Opiate Morphine Research Articles

Radiographic and perioperative outcomes following anterior thoracic vertebral body tethering and posterior lumbar spine tethering: a pilot series

Background and context In patients with adolescent idiopathic scoliosis (AIS) of main thoracic and lumbar spine regions, combined anterior thoracic vertebral body tethering and posterior lumbar spine tethering (ATVBT/PLST) is a novel non-fusion treatment option for growth modulation and conservation of motion.Methods Fourteen patients with AIS who underwent ATVBT/PLST with at least 2-year follow-up were included. Primary outcomes included quality of life as assessed by SRS-22 instruments, radiographic analysis, and revision operations. We secondarily reported perioperative metrics and post-operative opiate morphine equivalents (OME). Clinical success was defined as patients who achieved skeletal maturity with ≤ 30° curve magnitude of both their main thoracic and thoracolumbar/lumbar curves and who did not undergo posterior spine instrumentation and fusion (PSIF).ResultsPatients had a mean age of 11.6 years (range 10–14 years), majority were girls (92%), and mean follow-up was 3.0 years (range 2–4.8 years). All patients were skeletally immature with a Risser ≤ 2. Included curves were Lenke 1C, 3C, or 6C. Mean preoperative curve magnitudes were 53° ± 8° (range 45°–65°) main thoracic and 49° ± 9° (range 40°–62°) thoracolumbar/lumbar curves. At most recent follow-up, patients had a mean main thoracic curve of 29° ± 8° (range 15°–40°) and a mean thoracolumbar/lumbar curve of 20° ± 15° (range 4°–35°). 50% required a revision operation. Cable breakage occurred in 43%, which did not always require revision. One patient progressed to thoracic fusion, but no patient underwent lumbar fusion. Patients had a mean SRS-22 outcome score of 4.2 ± 0.4.ConclusionsATVBT/PLST is a potential alternative to spine fusion for select immature patients with AIS at a minimum 2-year follow-up. ATVBT/PLST potentially offers motion conservation at the cost of a higher revision rate. Further study and reporting of results are necessary to refine indications and techniques, which in turn will improve outcomes of this procedure.Level of evidenceLevel IV—Case series without comparative group.

Rational Engineering of (S)-Norcoclaurine Synthase for Efficient Benzylisoquinoline Alkaloids Biosynthesis.

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics/Molecular Mechanics (QM/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale.

Perioperative Outcomes of Open Anterior Vertebral Body Tethering and Instrumented Posterior Spinal Fusion for Skeletally Immature Patients With Idiopathic Scoliosis.

Correcting adolescent idiopathic scoliosis (AIS) without fusion can be achieved with anterior vertebral body tethering (AVBT). However, little is known about the perioperative outcomes, pain control, and clinical outcomes in patients undergoing AVBT compared with instrumented posterior spinal fusion (IPSF). In this retrospective cohort study, we compared pediatric patients with AIS who underwent either AVBT or IPSF. Inclusion criteria were based on the AVBT group, which included primary thoracic idiopathic scoliosis, Risser ≤1, curve magnitude 40 to 70 degrees, age 9 to 15, no prior spine surgery, index surgery between 2014 and 2019, and minimum 2-year follow-up. Patient demographics, perioperative metrics, pain visual analog scale scores, opiate morphine equivalent usage, cost data, and radiographic outcomes were compared. We identified 23 patients who underwent AVBT and 24 matched patients in the IPSF group based on inclusion criteria. Patients undergoing AVBT and PSF were similar in age (12±1 y vs. 13±1 y, P =0.132) and average follow-up time (3.8±1.6 y vs. 3.3±1.4 y, P =0.210). There were 23 female patients (87%) in the AVBT group and 24 female (92%) patients in the IPSF group. Intraoperatively, estimated blood loss (498±290 vs. 120±47 mL, P <0.001) and procedure duration (419±95 vs. 331±83 min, P =0.001) was significantly greater in the IPSF group compared with AVBT. Length of stay was lower in the AVBT group compared with PSF (4±1 vs. 5±2 d, P =0.04). PSF patients had significantly greater total postoperative opiate morphine equivalent use compared with AVBT (2.2±1.9 vs. 5.6±3.4 mg/kg, P <0.001). Overall direct costs following PSF and AVBT were similar ($47,655+$12,028 vs. $50,891±$24,531, P =0.58). Preoperative radiographic parameters were similar between both the groups, with a major thoracic curve at 51±10 degrees for AVBT and 54±9 degrees for IPSF ( P =0.214). At the most recent follow-up, IPSF patients had greater curve reduction to a mean major thoracic curve of 11±7 degrees (79%) compared with 19±10 degrees (63%) in AVBT patients ( P =0.002). Nine patients (39%) required revision surgery following AVBT compared with 4 patients(17%) following IPSF ( P =0.09). In a select cohort of patients, AVBT offers decreased surgical time, blood loss, length of stay, and postoperative opiate usage compared with IPSF. Although IPSF resulted in greater deformity correction at 2-year follow-up, the majority of patients who underwent AVBT had ≤35 major curves and avoided fusion. There is optimism for AVBT as a treatment option for select AIS patients, but long-term complications are still being understood, and the risk for revision surgeries remains high. Level III.

Radiation-induced oral mucositis — radiation-induced oral mucositis: pathogenesis, risk factors, clinical manifestations, prevention, and treatment

This study presents the modern concepts of pathogenesis, risk factors, etiology, clinical manifestations, prevention, and treatment of oropharyngeal mucositis, one of the main complications of radiation therapy for head and neck region cancer. The leading role in the mechanisms of disease development belongs to rapidly dividing cells of the basal layer of the oropharyngeal mucous membrane. This damage is due to both direct (excitation and ionization) and indirect (accumulation of active oxygen and nitrogen compounds, activation of transcription factors, hyperfunction of pro-inflammatory cytokines, etc.) action of ionizing radiation on the most important biological molecules and supramolecular structures (polynucleotides, nucleoproteins, phospholipids, etc.). The main risk factors for mucositis include the localization and size of the tumor, the amount of radiation dose to the oral region, and individual body characteristics (young age, pernicious habits, metal structures of dentures, a history of periodontal disease, etc.). The disease severity is described from mild (erythema and moderate pain that does not require analgesia) to severe (ulceration, hemorrhage, necrosis, and other symptoms) to establishment necessary prescription of effective means of pathogenetic and symptomatic therapy. The main means and methods of prevention of radiation-induced mucositis include the following: non-steroidal anti-inflammatory drug benzydamine, means of protection against oxidative stress glutamine, and drugs with a complex stimulating effect on wound healing processes. Drug therapy for mucositis involves the use of benzydamine; the tricyclic antidepressant doxepin; and a gel consisting of polyvinylpyrrolidone (Belclaiz), mucolytic acetylcysteine. When non-narcotic analgesics are ineffective, low doses of opiates (fentanyl, morphine, and methadone) are used in oral, transdermal, or parenteral dosage forms, as well as low-intensity laser therapy. The most important components of the etiopathogenetic therapy of the disease include antiviral drugs (acyclovir and valacyclovir) and fungicides (clotrimazole, fluconazole, and itraconazole). Enteral nutrition difficulty indicates nasogastric or nasojejunal tube usage, and in more serious cases, surgical methods such as gastro- or jejunostomy.

Reduction in Opiate Use, Pain, Nausea, and Length of Stay After Implementation of a Bariatric Enhanced Recovery After Surgery Protocol.

Evaluate adherence to bariatric surgery enhanced recovery after surgery (ERAS) protocols in pre-operative, operative, and post-operative phases, and to compare opiate use, nausea control, and length of stay (LOS) versus historical controls. A retrospective, observational cohort study was conducted to evaluate adherence to ERAS protocols and compare opiate and antiemetic use, pain intensity, and LOS versus those of traditional care (TC) patients preceding protocol implementation at Erie County Medical Center, a community-based hospital in Buffalo, NY, USA. One hundred ERAS and TC patients were compared. Patients were similar in age (42.5 years), gender (female, ~ 80%), race (~ 80 white), and BMI (47 kg/m2). The primary procedure performed was sleeve gastrectomy (89% ERAS, 86% TC). Protocol adherence was high for ERAS phases: prior to admission (85-98%), pre-operative (96-100%), operative (93-99%), post-anesthesia care unit (PACU) (55-61%), and floor (86-98%). Opiate morphine milligram equivalent (MME) was reduced in ERAS vs. TC in hospital by 73% (43.5 ± 42.4 vs. 160 ± 116; p < 0.001), discharge prescribing by 53% (34.8 ± 38.2 vs. 74 ± 125 MME; p = 0.003), and in total by 69% (78.3 ± 67.5 vs. 252 ± 160; p < 0.001). Despite lower opiate use, ERAS had lower pain intensity entering PACU (1.1 ± 1.8 vs. 1.9 ± 2.6; p < 0.011), leaving PACU (1.7 ± 1.5 vs. 2.9 ± 1.5; p < 0.001), and floor day 0 (5.0 ± 2.1 vs. 5.9 ± 1.8; p < 0.001). Fewer ERAS required antiemetic day 0 (63% vs. 94%; p < 0.001). ERAS were discharged in fewer hours than TC (41.1 ± 15.5 vs. 52.1 ± 18.9 h; p < 0.001). Bariatric surgery ERAS protocols were implemented with a high rate of adherence and yielded profound reduction in operative and post-operative opiate use while improving pain control and nausea management in hospital and decreasing LOS.

Inhalational Anesthetics Induce Neuronal Protein Aggregation and Affect ER Trafficking

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Fluorescently Labeled Morphine Derivatives for Bioimaging Studies.

Opioids, like morphine, are the mainstay analgesics for the treatment and control of pain. Despite this, they often exhibit severe side effects that limit dose; patients often become tolerant and dependent on these drugs, which remains a major health concern. The analgesic actions of opioids are primarily mediated via the μ-opioid receptor, a member of the G protein-coupled receptor superfamily. Thus far, development of small molecule fluorescent ligands for this receptor has resulted in antagonists, somewhat limiting the use of these probes. Herein, we describe our work on the development of a small molecule fluorescent probe based on the clinically used opiate morphine and initial characterization of its behavior in cell-based assays.

Analgesic Effects of 5-Alkyloxy-4-amino-2(5H)-furanones as Cholecystokinin-2 Antagonists.

4-Amino-2(5H)-furanones were synthesized in high yields over two synthetic steps from readily available mucochloric acid. These 5-alkyloxy-4-amino-2(5H)-furanones were screened in a ([125]) I-CCK-8 radioligand receptor binding assay for CCK2 affinity and novel active ligands in the nanomolar range were identified. SAR was optimized leading to the cyclohexyl derivative 25 with an IC50 of 27 nM. Furanone 18 was obtained as a stable crystalline material with an IC50 of 85 nM, but had a higher CCK2 selectivity. It was subsequently tested in the isolated guinea pig ileum assay with sulfated CCK8 , and the CCK antagonizing properties of the ligand were confirmed. The CCK2 selective antagonist 18 was found to potentiate analgesia in the tail flick assay in mice, for the strong opiate morphine, the partial opiate agonist tramadol and the tricyclic antidepressant desimipramine.

New challenges are “brewing” for the regulation of opiates.

Opioids, including the naturally occurring opiates morphine and codeine, are commonly prescribed medications for the treatment of chronic pain. Opioids for chronic pain are variably effective, since tolerance may develop with extended use. Because of their highly addictive nature and the sensation of euphoria commonly produced, opioids are often abused recreationally. Potential sources of opioids for recreational abuse include the diversion of prescription medications and illegal street production. The opium poppy plant, Papaver somniferum, is the natural source for the opiates morphine and codeine, both of which produce analgesic effects, as well as thebaine, which is a precursor to synthetic opioids. Although chemical syntheses of morphine have been published since the 1950s, commercial production …

Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.

Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca2+]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca2+]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca2+]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca2+]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.

Patented Routes for the Preparation of the Morphinan Derivatives Hydromorphone and Hydrocodone Via Catalytic Isomerization

Hydromorphone and hydrocodone are widely used narcotic analgesics. In this mini-review article, processes for the preparation of these semi-synthetic opioids from the naturally occurring opiates morphine and codeine, respectively, via catalytic isomerization of the allylic alcohol unit of the latter are discussed. Relevant patents in the field are presented. Keywords: Codeine, hydrocodone, hydromorphone, morphinan derivatives, morphine, redox isomerization of allylic alcohols, transition-metal complexes.

Glucuronidation of Paracetamol by Human Liver Microsomes in vitro

In this study, glucuronidation of paracetamol (CAS 103-90-2) by human liver microsomes and the effects of aliphatic alcohols and opiates were investigated. Paracetamol glucuronidation was optimised for various incubation conditions. Ten different aliphatic alcohols and the opiates morphine, codeine and dihydrocodeine were analysed as inhibitors of paracetamol glucuronidation. Furthermore, the effects of paracetamol on morphine-3 and codeine glucuronidation were investigated. Enzyme kinetic analysis was carried out via determination of the parameters Km, Vmax, Ki and the type of inhibition. Except for methanol and ethanol, all Investigated alcohols inhibited glucuronidation of paracetamol. Ki values ranged between 4.59 mmol/l (n-pentanol) and 340.54 mmol/l (2-propanol). Extent of inhibition strongly depended on the structure and clearly increased with the length of the alkyl chain. All tested opiates inhibited paracetamol glucuronidation with Ki values between 4.02 mmol/l (dihydrocodeine) and 11.44 mmol/l (morphine). Paracetamol itself turned out to be an inhibitor of opiate glucuronidation. The apparent Ki values were 4.62 mmol/l (inhibition of morphine-3 glucuronidation) and 9.44 mmol/l (inhibition of codeine glucuronidation). A mixed inhibition type was determined for all substances. The in vitro studies show a great inhibition potential for the analysed substances. Transferring the results to the in vivo situation, a higher liver toxicity of paracetamol can be assumed, if concomitantly a lot of alcoholic beverages with congener alcohols--e.g. fruit schnapps or whisky--are drunk or if opiates--as analgesics or narcotics--are taken in higher doses.

The standardization of results on hair testing for drugs of abuse: An interlaboratory exercise in Lombardy Region, Italy

Hair testing for drugs of abuse is performed in Lombardy by eleven analytical laboratories accredited for forensic purposes, the most frequent purposes being driving license regranting and workplace drug testing. Individuals undergoing hair testing for these purposes can choose the laboratory in which the analyses have to be carried out. The aim of our study was to perform an interlaboratory exercise in order to verify the level of standardization of hair testing for drugs of abuse in these accredited laboratories; nine out of the eleven laboratories participated in this exercise. Sixteen hair strands coming from different subjects were longitudinally divided in 3-4 aliquots and distributed to participating laboratories, which were requested to apply their routine methods. All the participants analyzed opiates (morphine and 6-acetylmorphine) and cocainics (cocaine and benzoylecgonine) while only six analyzed methadone and amphetamines (amphetamine, methamphetamine, MDMA, MDA and MDEA) and five Δ(9)-tetrahydrocannabinol (THC). The majority of the participants (seven labs) performed acidic hydrolysis to extract the drugs from the hair and analysis by GC-MS, while two labs used LC-MS/MS. Eight laboratories performed initial screening tests by Enzyme Multiplied Immunoassay Technique (EMIT), Enzyme-linked Immunosorbent Assay (ELISA) or Cloned Enzyme Donor Immunoassay (CEDIA). Results demonstrated a good qualitative performance for all the participants, since no false positive results were reported by any of them. Quantitative data were quite scattered, but less in samples with low concentrations of analytes than in those with higher concentrations. Results from this first regional interlaboratory exercise show that, on the one hand, individuals undergoing hair testing would have obtained the same qualitative results in any of the nine laboratories. On the other hand, the scatter in quantitative results could cause some inequalities if any interpretation of the data is required.

Morphine Alters M. bovis Infected Microglia’s Ability to Activate γδ T Lymphocytes

Microglia, the macrophages of the central nervous system (CNS), are both the principle target cells for Mycobacterium infection in the CNS and serve a critical role in defense of the brain. If microglia's functions are altered due to immunosuppressive agents such as opiates, perturbation in defense of the brain may occur, including defense against CNS Tuberculosis. This study was designed to determine if Mycobacterium infected microglia activate γδT lymphocytes and if the opiate morphine alters the capability of microglia to activate γδT lymphocytes. γδT lymphocytes proliferated, produced IFN-γ, and demonstrated cytolytic response upon exposure to Mycobacterium bovis infected microglia. IFN-γ, and antigen specific cytotoxicity were both markedly impaired due to morphine treatment.

Morphine induces splenocyte trafficking into the CNS.

Opioids significantly alter functional responses of lymphocytes following activation. The opiate Morphine, alters the Th1 to Th2 response and modulates functional responses such as cytolytic activity and T-cell proliferation. Although there has been extensive research involving morphine's effects on lymphocytes, little is known about the effects morphine has on lymphocyte trafficking. The objective of the study was to use in vivo bioluminescent imaging to determine morphine's effect on the trafficking pattern of splenocytes systemically and into the CNS either in a naïve state or following a neuroinflammatory stimulus. A neuroinflammatory response was induced by intracerebrally administering a DNA IFN-γ DNA plasmid into morphine-dependent or placebo wildtype mice. Mice with or without a neurostimulus received adoptively transferred firefly luciferase transgenic splenocytes and imaged. Morphine dependence significantly altered the inherent ability of splenocytes to traffic into the spleen, and lead to non-directed chaotic trafficking throughout the animal, including into the CNS. The morphine-mediated effects on trafficking were blocked by the antagonist naltrexone. Morphine dependence intensified splenocyte infiltration into the CNS following neuroinflammation induced by IFN-γ gene transfer. The study precented determined that morphine severely altered the ability of non-activated splenocytes to home to the spleen, inducing extrasplenic trafficking thoughout the animal. In addition to altering the ability of naive splenocyte to traffic to the spleen, this study demonstrated that morphine profoundly exacerbated lymphocyte infiltration into the CNS following a neurostimulus.

ChemInform Abstract: Recent Advances in Endomorphin Engineering

AbstractReview: 171 refs.

범밀도 함수법과 Molecular Descriptor를 이용한 모르핀 유도체에 대한 분자 모델링 연구

마약인 모르핀, 헤로인, 코데인, 펜타조신 그리고, 버프레노파인에 대하여 범밀도함수이론에 근거하여 계산 연구를 수행하였다. 약물특이 분자단과 치환기의 기하학적 파라미터는 B3LYP/6-31+G(d) 레벨로 계산하였고, 전자의 구조는B3LYP/6-311++G(d,p) 레벨로 같은 혼성 범함수를 사용하여 계산하였다. 원자의 전하분포는 Mulliken 개체 수 분석에 의하여 구하였다. 보고된 생물학적 활성, 계산된 분배 계수, 전자 및 기하학적 분석을 토대로 펜타조신과 버프레노파인을 새로 제시된 유사화합물에 대한 모델화합물로 선택하였으며, 이들 유사화합물에 대하여 연구한 뒤, 모델화합물과 비교하였다. 본 연구 결과는 약물특이 분자단의 기하학적 구조와 전자 구조가 다른 치환기의 존재 하에서도 변함없이 유지된다는 것을 보여주었다. 제시된 유사화합물들도 모델 분자의 특성을 갖고 있기 때문에, 이들 유사화합물들도 생물학적 활성을 나타낼 것 같다. Computational studies were carried out on the opiates morphine, heroin, codeine, pentazocine, and buprenorphine, under the density functional theory. The geometric parameters of the pharmacophore and substituents were evaluated at the B3LYP/6-31+G(d) level of theory. The electronic structure calculations were performed using the same hybrid functional at the B3LYP/6-311++G (d,p) level of theory. The atomic charges were obtained by Mulliken population analysis. Given the reported biological activity, calculated partition coefficients, and electronic and geometric analysis, pentazocine and buprenorphine were chosen as models for proposed analogues. These analogues were then studied and compared with the model molecules. The study reveals that the geometry and electronic structure of the pharmacophore remains consistent in the presence of different substituents. Because the proposed analogues preserve the studied properties of the model molecules, it is likely that these analogues display biological activity.

Challenging Small Human Hepatocytes with Opiates: Further Characterization of a Novel Prototype Bioartificial Liver

Bioartificial liver (BAL) systems can take over liver functions in patients undergoing liver failure until transplantation. Recently, a novel prototype rotary BAL has been developed using small human hepatocytes (SH). This study investigated the metabolism of opiates morphine and methadone in the BAL and their influence on the basic cell culture parameters, viability, and growth of SH. Opiates may be present in patients due to pain therapy, anticancer treatment, or drug abuse. Cells were cultivated in the BAL for a total of 12 days and exposed twice to 100 microg/L of morphine or methadone. Morphine and methadone concentrations were analyzed using gas chromatography with a mass spectrometry detector. Further, the production of albumin, lactate dehydrogenase release, lactate release, urea production, and glucose consumption were measured. Cell viability and growth were determined by confocal microscopy. Cytochrome P 3A4 and uridindiphosphat (UDP) glucuronosyl transferase 2B7 in SH were analyzed by western blot. The mean cell density during treatment was 5.5 +/- 0.7 x 10(6) cells/mL (n = 6) and was not altered significantly by the opiates. Cell viability stayed above 90%. Morphine was not reduced by SH and was a stress factor as determined by decreased metabolic activity. On the other hand, SH metabolized methadone showing first-order kinetics: the first-order rate constant k = 0,019, half-life t(1/2) = 36 h. Methadone metabolism led to decreased urea and albumin production. The expression of cytochrome P 3A4, mainly responsible for methadone metabolism, was proved in SH. The prototype BAL is basically suited to support liver functions, provided patients receive therapy with methadone.

Septal co-infusions of glucose with the benzodiazepine agonist chlordiazepoxide impair memory, but co-infusions of glucose with the opiate morphine do not

We have found repeatedly that medial septal (MS) infusions of glucose impair memory when co-infused with the γ-amino butyric acid (GABA) agonist muscimol. The present experiments sought to determine whether the memory-impairing effects of this concentration of glucose would generalize to another GABA A receptor agonist and to an agonist from another neurotransmitter system that is known to impair memory. Specifically, we determined whether the dose of glucose that produces memory deficits when combined with muscimol in the MS would also impair memory when co-infused with the GABA A receptor modulator chlordiazepoxide (CDP) or the opiate morphine. Male Sprague–Dawley rats were given MS co-infusions and then 15 min later tested for spontaneous alternation or given shock avoidance training (retention tested 48 h later). The results showed that MS infusions of the higher dose of glucose with morphine did not produce memory deficits, whereas, the performance of rats given MS co-infusions of CDP with glucose was impaired. These findings suggest that the memory-impairing effects of brain glucose administration may involve an interaction with the GABA A receptor.

The effect of opioids and their antagonists on the nocifensive response of Caenorhabditis elegans to noxious thermal stimuli

Opiates modulate nociception in vertebrates. This has also been demonstrated in a number of invertebrate models. Herein, the effect of the opiate morphine and opioid neuropeptides Endomorphin 1 and 2 on the thermal avoidance (Tav) behavior of Caenorhabditis elegans is explored. Adult wild-type C. elegans N2 were collected from NGM plates using M9 buffer and exposed to morphine and endomorphine 1 and 2 in concentrations between 10(-8) and 10(-4) M (2.5 pmol/mg to 25 nmol/mg) for 30 min and tested for Tav. The opioid receptor antagonists Naloxone and CTOP were tested in combination with the drugs. Forty-seven percentage of the morphine exposed worms exhibited a class I response versus 76% of the control group (P < 0.001). Endomorphin 1 and 2 also caused a statistically significant reduction in class I responses, 36 and 39%, respectively. These effects were reversed with Naloxone and CTOP. Thermonocifensive behavior in C. elegans is modulated by opioids.