g ethanol/kg, urinary excretion of ACT increased approximately 5.8-fold from 6 to 12 hr posttreatment, and decreased thereafter. FA excretion decreased by approximately 50% from 0 to 12 hr, returned to control values in the 18-24 hr urine samples, and was 1.3-fold greater than control values at 42-48 hr. ACON increased 3.1-fold over control values from 0 to 30 hr and remained elevated throughout the remaining 18 hr of the study. The excretion of MDA increased approximately 1.5-fold from 18 to 36 hr, then remained constant through the 48 hr time point. In a separate series of experiments, a chronic oral dose of 0.5 g ethanol/kg was administered to rats for 10 consecutive days and the urinary excretion of the lipid metabolites MDA, FA, ACT and ACON was examined for 11 days, beginning with the first day of ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8352840

  17. Effect of granulocyte colony-stimulating factor administration on renal regeneration after experimentally induced acute kidney injury in dogs.

    PubMed

    Lim, Chae-Young; Han, Jae-Ik; Kim, Seung-Gon; Lee, Chang-Min; Park, Hee-Myung

    2016-02-01

    OBJECTIVE To evaluate the effects of granulocyte colony-stimulating factor (GCSF) administration in dogs with experimentally induced acute kidney injury. ANIMALS 6 healthy dogs. PROCEDURES After induction of kidney injury (day 0) with cisplatin (5 mg/kg, IV), the dogs were randomly assigned into 2 groups (n = 3 dogs/group). Then dogs immediately received GCSF (10 μg/kg) or 1 mL of saline (0.9% NaCl) solution (control group) SC; this treatment was repeated once daily for 4 additional days (days 1 through 4). A once-daily CBC (day 0 to 4), serum biochemical analysis (day 0 to 3), and urinalysis (day 0 to 3) were performed for each dog; samples were collected before administration of cisplatin (day 0) and before treatment with GCSF or saline solution (days 1 through 4). After sample collection and treatment on day 4, all dogs were euthanized; kidney tissue samples underwent histologic evaluation, immunohistochemical analyses, and cytokine profiling via reverse transcriptase PCR assay. RESULTS In the GCSF-treated group, the histologic evaluation and immunohistochemical analyses of kidney tissue revealed less fibrotic change and greater proliferation of renal tubular epithelial cells, compared with findings in the control group. The mRNA profiles of kidney tissue from the GCSF-treated group indicated lower expression of tumor necrosis factor-α and tumor growth factor-β, compared with findings in the control group; however, concentrations of factors related to renal regeneration were not greater in the GCSF-treated group. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that GCSF treatment can impede renal fibrosis and increase proliferation of renal tubules after experimentally induced acute kidney injury in dogs. (Am J Vet Res 2016;77:199-207). PMID:27027715

  18. Basolateral amygdala CB1 cannabinoid receptors are involved in cross state-dependent memory retrieval between morphine and ethanol.

    PubMed

    Ofogh, Sattar Norouzi; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

    2016-09-01

    Ethanol and morphine are largely co-abused and affect memory formation. The present study intended to investigate the involvement of cannabinoid CB1 receptors of the basolateral amygdala (BLA) in cross state-dependent memory retrieval between morphine and ethanol. Adult male Wistar rats received bilateral cannulation of the BLA, and memory retrieval was measured in step-through type passive avoidance apparatus. Our results showed that post-training intraperitoneal (i.p.) administration of morphine (6mg/kg) induced amnesia. Pre-test administration of ethanol (0.5g/kg, i.p.) significantly improved morphine-induced memory impairment, suggesting that there is cross state-dependent memory retrieval between morphine and ethanol. It should be considered that pre-test administration of ethanol (0.1 and 0.5g/kg, i.p.) by itself had no effect on memory retrieval in the passive avoidance task. Interestingly, pre-test intra-BLA microinjection of different doses of WIN55,212-2 (0.1, 0.2 and 0.3μg/rat), a non-selective CB1/CB2 receptor agonist, plus an ineffective dose of ethanol (0.1g/kg, i.p.) improved morphine-induced memory impairment. Intra-BLA microinjection of AM251 (0.4-0.6ng/rat), a selective CB1 receptor antagonist, inhibited the improved effect of ethanol (0.5g/kg, i.p.) on morphine response. Pre-test intra-BLA microinjection of WIN55,212-2 or AM251 had no effect on memory retrieval or morphine-induced amnesia. Taken together, it can be concluded that morphine and ethanol can induce state-dependent memory retrieval. In addition, the BLA endocannabinoid system mediates via CB1 receptors the functional interaction of morphine and ethanol state-dependent memory retrieval which may depend on the rewarding effects of the drugs. PMID:27327764

  19. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens.

    PubMed

    Sun, Haosheng; Maze, Ian; Dietz, David M; Scobie, Kimberly N; Kennedy, Pamela J; Damez-Werno, Diane; Neve, Rachael L; Zachariou, Venetia; Shen, Li; Nestler, Eric J

    2012-11-28

    Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine