Ing-kang Ho - Academia.edu (original) (raw)
Papers by Ing-kang Ho
Journal of cellular and molecular medicine, Jan 8, 2015
Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- ... more Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- (KOP), μ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. Previously, we investigated its effects in an in vitro model expressing human MOP and NOP receptors individually or simultaneously (MOP, NOP, and MOP+NOP) in human embryonic kidney 293 cells. Here, we expanded this cell model by expressing human KOP, MOP and NOP receptors individually or simultaneously (KOP, KOP+MOP, KOP+NOP and KOP+MOP+NOP). Radioligand binding with tritium-labelled diprenorphine confirmed the expression of KOP receptors. Immunoblotting and immunocytochemistry indicated that the expressed KOP, MOP and NOP receptors are N-linked glycoproteins and colocalized in cytoplasmic compartments. Acute application of the opioid receptor agonists- U-69593, DAMGO and nociceptin- inhibited adenylate cyclase (AC) activity in cells expressing KOP, MOP and NOP receptors respectively. Buprenorphine, when applied...
Physical therapy, 2014
Lumbar disk degeneration (LDD) has been related to heavy physical loading. However, the quantific... more Lumbar disk degeneration (LDD) has been related to heavy physical loading. However, the quantification of the exposure has been controversial, and the dose-response relationship with the LDD has not been established. The purpose of this study was to investigate the dose-response relationship between lifetime cumulative lifting load and LDD. This was a cross-sectional study. Every participant received assessments with a questionnaire, magnetic resonance imaging (MRI) of the lumbar spine, and estimation of lumbar disk compression load. The MRI assessments included assessment of disk dehydration, annulus tear, disk height narrowing, bulging, protrusion, extrusion, sequestration, degenerative and spondylolytic spondylolisthesis, foramina narrowing, and nerve root compression on each lumbar disk level. The compression load was predicted using a biomechanical software system. A total of 553 participants were recruited in this study and categorized into tertiles by cumulative lifting load ...
Drug and alcohol dependence, Jan 10, 2015
Children of heroin-using women have a higher risk of unfavorable health and developmental outcome... more Children of heroin-using women have a higher risk of unfavorable health and developmental outcomes. Although methadone maintenance treatment (MMT) has been widely used to treat heroin-using pregnant women, potential effects on accessibility and utilization of healthcare service for their offspring are less explored. We used four national registry and health insurance datasets in Taiwan from 2004 to 2009 to form a population-based matched retrospective cohort study. A total of 1056 neonates born to women in the MMT program (857 born before mother's enrollment in the MMT program [BM], 199 born after mother's enrollment in the MMT program [AM]) was established; 10547 matched non-drug [ND] exposed neonates were identified for comparison. Outcome variables included offspring's health insurance coverage and utilization of preventive, outpatient, and emergency room cares in the first year after birth. Infants born to mothers on MMT were more likely to have no or incomplete insu...
International journal of cardiology, Jan 12, 2015
Journal of biomedical science, 2015
Heroin use among young women of reproductive age has drawn much attention around the world. Altho... more Heroin use among young women of reproductive age has drawn much attention around the world. Although methadone is widely used in maintenance therapy for heroin/morphine addiction, the long-term effects of prenatal exposure to methadone and preventative therapy remain unclear. For revealing this question, female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) methadone 5 mg/kg at embryonic day 3 (E3) and then 7 mg/kg from E4 to E20, (3) dextromethorphan (DM) 3 mg/kg, and (4) methadone + DM (the rats received methadone followed by DM treatment), subcutaneously, twice a day from E3 to E20. The body weight, natural withdrawal, pain sensitivity, ED50, conditioned place preference and water maze were conducted at different postnatal stages (P1 to P79) of offspring. The quantitative real-time RT-PCR and electrophysiology were also used to measure the gene expression of opioid receptors in the spinal cord and changes of LTP/LTD in the hippocampus, separately. Prena...
Neuropsychiatric disease and treatment, 2015
Methadone and buprenorphine are widely used for treating people with opioid dependence, including... more Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both m...
![Research paper thumbnail of Modulation of the levels of NMDA receptor subunit mRNA and the bindings of [3H]MK-801 in rat brain by chronic infusion of subtoxic dose of MK-801](https://attachments.academia-assets.com/42265961/thumbnails/1.jpg)
](Neurochemical research, 2001
The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA r... more The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA receptor subunits NR1, NR2A, NR2B, and NR2C were investigated by using in situ hybridization study. Differential assembly of NMDA receptor subunits determines their functional characteristics. Continuous intracerebroventricular (i.c.v.) infusion with MK-801 (1 pmol/10 microl/h) for 7 days resulted in significant modulations in the NR1, NR2A, and NR2B mRNA levels without producing stereotypic motor syndromes. The levels of NR1 mRNA were significantly increased (9-20%) in the cerebral cortex, striatum, septum, and CA1 of hippocampus in MK-801-infused rats. The levels of NR2A mRNA were significantly decreased (11-16%) in the CA3 and dentate gyrus of hippocampus in MK-801-infused rats. In contrast to NR2A, NR2B subunit mRNA levels were increased (10-14%) in the cerebral cortex, caudate putamen, and thalamus. However, no changes of NR2C subunits in cerebellar granule layer were observed. Using...
Previous studies from our laboratory have indicated possible interactions between opioidergic and... more Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the mu-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2mg/kg, i.p.) for a period of 90min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [3H] SCH23390 and [3H] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated mu-opioid receptor knockout mice between 5 and 40min after administration. The results obtained also show that the binding of D2 dopamine receptor in mu-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in mu-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated mu-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking mu-opioid receptor genes.
Journal of Neuroimmune Pharmacology, 2010
Neuroimmune pharmacology is a newly emerging field that intersects with neuroscience, immunology,... more Neuroimmune pharmacology is a newly emerging field that intersects with neuroscience, immunology, and pharmacology and that is seeking avenues for translational research and better understanding of disease mechanisms. It focuses on the immunity of the central nervous system (CNS) which is greatly influenced by endogenous effectors, such as cytokines and neurotransmitters, and by exogenous substances, including therapeutic compounds, infectious pathogens, and drugs of abuse. In this article, we attempt to raise awareness of the pivotal discovery of how those mediators affect the immunity of the CNS in both physiological conditions and processes of certain mental illnesses, including psychiatric disorders, neurodegenerative diseases, and cerebral dysfunctions due to drugs of abuse. The abnormality in cytokine networks, neurotransmitter homeostasis, and other immune responses may be involved in the neuropathology associated with those mental illnesses, and the therapeutic effects of the potential treatments can be attributed, at least partially, to their immunomodulatory activities. However, the resulting inflammatory cytokines from certain treatments frequently cause psychiatric complications. In addition, the poor neuropathological outcomes frequently found among drug abusers with HIV-1 infection appear to be related to the neurotoxic and immunomodulatory effects of the drugs used. Importantly, glial cells, especially microglia and astrocytes, are key players in the immunomodulatory activities in the CNS, and the functioning CNS is largely dependent upon the reciprocal interactions between neurons and glial cells. Therefore, glia-neuron interactions have become a critical issue for further understanding the disease mechanism. From this review, readers will gain insights into the new field of neuroimmune pharmacology, with a focus on the impacts of CNS immunity on the mental illnesses.
International Journal of Drug Policy, 2015
Aims: To identify sociodemographic and clinical factors predicting the overall risk of adverse ob... more Aims: To identify sociodemographic and clinical factors predicting the overall risk of adverse obstetric outcomes and the length of maternal hospital stay among heroin-exposed and methadone-treated women in Taiwan. Methods: Using the retrospective matched cohort study design, 396 births to women on methadone treatment during pregnancy (the methadone-treated group) and 609 to women who started methadone treatment after childbirth (the heroin-exposed group) were identified in the National Methadone Maintenance Program. Adverse pregnancy outcomes were assessed by still birth, low birth weight and preterm delivery. We used multivariate methods and zero-truncated negative binomial regression to evaluate association estimates. Finding: Both heroin-exposed and methadone-treated women had 2-4-fold greater risk of adverse pregnancy outcomes. HIV infection increased the overall risk of adverse pregnancy outcome in the methadone-treated group, whereas being unmarried and having treatment history of substance use disorders increased such risk in the heroin-exposed group. Maternal ages at delivery and healthcare facility used had moderate effects on the length of maternal hospital stay; HIV infection significantly increased the length of hospital stay for women in the heroin-exposed group (adjusted relative risk = 1.32, 95% CI = 1.05-1.68). Conclusions: Our results showed no appreciable differences in the occurrence of adverse obstetric outcomes and the length of maternity hospitalization between the methadone-treated and the heroinexposed women; the profile of sociodemographic and clinical predictors was similar as well. Coordination of addiction treatment and prenatal care may help reduce unfavorable obstetric outcomes among female heroin addicts seeking substitution treatment.
ChemInform, 2000
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Toxicological Sciences, 1994
The outcome of concurrent abuse of cocaine and anabolic steroids is largely unknown and merits in... more The outcome of concurrent abuse of cocaine and anabolic steroids is largely unknown and merits investigation. The present study was designed to determine whether an animal model could be developed for investigation of the toxic responses to simultaneous administration of cocaine and an anabolic steroid, nandrolone decanoate. Twenty-four male spontaneously hypertensive rats (SHR), all 7 weeks of age, were assigned randomly to four groups: (1) control, (2) cocaine, (3) nandrolone, and (4) cocaine plus nandrolone. Metabolic measurements and indirect (tail-cuff) blood pressure and heart rate measurements were performed on all rats every 2 weeks. All drug treatment groups exhibited significantly (p < 0.05) higher levels of blood pressure after 6 weeks of treatment when compared to the control group. Cocaine plus nandrolone group exhibited the lowest heart rate compared to other groups. Rats were euthanized at 13 weeks of age, and different tissues were removed, blotted dry, and weighed. The kidney, levator ani muscle, and seminal vesicle (with prostate glands) weights in both nandrolone-receiving groups were higher than those of the control and cocaine groups. Testicular weights of the cocaine plus nandrolone group were less than those of the control and cocaine groups. Hearts were fixed in 10% buffered formaldehyde before myocardial dimension measurements were performed. The nandrolone group showed increased vertical ventricular diameters when compared to the control and cocaine groups. The nandrolone group also displayed higher vertical ventricular circumferences when compared to all the other groups. Finally, the cocaine plus nandrolone group had the greatest ventricular weights (per 100 g body weight) and left ventricular volumes.(ABSTRACT TRUNCATED AT 250 WORDS)
Obesity, 2010
Obesity, in addition to being a risk factor for cardiovascular and metabolic diseases, has been i... more Obesity, in addition to being a risk factor for cardiovascular and metabolic diseases, has been implicated in degrading cognitive operation (1). Elias et al. (2) found that obesity was associated with lower cognitive functioning in late middleaged and elderly (55-88 years) men, but not women. This association is independent of other cardiovascular risk factors. Gustafson et al. (3) also found that overweight at older ages (79-88 years) is a risk factor for dementia, particularly the Alzheimer's disease. Additionally, obesity in the midlife (40-45 years) is a risk factor for dementia and Alzheimer's disease in American (both sexes) (4) and in Swedish men (5). Impaired spatial memory and hippocampal synaptic plasticity were also reported in genetically obese animal models (6,7). However, instead of genetic factors, consumption of high-fat diet (HFD) is conceived to be a common cause of obesity in humans (8). Therefore, the animal models of HFD-induced obesity could better mimic the pathological changes in obese humans.
Neurochemical Research, 2011
Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we... more Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we compared their effects on adenylate cyclase (AC) activity in human embryonic kidney (HEK) 293 cells stably overexpressing human l-opioid receptor (MOR) and nociceptin/opioid receptor-like 1 receptor (ORL1) simultaneously. After acute exposure, methadone inhibited AC activity; however, buprenorphine induced compromised AC inhibition. When naloxone was introduced after 30 min incubation with methadone, the AC activity was enhanced. This was not observed in the case of buprenorphine. Enhancement of the AC activity was more significant when the incubation lasted for 4 h, and prolonged exposure to buprenorphine elevated the AC activity as well. The removal of methadone and buprenorphine by washing also obtained similar AC superactivation as that revealed by naloxone challenge. The study demonstrated that methadone and buprenorphine exert initially different yet eventually convergent adaptive changes of AC activity in cells coexpressing human MOR and ORL1 receptors.
Life Sciences, 1995
Changes in benzodiazepine binding sites labeled by [3H]flunitrazepan (FNZ) in twenty discrete bra... more Changes in benzodiazepine binding sites labeled by [3H]flunitrazepan (FNZ) in twenty discrete brain regions of rats made tolerant to and dependent upon pentobarbital were examined. Animals were rendered tolerant by intracerebroventricular (i.c.v.) infusion with pentobarbital (300 micrograms/ 10 microliters/ hr for six days) through pre-implanted cannulae connected to osmotic mini-pumps. The pentobarbital dependence was assessed 24 hr after abrupt withdrawal from pentobarbital. In the tolerant rats, a significant increase in [3H]FNZ binding sites was found in layer IV of frontal cortex and the molecular layer of olfactory bulb. [3H]FNZ binding sites in the pentobarbital dependent rats were significantly increased in layers I-III and V-VI of frontal cortex, caudate-putamen, olfactory tubercle, globus pallidus and ventral pallidum, in addition to those observed in the tolerant group. There was, however, no significant difference in the hippocampus and several regions in the hindbrain in either pentobarbital-treated group. Taken together with characteristics of subtypes of benzodiazepine receptors and changes in GABA-benzodiazepine receptor complexes elucidated in our previous studies, these findings suggest that both types of benzodiazepine receptors are involved in the development of pentobarbital intoxication mediated by GABAA receptors.
Life Sciences, 1996
Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesth... more Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesthetics and anticonvulsants. However, prolonged use of the drugs produces physical dependence, and the drugs have a high abuse liability. The gamma-aminobutyric acidA (GABAA) receptor is one of barbiturates' main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates. Recent advances in the study of the GABAA receptor/chloride channel complex allow us to examine possible mechanisms that underlie barbiturate tolerance/dependence in a new light. In this minireview, we mainly focus on molecular and cellular aspects of the action of barbiturates and the possible mechanisms that contribute to development of tolerance to and dependence on barbiturates.
Journal of Neuroscience Research, 2003
Autoradiographic characterization of binding for brain 1 ([ 3 H]CI-977) and 2 ([ 3 H]bremazocine)... more Autoradiographic characterization of binding for brain 1 ([ 3 H]CI-977) and 2 ([ 3 H]bremazocine) in the presence of DAMGO ([D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin), DP-DPE ([D-Pen 2 , D-Pen 5 ]-enkephalin), and U-69,593 opioid receptors, in the presence of different concentrations of a selective unlabeled -opioid receptor antagonist, norbinaltorphimine (nor-BNI), was performed in rats in which dependence on or withdrawal from butorphanol had been established. Dependence was induced by a 72 hr intracerebroventricular (i.c.v.) infusion with butorphanol (26 nmol/l/hr; butorphanol dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 hr following termination (butorphanol withdrawal). IC 50 values from competition studies were estimated by fitting inhibition curves for both 1 -and 2opioid receptor assays. In both dependent and withdrawal groups, the IC 50 values obtained against [ 3 H]CI-977 or [ 3 H]bremazocine with nor-BNI were decreased (ratios of ϳ0.03-0.21 and ϳ0.05-0.42 vs. control, respectively) in brain regions, including frontal cortex, nucleus accumbens, claustrum, dorsal endopiriform nucleus, caudate putamen, parietal cortex, posterior basolateral amygdaloid nucleus, dorsomedial hypothalamus, hippocampus, posterior paraventricular thalamic nucleus, periaqueductal gray, substantia nigra, superficial gray layer of the superior colliculus, ventral tegmental area, and locus coeruleus, compared with control. These results indicate that, in butorphanol-dependent and butorphanol-withdrawal rats, the brain 1 -and 2 -opioid receptors developed a supersensitivity to antagonist binding.
Journal of Neuroscience Research, 2004
The potential involvement of mu-opioid receptors in mediating the changes of toxic signs and musc... more The potential involvement of mu-opioid receptors in mediating the changes of toxic signs and muscarinic receptor bindings after acute administration of irreversible antiacetylcholinesterase diisopropylfluorophosphate (DFP) was investigated. DFP-induced chewing movement and tremors were monitored for a period of 180 min in mu-opioid receptor knockout and wild-type mice. The autoradiographic studies of total, M1, and M2 muscarinic receptors were conducted using [(3)H]quinuclidinyl benzilate, [(3)H]pirenzepine, and [(3)H]AF-DX384 as ligands, respectively. Saline-treated mu-opioid receptor knockout and wild-type mice did not show chewing movement or tremors. Although DFP (1, 2, or 3 mg/kg, subcutaneous injection, s.c.)-induced chewing movement and tremors were shown in a dose-dependent manner, there were no significant differences in tremors induced by 1 or 2 mg/kg of DFP between mu-opioid receptor knockout and wild-type mice. There were also no significant differences in chewing movement induced by all doses of DFP between mu-opioid receptor knockout and wild-type mice. However, DFP (3 mg/kg)-induced tremors in mu-opioid receptor knockout mice were significantly increased over those in wild-type controls. Acetylcholinesterase activity in the striatum of saline-treated mu-opioid receptor knockout mice was significantly higher than that of the wild-type controls. After administration of DFP, acetylcholinesterase activity in the striatum of both mu-opioid receptor knockout and wild-type mice was significantly decreased (more than 36%, 58%, and 94% reduced at the doses of 1, 2, and 3 mg/kg, respectively) than that of their respective saline controls. M2 muscarinic receptor binding in saline-treated mu-opioid receptor knockout mice was significantly lower than that of the wild-type controls in the striatum. However, there were no significant differences in total, M1, or M2 muscarinic receptor binding in the cortex, striatum, or hippocampus of mu-opioid receptor knockout and wild-type mice after DFP administration. Our data show increased DFP-induced tremors, compensatory up-regulation of acetylcholinesterase activity, and compensatory down-regulation of M2 muscarinic receptors in the striatum of mice lacking mu-opioid receptor gene. These results suggest that the enhancement of DFP-induced tremors may be associated with the compensatory up-regulation of acetylcholinesterase activity and compensatory down-regulation of M2 muscarinic receptors in the striatum of mu-opioid receptor knockout mice.
Journal of Food and Drug Analysis, 2013
ABSTRACT Pharmacogenomics is research to study the drug treatment responses in subgroups of patie... more ABSTRACT Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions.
Journal of Biomedical Science, 2010
Background: Abuse of addictive substances is a serious problem that has a significant impact on a... more Background: Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring.
Journal of cellular and molecular medicine, Jan 8, 2015
Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- ... more Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- (KOP), μ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. Previously, we investigated its effects in an in vitro model expressing human MOP and NOP receptors individually or simultaneously (MOP, NOP, and MOP+NOP) in human embryonic kidney 293 cells. Here, we expanded this cell model by expressing human KOP, MOP and NOP receptors individually or simultaneously (KOP, KOP+MOP, KOP+NOP and KOP+MOP+NOP). Radioligand binding with tritium-labelled diprenorphine confirmed the expression of KOP receptors. Immunoblotting and immunocytochemistry indicated that the expressed KOP, MOP and NOP receptors are N-linked glycoproteins and colocalized in cytoplasmic compartments. Acute application of the opioid receptor agonists- U-69593, DAMGO and nociceptin- inhibited adenylate cyclase (AC) activity in cells expressing KOP, MOP and NOP receptors respectively. Buprenorphine, when applied...
Physical therapy, 2014
Lumbar disk degeneration (LDD) has been related to heavy physical loading. However, the quantific... more Lumbar disk degeneration (LDD) has been related to heavy physical loading. However, the quantification of the exposure has been controversial, and the dose-response relationship with the LDD has not been established. The purpose of this study was to investigate the dose-response relationship between lifetime cumulative lifting load and LDD. This was a cross-sectional study. Every participant received assessments with a questionnaire, magnetic resonance imaging (MRI) of the lumbar spine, and estimation of lumbar disk compression load. The MRI assessments included assessment of disk dehydration, annulus tear, disk height narrowing, bulging, protrusion, extrusion, sequestration, degenerative and spondylolytic spondylolisthesis, foramina narrowing, and nerve root compression on each lumbar disk level. The compression load was predicted using a biomechanical software system. A total of 553 participants were recruited in this study and categorized into tertiles by cumulative lifting load ...
Drug and alcohol dependence, Jan 10, 2015
Children of heroin-using women have a higher risk of unfavorable health and developmental outcome... more Children of heroin-using women have a higher risk of unfavorable health and developmental outcomes. Although methadone maintenance treatment (MMT) has been widely used to treat heroin-using pregnant women, potential effects on accessibility and utilization of healthcare service for their offspring are less explored. We used four national registry and health insurance datasets in Taiwan from 2004 to 2009 to form a population-based matched retrospective cohort study. A total of 1056 neonates born to women in the MMT program (857 born before mother's enrollment in the MMT program [BM], 199 born after mother's enrollment in the MMT program [AM]) was established; 10547 matched non-drug [ND] exposed neonates were identified for comparison. Outcome variables included offspring's health insurance coverage and utilization of preventive, outpatient, and emergency room cares in the first year after birth. Infants born to mothers on MMT were more likely to have no or incomplete insu...
International journal of cardiology, Jan 12, 2015
Journal of biomedical science, 2015
Heroin use among young women of reproductive age has drawn much attention around the world. Altho... more Heroin use among young women of reproductive age has drawn much attention around the world. Although methadone is widely used in maintenance therapy for heroin/morphine addiction, the long-term effects of prenatal exposure to methadone and preventative therapy remain unclear. For revealing this question, female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) methadone 5 mg/kg at embryonic day 3 (E3) and then 7 mg/kg from E4 to E20, (3) dextromethorphan (DM) 3 mg/kg, and (4) methadone + DM (the rats received methadone followed by DM treatment), subcutaneously, twice a day from E3 to E20. The body weight, natural withdrawal, pain sensitivity, ED50, conditioned place preference and water maze were conducted at different postnatal stages (P1 to P79) of offspring. The quantitative real-time RT-PCR and electrophysiology were also used to measure the gene expression of opioid receptors in the spinal cord and changes of LTP/LTD in the hippocampus, separately. Prena...
Neuropsychiatric disease and treatment, 2015
Methadone and buprenorphine are widely used for treating people with opioid dependence, including... more Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both m...
Neurochemical research, 2001
The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA r... more The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA receptor subunits NR1, NR2A, NR2B, and NR2C were investigated by using in situ hybridization study. Differential assembly of NMDA receptor subunits determines their functional characteristics. Continuous intracerebroventricular (i.c.v.) infusion with MK-801 (1 pmol/10 microl/h) for 7 days resulted in significant modulations in the NR1, NR2A, and NR2B mRNA levels without producing stereotypic motor syndromes. The levels of NR1 mRNA were significantly increased (9-20%) in the cerebral cortex, striatum, septum, and CA1 of hippocampus in MK-801-infused rats. The levels of NR2A mRNA were significantly decreased (11-16%) in the CA3 and dentate gyrus of hippocampus in MK-801-infused rats. In contrast to NR2A, NR2B subunit mRNA levels were increased (10-14%) in the cerebral cortex, caudate putamen, and thalamus. However, no changes of NR2C subunits in cerebellar granule layer were observed. Using...
Previous studies from our laboratory have indicated possible interactions between opioidergic and... more Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the mu-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2mg/kg, i.p.) for a period of 90min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [3H] SCH23390 and [3H] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated mu-opioid receptor knockout mice between 5 and 40min after administration. The results obtained also show that the binding of D2 dopamine receptor in mu-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in mu-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated mu-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking mu-opioid receptor genes.
Journal of Neuroimmune Pharmacology, 2010
Neuroimmune pharmacology is a newly emerging field that intersects with neuroscience, immunology,... more Neuroimmune pharmacology is a newly emerging field that intersects with neuroscience, immunology, and pharmacology and that is seeking avenues for translational research and better understanding of disease mechanisms. It focuses on the immunity of the central nervous system (CNS) which is greatly influenced by endogenous effectors, such as cytokines and neurotransmitters, and by exogenous substances, including therapeutic compounds, infectious pathogens, and drugs of abuse. In this article, we attempt to raise awareness of the pivotal discovery of how those mediators affect the immunity of the CNS in both physiological conditions and processes of certain mental illnesses, including psychiatric disorders, neurodegenerative diseases, and cerebral dysfunctions due to drugs of abuse. The abnormality in cytokine networks, neurotransmitter homeostasis, and other immune responses may be involved in the neuropathology associated with those mental illnesses, and the therapeutic effects of the potential treatments can be attributed, at least partially, to their immunomodulatory activities. However, the resulting inflammatory cytokines from certain treatments frequently cause psychiatric complications. In addition, the poor neuropathological outcomes frequently found among drug abusers with HIV-1 infection appear to be related to the neurotoxic and immunomodulatory effects of the drugs used. Importantly, glial cells, especially microglia and astrocytes, are key players in the immunomodulatory activities in the CNS, and the functioning CNS is largely dependent upon the reciprocal interactions between neurons and glial cells. Therefore, glia-neuron interactions have become a critical issue for further understanding the disease mechanism. From this review, readers will gain insights into the new field of neuroimmune pharmacology, with a focus on the impacts of CNS immunity on the mental illnesses.
International Journal of Drug Policy, 2015
Aims: To identify sociodemographic and clinical factors predicting the overall risk of adverse ob... more Aims: To identify sociodemographic and clinical factors predicting the overall risk of adverse obstetric outcomes and the length of maternal hospital stay among heroin-exposed and methadone-treated women in Taiwan. Methods: Using the retrospective matched cohort study design, 396 births to women on methadone treatment during pregnancy (the methadone-treated group) and 609 to women who started methadone treatment after childbirth (the heroin-exposed group) were identified in the National Methadone Maintenance Program. Adverse pregnancy outcomes were assessed by still birth, low birth weight and preterm delivery. We used multivariate methods and zero-truncated negative binomial regression to evaluate association estimates. Finding: Both heroin-exposed and methadone-treated women had 2-4-fold greater risk of adverse pregnancy outcomes. HIV infection increased the overall risk of adverse pregnancy outcome in the methadone-treated group, whereas being unmarried and having treatment history of substance use disorders increased such risk in the heroin-exposed group. Maternal ages at delivery and healthcare facility used had moderate effects on the length of maternal hospital stay; HIV infection significantly increased the length of hospital stay for women in the heroin-exposed group (adjusted relative risk = 1.32, 95% CI = 1.05-1.68). Conclusions: Our results showed no appreciable differences in the occurrence of adverse obstetric outcomes and the length of maternity hospitalization between the methadone-treated and the heroinexposed women; the profile of sociodemographic and clinical predictors was similar as well. Coordination of addiction treatment and prenatal care may help reduce unfavorable obstetric outcomes among female heroin addicts seeking substitution treatment.
ChemInform, 2000
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Toxicological Sciences, 1994
The outcome of concurrent abuse of cocaine and anabolic steroids is largely unknown and merits in... more The outcome of concurrent abuse of cocaine and anabolic steroids is largely unknown and merits investigation. The present study was designed to determine whether an animal model could be developed for investigation of the toxic responses to simultaneous administration of cocaine and an anabolic steroid, nandrolone decanoate. Twenty-four male spontaneously hypertensive rats (SHR), all 7 weeks of age, were assigned randomly to four groups: (1) control, (2) cocaine, (3) nandrolone, and (4) cocaine plus nandrolone. Metabolic measurements and indirect (tail-cuff) blood pressure and heart rate measurements were performed on all rats every 2 weeks. All drug treatment groups exhibited significantly (p < 0.05) higher levels of blood pressure after 6 weeks of treatment when compared to the control group. Cocaine plus nandrolone group exhibited the lowest heart rate compared to other groups. Rats were euthanized at 13 weeks of age, and different tissues were removed, blotted dry, and weighed. The kidney, levator ani muscle, and seminal vesicle (with prostate glands) weights in both nandrolone-receiving groups were higher than those of the control and cocaine groups. Testicular weights of the cocaine plus nandrolone group were less than those of the control and cocaine groups. Hearts were fixed in 10% buffered formaldehyde before myocardial dimension measurements were performed. The nandrolone group showed increased vertical ventricular diameters when compared to the control and cocaine groups. The nandrolone group also displayed higher vertical ventricular circumferences when compared to all the other groups. Finally, the cocaine plus nandrolone group had the greatest ventricular weights (per 100 g body weight) and left ventricular volumes.(ABSTRACT TRUNCATED AT 250 WORDS)
Obesity, 2010
Obesity, in addition to being a risk factor for cardiovascular and metabolic diseases, has been i... more Obesity, in addition to being a risk factor for cardiovascular and metabolic diseases, has been implicated in degrading cognitive operation (1). Elias et al. (2) found that obesity was associated with lower cognitive functioning in late middleaged and elderly (55-88 years) men, but not women. This association is independent of other cardiovascular risk factors. Gustafson et al. (3) also found that overweight at older ages (79-88 years) is a risk factor for dementia, particularly the Alzheimer's disease. Additionally, obesity in the midlife (40-45 years) is a risk factor for dementia and Alzheimer's disease in American (both sexes) (4) and in Swedish men (5). Impaired spatial memory and hippocampal synaptic plasticity were also reported in genetically obese animal models (6,7). However, instead of genetic factors, consumption of high-fat diet (HFD) is conceived to be a common cause of obesity in humans (8). Therefore, the animal models of HFD-induced obesity could better mimic the pathological changes in obese humans.
Neurochemical Research, 2011
Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we... more Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we compared their effects on adenylate cyclase (AC) activity in human embryonic kidney (HEK) 293 cells stably overexpressing human l-opioid receptor (MOR) and nociceptin/opioid receptor-like 1 receptor (ORL1) simultaneously. After acute exposure, methadone inhibited AC activity; however, buprenorphine induced compromised AC inhibition. When naloxone was introduced after 30 min incubation with methadone, the AC activity was enhanced. This was not observed in the case of buprenorphine. Enhancement of the AC activity was more significant when the incubation lasted for 4 h, and prolonged exposure to buprenorphine elevated the AC activity as well. The removal of methadone and buprenorphine by washing also obtained similar AC superactivation as that revealed by naloxone challenge. The study demonstrated that methadone and buprenorphine exert initially different yet eventually convergent adaptive changes of AC activity in cells coexpressing human MOR and ORL1 receptors.
Life Sciences, 1995
Changes in benzodiazepine binding sites labeled by [3H]flunitrazepan (FNZ) in twenty discrete bra... more Changes in benzodiazepine binding sites labeled by [3H]flunitrazepan (FNZ) in twenty discrete brain regions of rats made tolerant to and dependent upon pentobarbital were examined. Animals were rendered tolerant by intracerebroventricular (i.c.v.) infusion with pentobarbital (300 micrograms/ 10 microliters/ hr for six days) through pre-implanted cannulae connected to osmotic mini-pumps. The pentobarbital dependence was assessed 24 hr after abrupt withdrawal from pentobarbital. In the tolerant rats, a significant increase in [3H]FNZ binding sites was found in layer IV of frontal cortex and the molecular layer of olfactory bulb. [3H]FNZ binding sites in the pentobarbital dependent rats were significantly increased in layers I-III and V-VI of frontal cortex, caudate-putamen, olfactory tubercle, globus pallidus and ventral pallidum, in addition to those observed in the tolerant group. There was, however, no significant difference in the hippocampus and several regions in the hindbrain in either pentobarbital-treated group. Taken together with characteristics of subtypes of benzodiazepine receptors and changes in GABA-benzodiazepine receptor complexes elucidated in our previous studies, these findings suggest that both types of benzodiazepine receptors are involved in the development of pentobarbital intoxication mediated by GABAA receptors.
Life Sciences, 1996
Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesth... more Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesthetics and anticonvulsants. However, prolonged use of the drugs produces physical dependence, and the drugs have a high abuse liability. The gamma-aminobutyric acidA (GABAA) receptor is one of barbiturates' main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates. Recent advances in the study of the GABAA receptor/chloride channel complex allow us to examine possible mechanisms that underlie barbiturate tolerance/dependence in a new light. In this minireview, we mainly focus on molecular and cellular aspects of the action of barbiturates and the possible mechanisms that contribute to development of tolerance to and dependence on barbiturates.
Journal of Neuroscience Research, 2003
Autoradiographic characterization of binding for brain 1 ([ 3 H]CI-977) and 2 ([ 3 H]bremazocine)... more Autoradiographic characterization of binding for brain 1 ([ 3 H]CI-977) and 2 ([ 3 H]bremazocine) in the presence of DAMGO ([D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin), DP-DPE ([D-Pen 2 , D-Pen 5 ]-enkephalin), and U-69,593 opioid receptors, in the presence of different concentrations of a selective unlabeled -opioid receptor antagonist, norbinaltorphimine (nor-BNI), was performed in rats in which dependence on or withdrawal from butorphanol had been established. Dependence was induced by a 72 hr intracerebroventricular (i.c.v.) infusion with butorphanol (26 nmol/l/hr; butorphanol dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 hr following termination (butorphanol withdrawal). IC 50 values from competition studies were estimated by fitting inhibition curves for both 1 -and 2opioid receptor assays. In both dependent and withdrawal groups, the IC 50 values obtained against [ 3 H]CI-977 or [ 3 H]bremazocine with nor-BNI were decreased (ratios of ϳ0.03-0.21 and ϳ0.05-0.42 vs. control, respectively) in brain regions, including frontal cortex, nucleus accumbens, claustrum, dorsal endopiriform nucleus, caudate putamen, parietal cortex, posterior basolateral amygdaloid nucleus, dorsomedial hypothalamus, hippocampus, posterior paraventricular thalamic nucleus, periaqueductal gray, substantia nigra, superficial gray layer of the superior colliculus, ventral tegmental area, and locus coeruleus, compared with control. These results indicate that, in butorphanol-dependent and butorphanol-withdrawal rats, the brain 1 -and 2 -opioid receptors developed a supersensitivity to antagonist binding.
Journal of Neuroscience Research, 2004
The potential involvement of mu-opioid receptors in mediating the changes of toxic signs and musc... more The potential involvement of mu-opioid receptors in mediating the changes of toxic signs and muscarinic receptor bindings after acute administration of irreversible antiacetylcholinesterase diisopropylfluorophosphate (DFP) was investigated. DFP-induced chewing movement and tremors were monitored for a period of 180 min in mu-opioid receptor knockout and wild-type mice. The autoradiographic studies of total, M1, and M2 muscarinic receptors were conducted using [(3)H]quinuclidinyl benzilate, [(3)H]pirenzepine, and [(3)H]AF-DX384 as ligands, respectively. Saline-treated mu-opioid receptor knockout and wild-type mice did not show chewing movement or tremors. Although DFP (1, 2, or 3 mg/kg, subcutaneous injection, s.c.)-induced chewing movement and tremors were shown in a dose-dependent manner, there were no significant differences in tremors induced by 1 or 2 mg/kg of DFP between mu-opioid receptor knockout and wild-type mice. There were also no significant differences in chewing movement induced by all doses of DFP between mu-opioid receptor knockout and wild-type mice. However, DFP (3 mg/kg)-induced tremors in mu-opioid receptor knockout mice were significantly increased over those in wild-type controls. Acetylcholinesterase activity in the striatum of saline-treated mu-opioid receptor knockout mice was significantly higher than that of the wild-type controls. After administration of DFP, acetylcholinesterase activity in the striatum of both mu-opioid receptor knockout and wild-type mice was significantly decreased (more than 36%, 58%, and 94% reduced at the doses of 1, 2, and 3 mg/kg, respectively) than that of their respective saline controls. M2 muscarinic receptor binding in saline-treated mu-opioid receptor knockout mice was significantly lower than that of the wild-type controls in the striatum. However, there were no significant differences in total, M1, or M2 muscarinic receptor binding in the cortex, striatum, or hippocampus of mu-opioid receptor knockout and wild-type mice after DFP administration. Our data show increased DFP-induced tremors, compensatory up-regulation of acetylcholinesterase activity, and compensatory down-regulation of M2 muscarinic receptors in the striatum of mice lacking mu-opioid receptor gene. These results suggest that the enhancement of DFP-induced tremors may be associated with the compensatory up-regulation of acetylcholinesterase activity and compensatory down-regulation of M2 muscarinic receptors in the striatum of mu-opioid receptor knockout mice.
Journal of Food and Drug Analysis, 2013
ABSTRACT Pharmacogenomics is research to study the drug treatment responses in subgroups of patie... more ABSTRACT Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions.
Journal of Biomedical Science, 2010
Background: Abuse of addictive substances is a serious problem that has a significant impact on a... more Background: Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring.