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PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.
de Guglielmo G, Melis M, De Luca MA, Kallupi M, Li HW, Niswender K, Giordano A, Senzacqua M, Somaini L, Cippitelli A, Gaitanaris G, Demopulos G, Damadzic R, Tapocik J, Heilig M, Ciccocioppo R
(2015) Neuropsychopharmacology 40: 927-37
MeSH Terms: Anilides, Animals, Conditioning, Operant, Dopamine, Dopaminergic Neurons, Heroin, Hypoglycemic Agents, Male, Mice, Transgenic, Morphine, Narcotics, Nucleus Accumbens, PPAR gamma, Pioglitazone, Prefrontal Cortex, Rats, Rats, Wistar, Self Administration, Synaptic Transmission, Thiazolidinediones, Time Factors, Ventral Tegmental Area, gamma-Aminobutyric Acid
Show Abstract · Added February 19, 2015
PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.
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23 MeSH Terms
Narcotic Use and Postoperative Doctor Shopping in the Orthopaedic Trauma Population.
Morris BJ, Zumsteg JW, Archer KR, Cash B, Mir HR
(2014) J Bone Joint Surg Am 96: 1257-1262
MeSH Terms: Adult, Drug Prescriptions, Female, Humans, Male, Morphine, Musculoskeletal System, Narcotics, Opioid-Related Disorders, Pain, Postoperative, Prospective Studies, United States
Show Abstract · Added February 19, 2015
BACKGROUND - The negative consequences of narcotic use and diversion for nonmedical use are on the rise. A growing number of narcotic abusers obtain narcotic prescriptions from multiple providers ("doctor shopping"). This study sought to determine the effects of multiple postoperative narcotic providers on the number of narcotic prescriptions, duration of narcotics, and morphine equivalent dose per day in the orthopaedic trauma population.
METHODS - Our prospective cohort study used the state-controlled substance monitoring database to identify all narcotic prescriptions filled three months prior to admission and six months following discharge for enrolled patients. Patients were assigned into two groups: a single narcotic provider group with prescriptions only from the treating surgeon (or extenders) or a multiple narcotic provider group with prescriptions from both the treating surgeon and an additional provider or providers.
RESULTS - Complete data were available for 130 of 151 eligible patients. Preoperative narcotic use, defined by three or more narcotic prescriptions within three months of admission, was noted in 8.5% of patients. Overall, 20.8% of patients sought multiple narcotic providers postoperatively. There were significant increases in postoperative narcotic prescriptions (p < 0.001) between the single narcotic provider group (two prescriptions) and the multiple narcotic provider group (seven prescriptions), in duration of postoperative narcotic use (p < 0.001) between the single narcotic provider group (twenty-eight days) and the multiple narcotic provider group (110 days), and in morphine equivalent dose per day (p = 0.002) between the single narcotic provider group (26 mg) and the multiple narcotic provider group (43 mg). Patients with a high school education or less were 3.2 times more likely to seek multiple providers (p = 0.02), and patients with a history of preoperative narcotic use were 4.5 times more likely to seek multiple providers (p < 0.001).
CONCLUSIONS - There is a 20.8% prevalence of postoperative doctor shopping in the orthopaedic trauma population. Patients with multiple postoperative narcotic providers had a significant increase in postoperative narcotic prescriptions, duration of narcotics, and morphine equivalent dose per day.
Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.
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12 MeSH Terms
Preoperative narcotic use and its relation to depression and anxiety in patients undergoing spine surgery.
Armaghani SJ, Lee DS, Bible JE, Archer KR, Shau DN, Kay H, Zhang C, McGirt MJ, Devin CJ
(2013) Spine (Phila Pa 1976) 38: 2196-200
MeSH Terms: Adolescent, Adult, Aged, Anxiety, Depression, Female, Humans, Male, Middle Aged, Narcotics, Pain Measurement, Postoperative Complications, Prospective Studies, Psychiatric Status Rating Scales, Spine, Surveys and Questionnaires, Treatment Outcome, Young Adult
Show Abstract · Added February 19, 2015
STUDY DESIGN - Prospective review of registry data at a single institution from October 2010 to June 2012.
OBJECTIVE - To assess whether the amount of preoperative narcotic use is associated with preoperative depression and anxiety in patients undergoing spine surgery for a structural lesion.
SUMMARY OF BACKGROUND DATA - Previous work suggests that narcotic use and psychiatric comorbidities are significantly related. Among other psychological considerations, depression and anxiety may be associated with the amount of preoperative narcotic use in patients undergoing spine surgery.
METHODS - Five hundred eighty-three patients undergoing lumbar (60%), thoracolumbar (11%), or cervical spine (29%) were included. Self-reported preoperative narcotic consumption was obtained at the initial preoperative visit and converted to daily morphine equivalent amounts. Preoperative Zung Depression Scale (ZDS) and Modified Somatic Perception Questionnaire (MSPQ) scores were also obtained at the initial preoperative visit and recorded as measures of depression and anxiety, respectively. Resistant and robust bootstrapped multivariable linear regression analysis was performed to determine the association between ZDS and MSPQ scores and preoperative narcotics, controlling for clinically important covariates. Mann-Whitney U tests examined preoperative narcotic use in patients who were categorized as depressed (ZDS ≥ 33) or anxious (MSPQ ≥ 12).
RESULTS - Multivariable analysis controlling for age, sex, smoking status, preoperative employment status, and prior spinal surgery demonstrated that preoperative ZDS (P = 0.006), prior spine surgery (P = 0.007), and preoperative pain (0.014) were independent risk factors for preoperative narcotic use. Preoperative MSPQ (P = 0.083) was nearly a statistically significant risk factor. Patients who were categorized as depressed or anxious on the basis of ZDS and MSPQ scores also showed higher preoperative narcotic use than those who were not (P < 0.0001).
CONCLUSION - Depression and anxiety as assessed by ZDS and MSPQ scores were significantly associated with increased preoperative narcotic use, underscoring the importance of thorough psychological and substance use evaluation in patients being evaluated for spine surgery.
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18 MeSH Terms
Changes in cotherapies after initiation of disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis.
Kawai VK, Grijalva CG, Arbogast PG, Curtis JR, Solomon DH, Delzell E, Chen L, Ouellet-Hellstrom R, Herrinton L, Liu L, Mitchel EF, Stein CM, Griffin MR
(2011) Arthritis Care Res (Hoboken) 63: 1415-24
MeSH Terms: Adrenal Cortex Hormones, Adult, Aged, Anti-Inflammatory Agents, Non-Steroidal, Antirheumatic Agents, Arthritis, Rheumatoid, Cohort Studies, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Hydroxychloroquine, Isoxazoles, Leflunomide, Male, Methotrexate, Middle Aged, Narcotics, Retrospective Studies, Sulfasalazine, Time Factors, Treatment Outcome, Tumor Necrosis Factor-alpha
Show Abstract · Added December 10, 2013
Objective. We hypothesized that initiation of a new disease-modifying antirheumatic drug (DMARD) for treatment of rheumatoid arthritis (RA) would decrease the use of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and narcotics.Methods. Using administrative databases, we assembled 4 retrospective cohorts of RA patients (1998-2005) and identified 5 groups initiating DMARD regimens: methotrexate (MTX) with (new MTX) or without (first MTX) use of other nonbiologic DMARDs in the previous year; new hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ; new HCQ/SSZ)and new leflunomide (new LEF), both with previous use of MTX; and new tumor necrosis factor α (TNFα) antagonists(new anti-TNF). We compared within-person differences in any use of cotherapies (≥ prescription) between the 6 months before and the 6-12 months after DMARD initiation.Results. Among 32,476 DMARD initiators, the prevalence of corticosteroid, NSAID, and narcotic use increased by 15%, 5%,and 6%, respectively, in the 6 months before initiation compared to the previous 6 months, suggesting worsening of the disease. In the 6-12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% (95% confidence interval [95% CI] 8.4-9.4%) for corticosteroids and 12.9% (95%CI 12.3-13.4%) for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5%; 95% CI 1.9-3.0%).Conclusion. Use of all 3 cotherapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6-12 months after initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.
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23 MeSH Terms
The impact of parenteral narcotic choice in the development of acute chest syndrome in sickle cell disease.
Lewing K, Britton K, DeBaun M, Woods G
(2011) J Pediatr Hematol Oncol 33: 255-60
MeSH Terms: Acute Disease, Adolescent, Anemia, Sickle Cell, Chest Pain, Child, Child, Preschool, Choice Behavior, Female, Humans, Incidence, Male, Morbidity, Morphine, Nalbuphine, Narcotics, Parents, Retrospective Studies, Young Adult
Show Abstract · Added September 19, 2013
BACKGROUND - Acute chest syndrome (ACS) represents a serious morbidity and often fatal complication in patients with sickle cell disease. Painful episodes which require hospitalization are most often treated with opioids, which may then influence the development of ACS. Nalbuphine is a parenteral opioid which effectively treats pain and may cause less ACS.
PROCEDURE - This retrospective chart review documented 988 admissions for painful episodes at 2 institutions and recorded the incidence of ACS and opioid used.
RESULTS - At the Children's Hospital in St Louis, Missouri, the incidence of ACS in patients treated with morphine alone was 10.8% versus at the Children's Mercy Hospital in Kansas City, Missouri, the incidence was 2.1% for patients treated solely with nalbuphine.
CONCLUSIONS - When nalbuphine is used alone as the single parenteral opioid agent to treat painful episodes in patients with sickle cell disease, the incidence of ACS is less than when compared with other opioids used to treat pain.
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18 MeSH Terms
Dopamine-dependent increases in phosphorylation of cAMP response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures of rat striatum.
Chartoff EH, Papadopoulou M, Konradi C, Carlezon WA
(2003) J Neurochem 87: 107-18
MeSH Terms: Animals, Cells, Cultured, Colforsin, Corpus Striatum, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Dopamine, Dopamine Agonists, Enzyme Inhibitors, Morphine, Naloxone, Narcotic Antagonists, Narcotics, Phosphorylation, Proto-Oncogene Proteins c-fos, RNA, Messenger, Rats, Rats, Sprague-Dawley, Substance Withdrawal Syndrome
Show Abstract · Added May 27, 2014
Chronic morphine leads to compensatory up-regulation of cAMP signaling pathways in numerous brain regions. One potential consequence of up-regulated cAMP signaling is increased phosphorylation of cAMP response element binding protein (CREB), a transcription factor that may regulate neuroadaptations related to morphine dependence. Altered gene expression within the nucleus accumbens (NAc), a ventral component of the striatum that receives substantial dopaminergic input, may play a role in some of the motivational aspects of opiate withdrawal. To determine if morphine withdrawal leads to increased CREB phosphorylation in striatal tissues, we examined the effects of naloxone-precipitated morphine withdrawal on CREB phosphorylation in primary cultures of rat striatal neurons. Precipitated morphine withdrawal was associated with enhanced dopamine-, SKF 82958 (D1 receptor agonist)-, and forskolin-induced CREB phosphorylation. During precipitated withdrawal, D1 receptor-mediated CREB phosphorylation was dependent on cAMP-dependent protein kinase (PKA). Precipitated withdrawal also led to up-regulation of c-fos mRNA in response to SKF 82958. CREB protein levels were not altered by acute or chronic morphine. These results suggest that D1 receptor-mediated signal transduction is enhanced during morphine withdrawal. Furthermore, they are consistent with in vivo evidence suggesting that increased CREB activation in portions of the striatum (e.g. the NAc) is related to dysphoric states associated with drug withdrawal.
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19 MeSH Terms
Sex hormone suppression by intrathecal opioids: a prospective study.
Roberts LJ, Finch PM, Pullan PT, Bhagat CI, Price LM
(2002) Clin J Pain 18: 144-8
MeSH Terms: Adult, Chronic Disease, Genitalia, Male, Gonadal Steroid Hormones, Humans, Hypothalamo-Hypophyseal System, Injections, Spinal, Libido, Male, Middle Aged, Narcotics, Pain, Prospective Studies, Testosterone
Show Abstract · Added December 10, 2013
OBJECTIVE - Sexual dysfunction and low testosterone levels have been observed previously in males with chronic noncancer pain treated with intrathecal opioids. To investigate the hypothesis that intrathecal opioids suppress the hypothalamic-pituitary-gonadal axis, a prospective nonrandomized investigation of the function of this axis was undertaken.
DESIGN - Ten males with chronic noncancer pain were evaluated for clinical and biochemical evidence of hypogonadism at baseline and during the first twelve weeks of intrathecal opioid therapy.
RESULTS - Intrathecal opioid administration resulted in a significant (p <0.0001) reduction in serum testosterone, from 7.7 +/- 1.1 (mean +/- SEM) nmol/L at baseline to 2.0 +/- 0.7, 2.8 +/- 0.5, and 4.0 +/- 0.9 nmol/L at 1, 4, and 12 weeks, respectively. This was associated with a reduction in libido and potency. Luteinizing hormone and follicle-stimulating hormone levels remained within reference ranges, indicating central rather than peripheral suppression.
CONCLUSIONS - Administration of intrathecal opioids may result in hypogonadotrophic hypogonadism. As part of the consent for therapy process, patients should be informed about this effect and its management. With long-term intrathecal opioid administration, the hypothalamic-pituitary-gonadal axis should be monitored. Where indicated, testosterone replacement should be undertaken to improve sexual function and prevent the potential metabolic effects of hypogonadism, in particular, osteoporosis.
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14 MeSH Terms
The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization.
Young CD, Deutch AY
(1998) Pharmacol Biochem Behav 60: 753-8
MeSH Terms: Animals, Cocaine, Conditioning, Psychological, Male, Motor Activity, Narcotics, Rats, Rats, Sprague-Dawley, Thalamic Nuclei
Show Abstract · Added May 27, 2014
The brain circuitry that subserves the augmented locomotor response to repeated psychostimulant administration has been the subject of intense scrutiny. The dopaminergic innervation of the nucleus accumbens is critically involved in psychostimulant-elicited behavioral sensitization, and recent studies suggest that lesions of structures that send glutamatergic projections to the nucleus accumbens alter the acquisition or expression of psychostimulant-elicited sensitization. Although certain thalamic nuclei provide a major glutamatergic input to the striatum, the involvement of the thalamus in psychostimulant-elicited sensitization has not been investigated. We therefore examined the effects of lesions of the thalamic paraventricular nucleus, which projects to the shell of the nucleus accumbens, on cocaine-elicited locomotor sensitization. Lesions of the paraventricular nucleus did not alter basal locomotor activity, but significantly enhanced the acute locomotor response to cocaine. In contrast, repeated cocaine administration did not progressively augment locomotor activity in lesioned rats, but did so in sham-lesioned animals. The thalamic lesions also blocked the conditioned locomotor response to the environment in which the cocaine injections took place. These data suggest that the thalamic paraventricular nucleus may be an integral part of extended circuitry that subserves both the conditioned and nonconditioned components of psychostimulant-induced behavioral sensitization.
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9 MeSH Terms
Receptor mechanisms of opioid tolerance in SH-SY5Y human neural cells.
Carter BD, Medzihradsky F
(1993) Mol Pharmacol 43: 465-73
MeSH Terms: Adenylyl Cyclase Inhibitors, Amino Acid Sequence, Cyclic AMP, Down-Regulation, Drug Tolerance, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins, GTP Phosphohydrolases, Humans, Levorphanol, Molecular Sequence Data, Naltrexone, Narcotics, Neuroblastoma, Neurons, Receptors, Opioid, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
In differentiated SH-SY5Y human neuroblastoma cells, various opioids exhibited a wide range of potencies (Ki) in acutely inhibiting adenylate cyclase to different extents (Imax). After exposure of the cells to opioids for 24 hr, the initially reduced cAMP content of the cells recovered toward pre-exposure levels. Withdrawal of agonist from, or addition of antagonist to, the tolerant cells rapidly increased the cAMP content to 1.5 times the basal value. Long term treatment of the cells with agonists of high acute potency, such as Tyr-D-Ala-Gly-(Me)Phe-Gly-ol and levorphanol, decreased the Bmax of the antagonist [3H]naltrexone by 80-95%, increased the Ks for GTPase stimulation 10-14-fold, and increased the Ki for adenylate cyclase inhibition 2-3-fold. On the other hand, these parameters were only marginally affected by agonists of lower acute potency, such as profadol and morphiceptin, regardless of their Imax in inhibiting adenylate cyclase. The reduction in the level of receptor binding was experimentally not dissociable from effector desensitization. Tyr-D-Ala-Gly-(Me)Phe-Gly-ol retained the characteristics of a potent agonist in inducing tolerance even under conditions of submaximal signal, produced by lower concentrations of the peptide or by pretreatment with pertussis toxin. Alkylation of receptors by beta-chlornaltrexamine, although it reduced [3H]naltrexone binding by 50%, did not significantly alter the rank order of opioid agonists based on their ability to acutely inhibit adenylate cyclase. These results show that in opioid-tolerant SH-SY5Y cells the concurrently occurring down-regulation of receptor and shifts in the concentration dependence of effector response correlate with the potency of a given opioid in producing its acute effect but not with the maximum extent of that effect.
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The potency of mu-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17 beta-estradiol.
Lagrange AH, Ronnekleiv OK, Kelly MJ
(1994) J Neurosci 14: 6196-204
MeSH Terms: Animals, Arcuate Nucleus of Hypothalamus, Dose-Response Relationship, Drug, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins, Estradiol, Female, GTP-Binding Proteins, Guinea Pigs, In Vitro Techniques, Membrane Potentials, Narcotics, Neurons, Potassium Channels, Receptors, Opioid, mu, Sensitivity and Specificity, Stereoisomerism
Show Abstract · Added August 14, 2014
The mu-opioid agonist DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) hyperpolarizes the majority of arcuate hypothalamic (ARC) neurons by opening an inwardly rectifying potassium conductance. The EC50 for the DAMGO-induced hyperpolarization was 60 +/- 3 nM in ARC neurons from ovariectomized guinea pigs. Superfusion of 17 beta-estradiol (E2; 100 nM) for 20 min in vitro resulted in a significant decrease in DAMGO potency (EC50 = 212 +/- 16 nM) in 40% of the neurons that were tested. This rapid effect of E2 on the mu-opioid response was not mimicked by the biologically inactive isomer 17 alpha-estradiol. Multiple concentrations of E2 were used to generate an E2 concentration-response curve, with an EC50 of 9 nM and a maximal increase in the DAMGO EX50 of 411% of controls. The membrane properties and firing rate of E2-sensitive and E2-insensitive neurons were not different. Streptavidin-FITC labeling did not reveal any significant morphological differences between the groups, but a higher number of E2-sensitive cells was found in the lateral ARC and cell-poor zone. Moreover, immunocytochemical staining of the recorded cells revealed that beta-endorphin neurons were among those sensitive to E2. Therefore, E2 could increase beta-endorphin release by decreasing the potency of beta-endorphinergic autoinhibition, thus increasing the tonic opioid inhibition of E2-insensitive cells. Furthermore, the diffuse projections of hypothalamic beta-endorphin neurons would allow E2 to alter processes throughout the brain, as well as having local effects in the hypothalamus.
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17 MeSH Terms