High Doses Of Morphine Research Articles

Evaluation of CART peptide level in rat plasma and CSF: Possible role as a biomarker in opioid addiction

It has been shown previously that cocaine- and amphetamine-regulated transcript (CART) peptide has a modulatory role and homeostatic regulatory effect in motivation to and reward of the drugs of abuse specially psychostimulants. Recent data also showed that in addition to psychostimulants, CART is critically involved in the different stages of opioid addiction. Here we have evaluated the fluctuations in the level of CART peptide in plasma and CSF in different phases of opioid addiction to find out whether CART can serve as a suitable marker in opioid addiction studies. Male rats were randomly distributed in groups of control, acute low-dose (10mg/kg) morphine, acute high-dose morphine (80mg/kg), chronic escalating doses of morphine, withdrawal syndrome precipitated by administration of naloxone (1mg/kg), and abstinent after long-term drug-free maintenance of addicted animals. The level of CART peptide in CSF and plasma samples was measured by enzyme immunoassay. CART peptide concentration in the CSF and plasma was significantly elevated in acute high-dose morphine and withdrawal state animals and down-regulated in addicted rats. In abstinent group, CART peptide level was up-regulated in plasma but not in CSF samples. As the observed results are in agreement with data regarding the CART mRNA and protein expression in the brain reward pathway in opioid addiction phases, it may be suggested that evaluation of CART peptide level in CSF or plasma could be a suitable marker which reflects the rises and falls of the peptide concentration in brain in the development of opioid addiction.

Randomized study of postcesarean analgesia with intrathecal morphine alone or combined with clonidine

Study objectiveTo investigate the efficacy of the combination of intrathecal morphine with clonidine in comparison with 2 doses of intrathecal morphine alone for postcesarean analgesia. DesignProspective, double-blinded, randomized clinical trial. SettingMaternity ward of Hospital Santa Cruz, Curitiba, Paraná, Brazil (operating room and ward). PatientsThe study included 195 American Society of Anesthesiologist I to III singleton parturients undergoing elective cesarean section. InterventionsThe patients were randomized into 3 groups (M50, M100, and M/C). Patients were anesthetized intrathecally with 12 mg of 0.5% hyperbaric bupivacaine and 50 μg or 100 μg morphine (groups M50 and M100, respectively) or 50 μg morphine and 75 μg clonidine (group M/C). MeasurementsThe patients were subsequently assessed for pain levels and side effects at 9 to 11 hours and 22 to 24 hours after the injection. Main resultsThere was no difference in the quality of pain relief among the groups. In all 3 groups, pain was more intense during the first assessment. Pruritus and nausea were more frequent in group M100, and dizziness was more frequent in group M/C; however, these results were statistically insignificant. The group receiving clonidine showed a significantly lower incidence of shivering compared with the other groups. ConclusionsAt these doses, there was no benefit of associating clonidine with morphine to improve postcesarean analgesia. Considering that higher doses of morphine were associated with more side effects, 50 μg of intrathecal morphine alone seems to be a better option for analgesia. The use of clonidine to reduce postoperative shivering must be balanced against the potential risks of hypotension, bradycardia, dizziness, and sedation.

Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain.

In complementary medicine, aromatherapy uses essential oils to improve agitation and aggression observed in dementia, mood, depression, anxiety and chronic pain. Preclinical research studies have reported that the essential oil obtained from bergamot (BEO) fruit (Citrus bergamia, Risso) modifies normal and pathological synaptic plasticity implicated, for instance, in nociceptive and neuropathic pain. Interestingly, recent results indicated that BEO modulates sensitive perception of pain in different models of nociceptive, inflammatory and neuropathic pain modulating endogenous systems. Thus, local administration of BEO inhibited the nociceptive behavioral effect induced by intraplantar injection of capsaicin or formalin in mice. Similar effects were observed with linalool and linalyl acetate, major volatile components of the phytocomplex, Pharmacological studies showed that the latter effects are reversed by local or systemic pretreatment with the opioid antagonist naloxone hydrochloride alike with naloxone methiodide, high affinity peripheral μ-opioid receptor antagonist. These results and the synergistic effect observed following systemic or intrathecal injection of an inactive dose of morphine with BEO or linalool indicated an activation of peripheral opioid system. Recently, in neuropathic pain models systemic or local administration of BEO or linalool induced antiallodynic effects. In particular, in partial sciatic nerve ligation (PSNL) model, intraplantar injection of the phytocomplex or linalool in the ipsilateral hindpaw, but not in the contralateral, reduced PSNL-induced extracellularsignal- regulated kinase (ERK) activation and mechanical allodynia. In neuropathic pain high doses of morphine are needed to reduce pain. Interestingly, combination of inactive doses of BEO or linalool with a low dose of morphine induced antiallodynic effects in mice. Peripheral cannabinoid and opioid systems appear to be involved in the antinociception produced by intraplantar injection of β -caryophyllene, present in different essential oils including BEO. The data gathered so far indicate that the essential oil of bergamot is endowed with antinociceptive and antiallodynic effects and contribute to form the rational basis for rigorous testing of its efficacy in complementary medicine.

Clonidine as a First-Line Sedative Agent After Neonatal Cardiac Surgery: Retrospective Cohort Study.

To determine the cardiovascular tolerance of clonidine used as a first-line sedative after cardiac surgery in small infants. Retrospective chart review. A tertiary and quaternary referral cardiac PICU. All infants younger than 2 months who received a clonidine infusion for sedation after cardiac surgery from October 2011 to July 2013. None. Heart rate, blood pressure, central venous and left atrial pressure, vasoactive inotropic score, volume of fluid bolus, and lactate and central mixed venous saturation were assessed. Preinfusion values were compared with postinfusion values. Of 224 potentially eligible patients, only 23 infants met inclusion criteria, as most patients only received high doses of morphine and some received midazolam instead of clonidine. Clonidine administration was started at a median of 12 hours after surgery (Q1-Q3, 5-23), and infusion rate was 0.5-2 μg/kg/hr for a median duration of 30 hours (Q1-Q3, 12-54). Heart rate decreased (maximal mean decrease: 12% [149 beats/min (SD, 17) to 131 beats/min (SD, 17)]; p < 0.0001). Apart from a transient and limited drop in diastolic blood pressure of 13% (maximal mean decrease: from 42.8 mm Hg [SD, 5.9] to 37.1 mm Hg [SD, 4.0]; p = 0.018), all other cardiovascular variables were stable or improved. A contemporaneous cohort of patients who received midazolam, did so sooner after surgery, stayed longer in the PICU and showed less favorable hemodynamics. IV clonidine as sedative added to morphine in selected patients seems hemodynamically safe. The observed decrease in heart rate and diastolic blood pressure seems of minimal clinical importance as all other hemodynamic variables remained stable or improved. The safety of clonidine given early after cardiac surgery as alternative to midazolam merits further study.

The interaction between morphine and propranolol in chemical and electrical seizure models of mice

Objectives: Morphine and propranolol have different effects on seizure. Several studies have shown interaction between adrenergic and opioid systems in different models. In this study, interaction between morphine and propranolol in different seizure models was examined in mice.Methods: In this study, three seizure models, including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ and electroshock, were examined in mice. Animals were injected with different doses of morphine or propranolol in the 60th and 45th min, before seizure induction, respectively.Results: Acute administration of propranolol or lower doses of morphine induced an anticonvulsant effect in intravenous PTZ, intraperitoneal PTZ and electroshock-induced seizure models; on the contrary, higher doses of morphine exert proconvulsant effects in all three models. Also additive anticonvulsant effect of propranolol and lower doses of morphine was observed in all examined models. The additive anti-seizure effect of propranolol and lower doses of morphine was blocked by naltrexone in intraperitoneal PTZ model. Moreover, the anticonvulsant effect of propranolol was inhibited by naltrexone in intraperitoneal PTZ seizure model of mice. Propranolol restrained the proconvulsant effects in higher doses of morphine in clonic seizures of intravenous and intraperitoneal PTZ models.Discussion: In conclusion, we believe that this is the first study that has indicated the interaction of propranolol and lower doses of morphine in the anticonvulsant effects in three seizure models of intravenous PTZ, intraperitoneal PTZ and electroshock. The involvement of μ-opioid receptor in this interaction was also demonstrated. Simultaneously, we showed the interaction between propranolol and higher doses of morphine in proconvulsant effects.

Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts.

Morphine is an opioid analgesic drug often used for pain relief in cancer patients. However, there is growing evidence that morphine may modulate tumor growth, progression and metastasis. In this study, we evaluated whether morphine modulates cisplatin-induced apoptosis in human nasopharyngeal carcinoma CNE-2 cells and whether morphine affects the antitumor activity of cisplatin on tumor growth in human nasopharyngeal carcinoma CNE-2 xenografts in nude mice. We showed that a pretreatment with morphine (1 μg/ml) inhibited the sensitivity of CNE-2 cells to cisplatin by inhibiting cisplatin-induced CNE-2 cell apoptosis, decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. However, a high dose of morphine (1000 μg/ml) had the opposite effect. We also showed that at a low dose, morphine enhances chemoresistance in an in vivo nasopharyngeal carcinoma (NPC) model by inhibiting cisplatin-induced apoptosis and decreasing neovascularization. Taken together, our results indicate that a low dose of morphine may lead to chemoresistance of cisplatin in NPC models in vitro and in vivo by inhibiting cisplatin-induced apoptosis and decreasing neovascularization.

Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist.

BackgroundMethadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated β-arrestin recruitment.ResultsWe found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of β-arrestin-2 in µ-opioid receptor-overexpressing cells.ConclusionsThese results suggest that methadone may, at least partly, produce its pharmacological effect as a β-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone.

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.

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.

Risk of type 2 diabetes mellitus in female breast cancer patients treated with morphine: A retrospective population-based time-dependent cohort study

AimsWe aimed to examine whether morphine treatment is associated with type 2 diabetes mellitus (T2DM) in female breast cancer patients. MethodsWe conducted a retrospective cohort analysis of the Longitudinal Health Insurance Database for Catastrophic Illness Patients in Taiwan. A total of 31,112 women with breast cancer without T2DM history during the period 2000–2005 were identified, divided into morphine and non-morphine users (8071 and 23,041 patients, respectively), and the hazard ratios of newly diagnosed T2DM during the period 2005–2010 were calculated. We used a Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of T2DM. The dosage of morphine was counted as defined daily dose and its effect was assessed by multivariable Cox proportional hazard regression controlling age, Charlson comorbidity index, outpatient department visits, antipsychotics, and breast cancer drugs. ResultsMorphine users were 1.24 times more likely to suffer from T2DM than non-morphine users (95% CI=1.04–1.49). Risk increased slightly with the morphine dosage, in patients aged 35–49 years, and with tamoxifen, aromatase inhibitors, and antipsychotics treatment. ConclusionsThe incidence of T2DM is associated with morphine treatment in female breast cancer patients. A higher risk was observed in patients aged 35–49 years using higher dose of morphine, and may be increased by tamoxifen and aromatase inhibitors.

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery.

The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3days to 6years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum.

The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function.

Severe opioid withdrawal syndrome after a single dose of nalmefene

Case 1 A 43-year-old man was brought by ambulance to the emergency department (ED) with severe agitation and clinical signs of severe opioid withdrawal approximately 2 h after a single dose of nalmefene (Selincro®, Lundbeck (Switzerland)) for his alcohol dependence. His medical history included paranoid schizophrenia, depression, and alcohol and codeine dependence. He consumed up to two bottles of Makatussin®Hustentropfen (GebropharmaAG, Liestal, Switzerland), a codeine-containing cough medicine, per day (equivalent to 636 mg codeine base per day). The psychiatrist who prescribed the nalmefene was unaware of the extent of the patient’s codeine abuse. The patient needed high bolus doses of midazolam (cumulative dose 25 mg, commenced in the community prior to transfer to the ED), morphine (10 mg), and propofol (40 mg) to treat the agitation. He was transferred to the intensive care unit (ICU) for further monitoring and treatment, where he received midazolam, propofol, morphine, and clonidine by continuous intravenous infusion. After the first 12 h, it was possible to withdraw clonidine and propofol; however, midazolam and morphine were continued for a further 48 h. Attempts to stop the medication before this point resulted in reemergence of the opioid withdrawal symptoms. After 3 days of ICU treatment, we were able to transfer the patient to psychiatric inpatient services.

Hypothermia after accidental intrathecal administration of high-dose morphine

Hypothermia after accidental intrathecal administration of high-dose morphine

High-dose pentazocine antagonizes the antinociception induced by high-dose morphine.

To investigate the effects of high doses of pentazocine on antinociception induced by a high dose of morphine and the role of the kappa-opioid receptors (KORs) in these effects in mice. Sixty-six C57BL/6J mice were pretreated with a KOR antagonist, nor-binaltorphimine (nor-BNI) (10mg·kg(-1)), or a normal saline placebo. All the mice received a subcutaneous injection of morphine (10mg·kg(-1)) 120min later and different doses of pentazocine (3, 10, 30, 56, 100mg·kg(-1)) or a normal saline placebo. A tail pressure test, hot plate test and tail flick test were performed before and at 30, 60, 90 and 120min after the injection of morphine. The tail pressure test, hot plate test and tail flick test showed that pentazocine at doses of 10 to 100mg·kg(-1), but not at 3mg·kg(-1), had significant antagonizing effects on the antinociception induced by high-dose morphine to mechanical and thermal pain, and nor-BNI did not affect antinociception in combination with pentazocine at 10 to 100mg·kg(-1) and morphine at 10mg·kg(-1). High-doses of pentazocine antagonize the antinociception induced by a high-dose of morphine in a dose-dependent manner, and this antagonistic effect is not associated with the activation of KORs.

Causes systémiques ou originales de douleurs thoraciques

Takotsubo syndrome can rarely lead to ‘broken heart’ death. It is probably linked to spasms of coronary arteries induced by stress. Extensive akinesia of the heart apex has been demonstrated together with focal myocardial oedema on MRI and transient lower voltage of QRS on EKG. Several drugs like cocaine, high dose morphine, metamphetamine and cannabis can also induce coronary spasms, as well as some chemotherapies for cancer. Kounis syndrome, including de novo angina in young people together with various allergic features, can follow exposure to contrasts agents or other allergizing products. Right endocarditis leads to painful septic emboli in the lungs. Spontaneous dissections of coronary arteries rarely occur in post-partum, as well as isolated sub-clavian dissections in young women. Pain in basithoracic left flank worsened by exercise associated with transient haematuria is suggestive of nutcracker syndrome due to pinching of left renal vein between aorta and superior mesenteric artery. Hypercalcaemia and hypocalcaemia, carpal tunnel syndrome, and various disorders of dorsal back or spinal cord can also induce chest pain, as well as sternal infections and numerous costal tumours. Auto-inflammatory syndromes (mainly FMF and TRAPS), and various connectivitis and vasculitis can also foster thoracic pain: lupus, rheumatoid arthritis, rheumatoid vasculitis, granulomatous vasculitis, Kawasaki's disease, Behçet, sarcoidosis, polychondritis, IgG4 syndrome, hypereosinophilic syndromes, pulmonary fibrosis, as well as various types of porphyrias and Fabry's disease.

κ-opioid receptor as a key mediator in the regulation of appetitive 50-kHz ultrasonic vocalizations.

Acute administration of high doses of morphine reduced 50-kHz ultrasonic vocalizations (USVs). Although morphine meets the classical criteria for inducing 50-kHz USVs (it causes place preference and induces dopamine release in nucleus accumbens), it also inhibits appetitive vocalizations. The aims of this study were to (i) study the pharmacological impact of κ-opioid (KOR) and μ-opioid receptor (MOR) ligands on the emission of 50-kHz USVs triggered by social interaction after long-term isolation and (ii) analyze the concentrations of the main neurotransmitters in reward-related structures (ventral tegmental area (VTA), nucleus accumbens (NAcc), and medial prefrontal cortex (mPFC)). In an attempt to define the effects of opioid-receptor activation on the reward system, we used a social interaction test (after 21days isolation). HPLC analysis was used to determine the monoamine and amino acid concentrations in reward-related structures. U-50488 (10.0mg/kg), morphine (5.0 and 1.0mg/kg), and naltrexone (5.0mg/kg) decreased, and nor-BNI (10.0mg/kg) increased 50-kHz USVs. Acute pretreatment with nor-BNI or naltrexone reduced the 50-kHz suppression induced via morphine. The biochemical data showed several variations between groups regarding dopamine concentrations, serotonin, and their metabolites; these data may suggest that the levels of emitted ultrasound in the 50-kHz band are inversely proportional to the 5-hydroxyindoleacetic acid (5-HIAA)/3-methoxytyramine (3-MT) ratio in the VTA. These results indicate an important role for KOR in the regulation of 50-kHz USV emissions and suggest that KOR activation may be a key mediator in the regulation of reward responses. Changes in the balance between serotonin and dopamine concentrations in the VTA may be a key predictor for 50-kHz USV emission.

Mechanism of spinal pain transmission and its regulation

Morphine has been widely used for the treatment of acute, chronic, and cancer pain and is considered the strongest analgesic in clinical care. Conversely, morphine-induced analgesia may be accompanied by several side effects. Animal studies have demonstrated that low doses of morphine administered intrathecally can produce reliable analgesia for thermal, mechanical, and chemical nociceptive stimulation. On the other hand, high doses of morphine administered intrathecally may induce spontaneous nociceptive responses such as scratching, biting, and licking in mice as well as agitation and vocalization in rats. In addition, similar nociceptive responses including hyperalgesia, allodynia, and myoclonus have been observed in humans following intrathecal or systemic administration of high-dose morphine. It has been suggested that the spontaneous nociceptive behaviors evoked by high-dose morphine may be mediated by a non-opioid mechanism that is not yet fully understood. This review describes the mechanisms of spontaneous nociceptive behaviors evoked by high-dose morphine focusing on the neurotransmitters/neuromodulators released from primary afferent fibers.

Immunotherapy (IT) with ch14.18/CHO for high-risk neuroblastoma: First results from the randomised HR-NBL1/SIOPEN trial.

10026 Background: The HR-NBL1/SIOPEN trial randomised 2 essential treatment concepts: Randomisation R1 investigated BUMEL superiority (plenary session ASCO 2012), whilst the R2 randomisation tested...

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

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. 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. Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (s.c.)) 24 h after receiving a high dose of morphine (20 mg/kg, s.c.) 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 (i.p.)), PF-3845 (10 mg/kg, i.p.), AM251 (1 or 2.5 mg/kg, i.p.), AM4113 (1 or 2.5 mg/kg, i.p.), and AM6527 (5 mg/kg, oral) were administered prior to conditioning. 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. Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal.

Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses

The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL · min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro-excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3-glucuronide contribute to the dose-dependent excitation observed at high morphine doses.