Short-term hormonal effects of naloxone in man

Volavka, Jan; Bauman, Joan E.; Pevnick, Jeffrey S.; Reker, Dean M.; James, Bárbara; Cho, Dong

doi:10.1016/0306-4530(80)90026-8

Cited by 98 publications

(20 citation statements)

References 27 publications

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“…This complexity may partially explain the apparent differences in naloxone doses required in humans to effect various behaviors and physiologic changes as well as the apparent lack of correlation within subjects in these effects of naloxone. For example, the dose of naloxone required to produce effects on plasma cortisol levels in normals would seem to be lower than that required to produce effects on blood pressure regulation and mood (9,10,15). The results of this study would suggest that the threshold for naloxone's effects on food intake is lower than the threshold for its effects on mood.…”

Section: Discussionmentioning

confidence: 70%

Naloxone Reduces Food Intake in Humans

Cohen

Pickar

et al. 1985

Psychosomatic Medicine

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Hypotheses generated from animal studies that the endogenous opioid system is an important modulator of food intake suggest that blockade of the system in humans should affect eating behavior. To assess this hypothesis, seven normal volunteers were given 2 mg/kg naloxone or placebo on separate days in a double-blind, random but balanced cross-over experimental design. Compared to placebo, naloxone was found to reduce significantly total food intake from preselected prepared trays served 2.75 and 7.75 hours after drug administration (p < 0.02). The reduction was considerable (28%), and although the magnitude varied greatly among individuals, reduction occurred in each. This reduced food intake was not accompanied by a demonstrable alteration of the volunteers' perceptions of their hunger. Further cautious experimental investigation of naloxone's effects during long-term administration and in patients with eating disorders is warranted in light of its apparent effect of reducing food intake in humans while not decreasing their satiety.There is substantial evidence from animal studies that the endogenous opioid system (EOS) is an important modulator of eating behavior (1, 2). An important component of this evidence is the doserelated suppression of food intake produced by the administration of naloxone in the mg/kg range to rodents (3, 4). Because naloxone is considered a pure opiate receptor antagonist, this effect is consid- ered to reflect functional blockade of the EOS and thus active involvement of the EOS in the eating behavior of these animals.The evaluation of behavioral effects produced by the administration of naloxone has also been a major experimental approach in clinical research. However, clinical research began with the use of doses as low as 5 (xg/kg (0.4 mg) and still has not generally exceeded 0.3 mg/kg (20 mg) (5-7). These doses originated from the exceedingly small dose (less than 5 |xg/kg) needed to precipitate withdrawal from narcotic alkaloids (exogenous opioids) in humans (8).We have recently demonstrated dosedependent behavioral effects of naloxone given to normal volunteers in the mg/kg range that were not evident in previous clinical studies using lower doses (9, 10). Concomitant physiologic and hormonal evaluations supported the continuing specificity of naloxone as an opiate receptor antagonist at these doses. These data suggested that some EOS were not completely blocked at lower doses of naloxone, supporting the presence in humans 132

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Section: Discussionmentioning

confidence: 70%

Naloxone Reduces Food Intake in Humans

Cohen

Pickar

et al. 1985

Psychosomatic Medicine

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“…Other than one human study reporting an increase in serum prolactin following intramuscular administration of naloxone 210 mg (Kumor et al, 1988), extensive studies in non-human primates and humans have not found an effect of this mu-opioid receptor antagonist on serum prolactin (Volavka et al, 1980;Morley et al, 1980;Naber et al, 1981;Cohen et al, 1983Cohen et al, , 1985van Bergeijk et al, 1986;VanVugt et al, 1989b). Data for naltrexone and nalmefene, the two antagonists with greater affinity at mu-and kappa-opioid receptors than naloxone, are, however, mixed.…”

Section: Prolactin and Mu-and Kappa-opioidergic Drugsmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

123

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In humans, mu-and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu-and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappaopioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

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“…Studies of the opioid receptor antagonist naloxone have shown increased levels of ACTH and cortisol in normal volunteer subjects (Volavka et al, 1979(Volavka et al, , 1980Schluger et al, 1998). Other antagonists (naltrexone and nalmefene) with different affinities for the m-, k-, and d-opioid receptors also increase ACTH and cortisol (Mendelson et al, 1986;Schluger et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-Releasing Factor Testing Reveals a Dose-Dependent Difference in Methadone Maintained Vs Control Subjects

Schluger

Bart

Green

et al. 2003

Neuropsychopharmacol

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Opiate addiction is associated with abnormal function of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. In general, addiction and withdrawal are associated with abnormal HPA responsivity as demonstrated by baseline, dexamethasone, and metyrapone testing. Following stabilization in methadone maintenance treatment, normalization of HPA axis responsivity is observed. To further investigate HPA axis function associated with heroin addiction and its treatment, saline placebo and human corticotropin-releasing factor (hCRF) were administered intravenously in two doses, one dose lower (0.5 mg/kg) and one dose higher (2.0 mg/kg) than the dose used in standard clinical diagnostics (100 mg), to 16 normal male volunteer controls (NV) and eight male stable-dose methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM). Plasma adrenocorticotrophic hormone (ACTH) and cortisol levels were determined at serial time points. There was no difference in hormonal measurements between the two groups following placebo. NV as well as MM displayed a dose-response effect in plasma ACTH and cortisol levels. MM displayed a significantly greater increase in plasma ACTH levels than the NV following high-dose but not low-dose hCRF (po0.05). There was no significant difference in plasma cortisol levels between the two groups following high-dose hCRF. Thus, despite earlier documented normalization of behavioral function and of several measures of neuroendocrine function during long-term methadone maintenance, some abnormalities in HPA axis responsivity that may be a consequence of heroin exposure, or that may have existed prior to the addiction, can persist during stable methadone treatment.

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Short-term hormonal effects of naloxone in man

Cited by 98 publications

References 27 publications

Naloxone Reduces Food Intake in Humans

Naloxone Reduces Food Intake in Humans

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Corticotropin-Releasing Factor Testing Reveals a Dose-Dependent Difference in Methadone Maintained Vs Control Subjects

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