Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1323099 (sympathomimetic)
 2,957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the molecular mediators of its effects are not fully defined. Recently, skeletal muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of the thermogenic effects of the widely abused sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by norepinephrine (NE) and is dependent upon the availability of free fatty acids (FFAs). We hypothesized that UCP3 may be a molecular link between TH and hyperthermia, requiring increased levels of both NE and FFAs to accomplish the thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly increases plasma FFA levels 30 min after treatment. Pharmacologically increasing NE levels through the inhibition of phenylethanolamine N-methyltransferase with +/-2,3-dichloro-alpha-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.
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PMID:Roles of norepinephrine, free Fatty acids, thyroid status, and skeletal muscle uncoupling protein 3 expression in sympathomimetic-induced thermogenesis. 1701 7

Sympathomimetic drugs (MDMA; ecstasy) induce a potentially catastrophic hyperthermia that involves free fatty acid (FFA) activation of mitochondrial uncoupling proteins (UCP). Insulin is an important regulator of plasma FFA levels, although its role in thermogenesis is unclear. The aims of the present study were 1) to characterize the pharmacodynamic effects of MDMA on plasma insulin and glucose, 2) to examine the effects of insulin on MDMA-induced thermogenesis and 3) to examine MDMA-induced thermogenesis in an animal model of insulin resistance, the obese Zucker rat. Insulin levels peaked 15 min after MDMA (40 mg/kg, s.c.), which preceded the peak temperature change at 60 min. Plasma glucose levels also peaked 15 min. after MDMA and remained elevated throughout the 90-min. monitoring period. Insulin pretreatment (10 units/kg, s.c.) 30 min. before a low dose of MDMA (5 mg/kg, s.c.) potentiated the thermogenic response. Insulin resistant, fa/fa (obese) Zucker rats demonstrated an attenuated thermogenic response to MDMA (40 mg/kg, s.c.). Consistent with the role for FFA in UCP3 expression, immunoblot analysis showed significantly increased levels of UCP3 protein obese compared to lean Zucker skeletal muscle. In conclusion, the results of the present study suggest a potential role of insulin signaling in sympathomimetic-induced thermogenesis.
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PMID:Pharmacodynamic characterization of insulin on MDMA-induced thermogenesis. 1948 19

Thermoregulation is an essential homeostatic process in which critical mechanisms of heat production and dissipation are controlled centrally in large part by the hypothalamus and peripherally by activation of the sympathetic nervous system. Drugs that disrupt the components of this highly orchestrated multi-organ process can lead to life-threatening hyperthermia. In most cases, hyperthermic agents raise body temperature by increasing the central and peripheral release of thermoregulatory neurotransmitters that ultimately lead to heat production in thermogenic effector organs skeletal muscle (SKM) and brown adipose tissue (BAT). In many cases hyperthermic drugs also decrease heat dissipation through peripheral changes in blood flow. Drug-induced heat production is driven by the stimulation of mechanisms that normally regulate the adaptive thermogenic responses including both shivering and non-shivering thermogenesis (NST) mechanisms. Modulation of the mitochondrial electrochemical proton/pH gradient by uncoupling protein 1 (UCP1) in BAT is the most well characterized mechanism of NST in response to cold, and may contribute to thermogenesis induced by sympathomimetic agents, but this is far from established. However, the UCP1 homologue, UCP3, and the ryanodine receptor (RYR1) are established mediators of toxicant-induced hyperthermia in SKM. Defining the molecular mechanisms that orchestrate drug-induced hyperthermia will be essential in developing treatment modalities for thermogenic illnesses. This review will briefly summarize mechanisms of thermoregulation and provide a survey of pharmacologic agents that can lead to hyperthermia. We will also provide an overview of the established and candidate molecular mechanisms that regulate the actual thermogenic processes in heat effector organs BAT and SKM.
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PMID:The heat is on: Molecular mechanisms of drug-induced hyperthermia. 2762 45

The toxidrome associated with death from the synthetic cathinones includes hyperthermia as part of the sympathomimetic syndrome. Here, we examine the gender differences in the development of tolerance to the hyperthermia mediated by the synthetic cathinone methylone. In addition to temperature changes, expression differences in genes encoding the uncoupling proteins (UCP) 1 & 3, and TGR5 in skeletal muscle (SKM) and brown adipose tissue (BAT) were examined. Male and female rats were treated weekly with methylone (10 mg/kg). The females developed a tolerance to the methylone-induced hyperthermia by week two of drug exposure. By the third week, females displayed a hypothermic response to methylone. Conversely, males continued to display a hyperthermic response up to and including week four. At week four, the males demonstrated a significantly lower hyperthermia and a complete tolerance seen at week five with no significant hyperthermia. Tissue samples collected after treatment on the sixth week indicate that chronic exposure to methylone reduced UCP1 expression in SKM and BAT of the female rats. Only the females displayed increased TGR5 expression in BAT. UCP3 expression increased in both the SKM and BAT of the males and females. The differences between responses in male and female subjects further demonstrate the need for gender studies in the toxicology associated with drugs with abuse potential.
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PMID:Gender differences in tolerance to the hyperthermia mediated by the synthetic cathinone methylone. 3193 4