Naloxone (NX) potentiated epinephrine (EPI) induced submaximal vasoconstriction in canine renal and skeletal muscle arterial segments, yet had no vasoconstrictor action alone. Developed tension generated in-vitro by 4 x 1mm. O.D. rings from 1st degree branches of canine femoral arteries was expressed as % of KCI induced maximum response. NX (10^-5 M) potentiated EPI induced submaximal contractions (34.2%) significantly more than contractions induced by norepinephrine, phenylephrine, lofexidine, ADH, KCI and serotonin (13.8,13.4,4.7,13.5,14.4 and 11.4% respectively). The NX response was unaffected by beta-adrenergic blockade and NX did not reverse an isoproterenol mediated vasodilation. Alphaadrenergic blockade with phentolamine completely eliminated EPI plus NX induced vasoconstriction. After washout, vessels exposed to EPI plus NX relaxed by 50% significantly faster than vessels exposed to EPI alone (18.5 and 27.9 min respectively). EPI induced vasoconstrictions were potentiated by 10^-5 M corticosterone (49.0%) which inhibits extraneuronal catecholamine uptake, but not by 10^-7 M desipramine (1.1%) which inhibits neuronal uptake. EPI induced vasoconstrictions were also potentiated by 10^-4 M pyrogallol (33.0%) which inhibits catechol-o-methyl transferase activity, but not by 10^-5 M pargyline (-1.1%) which inhibits monoamine oxidase activity. The NX effect was endothelium independent. The dose-response of various opioid receptor agonists and antagonists were compared to the NX response. A specific opioid receptor subclass could not be identified as the mediator of the NX effect. The ED_50s for NX (3.7x^-6 M) and (+)NX (8.1x^-7M) indicated a significant stereoselectivity for the (+)enantiomer. A variety of sigma receptor ligands, steroids and steroid metabolites were tested for the ability to augment EPI vasoconstrictions. Several of the opioid, sigma and steroid ligands, all with polycyclic structures, induced responses similarto those of NX. NX exerted its effect independent of traditional opiate receptors and may have influenced the cellular uptake or degradation of EPI. Endogenous compounds with sigma or steroid activity may modulate these processes in-vivo.

Opioid abuse and addiction affects more than 2.4 million people in the United States. Medication assisted treatment (MAT), in combination with counseling, is recognized as the most effective treatment for patients with opioid dependence and abuse. Although MAT is considered the most effective treatment, previous research has found clinically significant weight gain with methadone. The purpose of this study was to determine if hedonic eating behaviors, sugar cravings, and addictive like eating was related to weight gain in opioid addicted patients receiving methadone and buprenorphine/naloxone (Suboxone™). Hedonic eating behaviors were measured using three validated surveys. Following survey collection, a chart review was completed to determine weight changes over time. One hundred twenty surveys were completed and 113 were analyzed. No differences were found between the medication groups in terms of mean age, weight at entry, BMI at entry, race, sex, and Hepatitis C status. A subset of 39 participants was analyzed for weight changes during treatment. There were no differences in food addiction scores, hedonic eating behaviors, and food cravings between the medication groups. We found significant weight gain in patients receiving methadone and no weight changes for those receiving Suboxone™. Weight gain in methadone maintenance does not appear to be related to addictive like eating, food craving, or hedonic eating. This research suggests that weight gain seen in methadone maintenance for opioid addiction treatment is related to something other than hedonic eating behaviors. Clinically significant weight gain should be considered when prescribing methadone for opioid addiction.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Graduation date: 1999

Exercise is often prescribed for patients with chronic pain, but there is little objective evidence supporting this recommendation. Therefore, we tested the effect of moderate aerobic exercise on the sensory hypersensitivity produced in an animal model of neuropathic pain. Male rats that underwent unilateral ligation of the L5 and L6 spinal nerves (SNL) were divided into exercise-trained or sedentary groups. Exercise training was performed using a treadmill, beginning 7 days after surgery, and continued 5 days a week for 5 weeks. Animals were exercised 30 min/day, at a speed of 14-16 m/min. Sensory testing was performed 23 hours after exercise training. Typical thermal and tactile hypersensitivity developed within 1 week after surgery. Treadmill training reversed thermal and tactile hypersensitivity in injured animals within 4 weeks, but had no effect on sham-operated or non-operated animals. One week after the cessation of exercise training, tactile hypersensitivity returned.The effects of exercise training on SNL-induced sensory hypersensitivity were reversed by the opioid receptor antagonist naloxone. Naloxone or naloxone methiodide reversed the effects of exercise when administered intracerebroventricularly (i.c.v.). Immunohistochemistry revealed increased immunostaining for B-endorphin and met-enkephalin in the periaquaductal grey (PAG) and rostral ventromedial medulla (RVM) regions of exercise-trained animals compared to sedentary animals. An ELISA immunoassay revealed a 31% increase in PAG B-endorphin content in exercise-trained SNL animals. More BDNF was also present in the brain's of exercise-trained animals compared to sedentary, specifically in the ventromedial hypothalamus, hippocampus, and outer rim of the PAG. Administering a BDNF sequestering agent reversed B-endorphin increases in the PAG of exercise-trained animals. Exercise-trained SNL animals treated with 25 ug BDNF sequestering agent (i.c.v.) had lower tactile thresholds compared to the exercise-trained vehicle group.These results support the recommendation of moderate aerobic exercise for patients suffering from neuropathic pain, and suggest that exercise-induced pain reversal results from the upregulation of endogenous opioids in the brainstem. Additionally, increased BDNF with exercise training may play a role in exercise-induced reversal of neuropathic pain by increasing the expression of endogenous opioids, but this needs to be verified further.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

No description available.

The opioid fentanyl is becoming an increasingly popular drug of abuse across the United States. With a potency up to 100 times greater than the common opioid morphine, fentanyl use can easily lead to overdoses. This is especially true as fentanyl is increasingly found mixed into other illicit drugs without users’ knowledge. However, there exists an antidote for opioid overdoses called naloxone. Naloxone is a pure antagonist at μ-opioid receptors in the brain and produces little known side-effects. Recently, the FDA has approved naloxone delivery devices designed for individuals without medical training, making naloxone layperson friendly. Under today’s policy, naloxone is a prescription medication. This means physicians must write a prescription for take-home naloxone or issue a standing order allowing other healthcare professionals to distribute naloxone. However, there are little federal laws governing naloxone as most of the statutes discussing naloxone access and administration are determined by individual states. For example, only some states allow physicians to prescribe naloxone to non-patients. Additionally, many states have differing laws regarding criminal liabilities for physicians who prescribe the drug and for laypersons who administer the drug. In the U.S. there exists a dilemma with naloxone, as topics ranging from public policy to insurance coverage are controversial. With increasing information on fentanyl and naloxone being published, the U.S. is currently looking into the idea of making naloxone more accessible as a way to reduce overdose deaths.

Existem vArias evidências exPerimentais e clinicas de que os Opióides Endógenos exercem um papel importante no controle cardiovascular. Com o objetivo de avaliaa influência destes peptideos, liberados durante o exercicio, sobre as respostas cardiovasculares, metabólicas e da percepção do esforco ao exercicio sub-màximo, foi administrado um antagonista opióide: Naloxone (14 mg), de maneira duplo-cega e, á 10 jovens normais, não treinados. Os individuas pedalaram durante 60 minutos, divididos em três estàgios de 20 minutos sob cargas que atingiram . (médias ± DP) 48 ± 7, 62 ± 4 e 83 ± 5% da frequência cardiaca màxima, aferida em teste màximo prévio. A avaliacâo da funcâo ventricular foi realizada por estudo eco-Dopplercardiogràfico obtido nos cinco minutos finais de cada estAgio. Durante os testes submàximos, ocorreu aumento significativo da pressão arterial sistólica, da frequência cardiaca. da percepção do esforco e do lactato sanguineo. A percepcâo do esforco. aferida através da escala de Borg, não foi diferente quando da administracâo de Naloxone A funcâo sistólica do ventriculo esquerdo, avaliada pelo volume sistólico e pela fracâo de encurtamento estimados pela ecocardiografia mono-dimensional, apresentou aumento significativo com o exercicio. Não houve correlacâo significativa entre a integral total do fluxo trans-mitral, calculada por planimetria, e o volume sistólico. Houve uma diminuição progressiva dos diâmetros diast6licos e dos diâmetros sistõlicos ventricular esquerdo do repouso em relação aos 60 minutos de esforco. A funcâo diastolica do ventriculo esquerdo, avaliada pela velocidade màxima de enchimento (pico "E") do fluxo trans-mitral e a taxa de enchimento màximo normalizada para o volume sistólico, aumentou progressivamente durante o exercicio. A curva bifàsica do fluxo trans-mitral tornou-se monofàsica com a diminuicâo do periodo diastolico. A administração de Naloxone não alterou as respostas das variàveis estudadas ao exercicio (ANOVA). Portanto, o presente estudo demonstra que o Naloxone , mesmo em altas doses, nâo modifica as respostas hemodinãmicas, metabõlicas e de Percepção do esforco em jovens normais submetidos a este protocolo de exercicio.

Existem vArias evidências exPerimentais e clinicas de que os Opióides Endógenos exercem um papel importante no controle cardiovascular. Com o objetivo de avaliaa influência destes peptideos, liberados durante o exercicio, sobre as respostas cardiovasculares, metabólicas e da percepção do esforco ao exercicio sub-màximo, foi administrado um antagonista opióide: Naloxone (14 mg), de maneira duplo-cega e, á 10 jovens normais, não treinados. Os individuas pedalaram durante 60 minutos, divididos em três estàgios de 20 minutos sob cargas que atingiram . (médias ± DP) 48 ± 7, 62 ± 4 e 83 ± 5% da frequência cardiaca màxima, aferida em teste màximo prévio. A avaliacâo da funcâo ventricular foi realizada por estudo eco-Dopplercardiogràfico obtido nos cinco minutos finais de cada estAgio. Durante os testes submàximos, ocorreu aumento significativo da pressão arterial sistólica, da frequência cardiaca. da percepção do esforco e do lactato sanguineo. A percepcâo do esforco. aferida através da escala de Borg, não foi diferente quando da administracâo de Naloxone A funcâo sistólica do ventriculo esquerdo, avaliada pelo volume sistólico e pela fracâo de encurtamento estimados pela ecocardiografia mono-dimensional, apresentou aumento significativo com o exercicio. Não houve correlacâo significativa entre a integral total do fluxo trans-mitral, calculada por planimetria, e o volume sistólico. Houve uma diminuição progressiva dos diâmetros diast6licos e dos diâmetros sistõlicos ventricular esquerdo do repouso em relação aos 60 minutos de esforco. A funcâo diastolica do ventriculo esquerdo, avaliada pela velocidade màxima de enchimento (pico "E") do fluxo trans-mitral e a taxa de enchimento màximo normalizada para o volume sistólico, aumentou progressivamente durante o exercicio. A curva bifàsica do fluxo trans-mitral tornou-se monofàsica com a diminuicâo do periodo diastolico. A administração de Naloxone não alterou as respostas das variàveis estudadas ao exercicio (ANOVA). Portanto, o presente estudo demonstra que o Naloxone , mesmo em altas doses, nâo modifica as respostas hemodinãmicas, metabõlicas e de Percepção do esforco em jovens normais submetidos a este protocolo de exercicio.