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- Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia. [JOURNAL ARTICLE]
- Neuroscience 2014 Jul 19.
The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training subcutaneous (s.c.) administration of morphine (3-7 mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3 and 0.5 mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2 μg/rat) with an ineffective dose of nicotine (0.1 mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2 μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2 μg/rat) or (S)-WAY 100135 (0.25-1 μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.
- African Americans With Cancer Pain Are More Likely to Receive an Analgesic With Toxic Metabolite Despite Clinical Risks: A Mediation Analysis Study. [JOURNAL ARTICLE]
- J Clin Oncol 2014 Jul 21.
Renal impairment is highly prevalent among patients with cancer, and many patients have undiagnosed chronic kidney disease (CKD) from underlying disease, treatment, or both. African American individuals have disproportionate risk factors (diabetes, hypertension) predisposing them to CKD. We investigated whether African American patients are more likely than white patients to receive morphine with 3- and 6-glucuronide metabolites, which are known to be neurotoxic and accumulate in CKD; whether insurance type mediates the relationship between race and the prescriber's opioid selection; and whether the chosen opioid has a resultant negative effect according to race.Patients (N = 182) were recruited from oncology clinics within the University of Pennsylvania Health System. Inclusion was based on self-identified African American or white race, age older than 18 years, and the presence of cancer-related pain plus a prescription for morphine or oxycodone. Kidney function was estimated using the abbreviated Modification of Diet in Renal Disease formula.Patients with CKD who received morphine reported a greater severity of analgesic-related adverse effects than patients with CKD who received oxycodone (P = .010). Controlling for health insurance type, African American patients had 71% lower odds of receiving a prescription of oxycodone than white patients (P < .001). Limiting analysis to those with CKD, the effect of private insurance became insignificant. However, race still remained a significant predictor of the prescribed opioid selection. Race was a strong predictor of adverse effect severity in the presence of CKD, and the type of opioid selection partially mediated this relationship.Reducing racial disparities in the type of opioid prescription and understanding mechanisms of disproportionate opioid-related adverse effects in African American patients might decrease the clinical disparities in cancer pain outcomes.
- Involvement of Moesin in the Development of Morphine Analgesic Tolerance through P-glycoprotein at the Blood-Brain Barrier. [JOURNAL ARTICLE]
- Drug Metab Pharmacokinet 2014 Jul 22.
Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.
- Analgesic tolerance to morphine is regulated by peroxisome proliferator-activated receptor γ (PPARγ). [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Jul 22.
Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of relevant side effects, including drug dependence and addiction. Here, we investigated the role of Peroxisome Proliferator Activated Receptor gamma (PPARγ) on the development of analgesic tolerance to morphine in mice.We monitored analgesia on alternate days using the tail immersion test.The results demonstrated that daily administration of morphine (30 mg/kg, bid) results in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg/kg, bid) significantly attenuated the development and expression of tolerance. However, pre-treatment with GW-9662 (5 mg/kg, bid), a selective PPARγ antagonist completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg/kg, 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 to wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent morphine tolerance development.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 the possibility of combining PPARγ agonists with opioid analgesics to reduce the development of tolerance and possibly to attenuate the potential for opioid abuse.
- Social housing conditions influence morphine dependence and the extinction of morphine place preference in adolescent mice. [JOURNAL ARTICLE]
- Drug Alcohol Depend 2014 Jul 8.
Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP.Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction.Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice.Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use.
- The NO/sGC/PKG signaling pathway in the NAc shell is necessary for the acquisition of morphine-induced place preference. [JOURNAL ARTICLE]
- Behav Neurosci 2014 Aug; 128(4):446-459.
There is evidence that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway in the basal lateral amygdala and hippocampus plays a key role in memory processing, but it is not known if this NO signaling pathway in the nucleus accumbens (Gomes et al., 2006), a known pivotal region in reward memory, is essential for drug-associated reward memory. We therefore investigated the effect of the NO/sGC/PKG signaling pathway in the nucleus accumbens (NAc) on morphine-induced conditioned place preference (CPP). Results showed that a preconditioning microinjection of the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) into the NAc shell, but not into the core, significantly blocked the acquisition of morphine CPP. The blockage effect of L-NAME on the acquisition of CPP was imitated by the neuronal NOS inhibitor 7-nitroindazole, 3-bromo-, sodium salt (7-NI), the sGC inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitor Rp-8Br-PET-cGMPS. The 7-NI- or ODQ-induced effect was reversed by premicroinjection of the sGC activator YC-1 or the PKG activator 8-Br-cGMP in the NAc shell. However, microinfusion of 7-NI, ODQ, or Rp-8Br-PET-cGMPS into the NAc shell or the core had no effect on the expression of morphine CPP. These findings indicate that the NO/sGC/PKG signaling pathway in the NAc shell is critical for the acquisition of morphine-induced place preference, whereas the same signaling pathway in the NAc shell or core is not involved in the retrieval of morphine-induced place preference. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
- Peripheral opioid receptor blockade increases postoperative morphine demands - a randomized, double-blind, placebo-controlled trial. [JOURNAL ARTICLE]
- Pain 2014 Jul 18.
Experimental studies suggest that a large proportion of opioid analgesia can be mediated by peripheral opioid receptors. This trial examined the contribution of such receptors to clinical analgesia induced by intravenous morphine. We hypothesized that the selective blockade of peripheral opioid receptors by methylnaltrexone (MNX) will increase the patients' demand for morphine to achieve satisfactory postoperative pain relief. In a double-blind, placebo-controlled, sequential two-center trial, 50 patients undergoing knee replacement surgery were randomized (1:1) to receive either subcutaneous MNX (0.9 mg/kg) (hospital I: n=14; hospital II: n=11) or saline (hospital I: n=13; hospital II: n=12) at the end of surgery. Primary endpoint was the cumulative amount of intravenous morphine administered during the first 8 hours. Secondary endpoints were pain scores at rest and during movement (by Numerical Rating Scale and McGill Questionnaire), vital signs, adverse side effects and withdrawal symptoms. After MNX, demands for morphine were strongly (by about 40%) increased (hospital I: 35.31 ± 12.99 mg vs. 25.51 ± 7.92 mg, P=0.03; hospital II: 35.42 ± 11.73 mg vs. 24.80 ± 7.84 mg, P=0.02; pooled data: P<0.001; means ± SD). Secondary endpoints were similar in all groups (P>0.05). Thus, a significant proportion of analgesia produced by systemically administered morphine is mediated by peripheral opioid receptors. Drugs that selectively activate such receptors should have the potential to produce powerful clinical pain relief.
- Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge. [JOURNAL ARTICLE]
- Open J Mol Integr Physiol 2013 Nov; 3(4):166-180.
The aim of this study was to determine whether morphine depresses the ventilatory responses elicited by a hypoxic challenge (10% O2, 90% N2) in conscious rats at a time when the effects of morphine on arterial blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient and minute ventilation (VM) had completely subsided. In vehicle-treated rats, each episode of hypoxia stimulated ventilatory function and the responses generally subsided during each normoxic period. Morphine (5 mg/kg, i.v.) induced an array of depressant effects on ABG chemistry, A-a gradient and VM (via decreases in tidal volume). Despite resolution of these morphine-induced effects, the first episode of hypoxia elicited substantially smaller increases in VM than in vehicle-treated rats, due mainly to smaller increases in frequency of breathing. The pattern of ventilatory responses during subsequent episodes of hypoxia and normoxia changed substantially in morphine-treated rats. It is evident that morphine has latent deleterious effects on ventilatory responses elicited by hypoxic challenge.
- Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge. [JOURNAL ARTICLE]
- Open J Mol Integr Physiol 2013 Aug 28; 3(3):134-145.
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.
- Synthesis of Natural Products Containing Cyclohexane Units Utilizing the Ferrier Carbocyclization Reaction. [JOURNAL ARTICLE]
- Chem Rec 2014 Jul 14.
The Ferrier carbocyclization reaction is one of the most powerful transformations of carbohydrates. This reaction provides enantiomerically pure cyclohexanone derivatives from aldohexoses, and is particularly useful in the chiral pool synthesis of cyclohexane-containing natural products from carbohydrates. We have investigated the synthesis of natural products utilizing the Ferrier carbocyclization reaction. This account provides a brief overview of the Ferrier carbocyclization and its application to natural product synthesis. The utility and versatility of the Ferrier carbocyclization reaction are showcased with the syntheses of hygromycin A, lycoricidine, actinobolin, galanthamine, and morphine starting from carbohydrates.