Tonic immobility produces hyperalgesia and antagonizes morphine analgesia.

Hyperalgesia was demonstrated during and immediately after termination of tonic immobility in the lizard Anolis carolinensis. Additionally, tonic immobility antagonized morphine-induced analgesia. In conjunction with other research, these data suggest that the response is accompanied by a reduced availability of serotonin, possibly at postsynaptic receptors of raphe neurons.

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism.

PURPOSE: Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity. METHODS: This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding. RESULTS: Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. CONCLUSIONS: IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.

The Tyr-MIF-1 family of peptides.

A review of research on the Tyr-MIF-1 family of peptides is presented with emphasis on Tyr-MIF-1 and its structure, passage through the blood-brain barrier, and both opiate antagonist and agonist properties. Family members MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1 are also included.

Behavioral effects of melanocyte stimulating hormone release-inhibiting factor-1 (MIF-1).

Consideration of the isolation, structure, localization, and behavioral effects of melanocyte stimulating hormone release inhibiting factor (MIF-1) is followed by a review of its opiate antagonistic and clinical effects. Evidence pertaining to various hypotheses offered in explanation of these behavioral effects is examined and evaluated. It is concluded that MIF-1 affects behavior in many instances with possible antagonistic effects as well as clinical possibilities.

Endogenous opiates: through 1978.

The discovery of receptors in the brain for opiates and the structure of the endogenous peptides for these receptors has led to an explosion of interest in this field. The present review is the first of an annual series. It summarizes many of the highlights of research with opiate peptides published with a date of 1978 or earlier.

Prazosin does not alter canine renin release in response to systemic hypotension or intrarenal isoprenaline and prostaglandin I2 infusion.

1. The effect of a hypotensive dose of intravenous prazosin (0.2 mg/kg) on heart rate and plasma renin activity was evaluated in anaesthetized mongrel dogs pretreated with indomethacin. 2. The effect of prazosin on the renin release elicited by the beta-adrenoceptor agonist isoprenaline and by prostaglandin I2 was also evaluated. 3. Prazosin administration was associated with a significant increase in heart rate and increase in plasma renin activity. 4. Prazosin did not interfere with the increase in plasma renin activity in response to either isoprenaline or prostaglandin I2. 5. We conclude that prazosin is not a unique peripheral vasodilator since hypotensive doses are associated with an increase in heart rate and plasma renin activity. In addition, prazosin does not inhibit the release of renin induced by either isoprenaline or prostaglandin I2.

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1. The present study evaluated the time-dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determining changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C-13 hydroxy metabolite, doxorubicinol. 2. Following addition of doxorubicin (175 microM) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3. Doxorubicin (175 microM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 microM), however, failed to produce time-related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4. During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5. To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration-response experiments with doxorubicinol (0.9-7.2 microM) were conducted. 6. Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin-treated than in doxorubicinol-treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function.7. Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 microM doxorubicinol promoted a 15 fold greater release rate than 3 microM doxorubicin.8. Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time-dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Prevention by dexrazoxane of down-regulation of ryanodine receptor gene expression in anthracycline cardiomyopathy in the rat.

Anthracyclines can cause cumulative dose-related cardiotoxicity characterized by changes in Ca(2+) metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca(2+)-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF-187), an iron chelator which prevents anthracycline cardiotoxicity, on RyR2 gene expression in rats treated chronically with daunorubicin. Daunorubicin (2.5 mg kg(-1) i.v. weekly for 6 weeks) produced cardiotoxicity as demonstrated by histopathologic changes. The ryanodine receptor/glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA ratio was decreased by 38+/-3% (P<0.02) compared to values in control rats. Dexrazoxane pre-treatment (50 mg kg(-1); 1 h prior to each daunorubicin injection) prevented the decrease in RyR2/GAPDH mRNA ratio and histopathologic lesions in daunorubicin-treated rats. This is the first report that a protective agent such as dexrazoxane can ameliorate the decreased expression of a specific gene involved in anthracycline-induced cardiotoxicity.

Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump.

An anticancer drug, doxorubicin, and a naturally occurring beta-amino acid, taurine, exert opposing actions on myocardial calcium content and lipid peroxidation. Thus, we tested the hypothesis that the two agents may interact to modify cardiac calcium metabolism and indices of lipid peroxidation. Cardiac taurine levels were reduced by half in rats given tap water containing a beta-amino transport inhibitor, beta-alanine. Taurine deficiency was associated with an increased susceptibility of the heart to doxorubicin-mediated calcium accumulation, a phenomenon commonly associated with doxorubicin cardiotoxicity. Taurine deficiency also predisposed the heart to enhanced formation of malondialdehyde caused by doxorubicin administration. While increases in malondialdehyde levels are often associated with lipid peroxidation, the failure of doxorubicin to cause changes in oxidized glutathione content makes peroxidative mechanisms a less likely explanation for the potentiation of doxorubicin-mediated myocardial calcium accumulation in taurine-deficient rats. A more likely possibility is the interaction between taurine deficiency and doxorubicin to inhibit the sarcolemmal calcium pump. The data also suggest that the interaction between doxorubicin and taurine deficiency does not involve alterations in the pharmacokinetics of doxorubicin or the cardiotoxic metabolite, doxorubicinol. It is concluded that reduction in sarcolemmal calcium pump activity by taurine deficiency may contribute to myocardial calcium accumulation in hearts whose calcium homeostasis has been compromised by doxorubicin.

Daunorubicin cardiotoxicity: evidence for the importance of the quinone moiety in a free-radical-independent mechanism.

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98+/-6% at 1 Hz, and 73+/-8 and 67+/-8% for 30 and 60 sec PRP, respectively, and 73+/-3 and 63 +/-3% at 2 and 3 Hz, respectively, for 88 microM Daun (P<0.05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force-frequency relationship or PRP contractions. Additional studies in Ca(2+)-loaded SR microsomes indicated that both Daun and 5-ID opened Ca(2+) release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca(2+) release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.

Aging increases the cardiotoxicity of daunorubicin and daunorubicinol in the rat.

This study examined effects of aging on the cardiac response in vitro to daunorubicin, a cancer chemotherapeutic agent that causes cardiotoxicity. Left ventricular trabeculae carneae from adult (aged 6-9 months) and old (aged 24-28 months) Fischer 344 rats were placed in oxygenated, physiological buffer. Preparations were treated with daunorubicin (175 microM) or saline (controls) over a 210-minute study period. Daunorubicin-induced decline in contractility (DS and dS/dt) was greater in old compared to adult myocardium (p < .02). Similarly, cardiac relaxation (90% relaxation time) was more impaired by daunorubicin in older preparations (p < 01). Although daunorubicin concentrations were unaffected by age, daunorubicinol concentrations in ventricular strips increased with time to a greater extent in the older group (p < .05). This study suggests that senescence increases the acute in vitro cardiotoxicity of daunorubicin and that the metabolite, daunorubicinol, may contribute to this toxicity.

Age-related effects in rabbit hearts of N6-R-phenylisopropyladenosine, an adenosine A1 receptor agonist.

Interventions known to increase cytoplasmic Ca2+ appear to amplify age-related impairment of cardiac function. In addition, increased release of interstitial adenosine, an endogenous nucleoside, has been suggested to mediate the diminished beta-adrenergic responsiveness in senescent heart. However, the direct effects of adenosine A1 receptor activation on senescent myocardium have not been investigated thoroughly. Therefore, the effects of N6-R-phenylisopropyladenosine (R-PIA), an A1 agonist, on atrial rate and contractility (+dF/dt) in adult (6-8 months) and senescent (5-7 years) New Zealand White rabbits were compared in spontaneously beating right atria and electrically stimulated isolated right papillary muscles. Although senescent right atria appeared to be more sensitive to the negative chronotropic-effects of R-PIA, the effective concentrations producing 50% of the maximum response (EC50 values) of R-PIA were not significantly different between adult (26 nM, 95% confidence limits: 12-52 nM) and senescent (13 nM; 95% confidence limits: 10-16 nM). However, senescent right ventricular papillary muscles were more sensitive to the negative inotropic effects of R-PIA. For example, at 90 contractions/min, 100 nM R-PIA decreased +dF/dt 25.3 +/- 7.4% and 61.9 +/- 4.8% in adult and senescent papillary muscles, respectively. To investigate whether R-PIA might alter sarcoplasmic reticulum (SR) function as a mechanism of decreased inotropy, we determined the inotropic effects of R-PIA on steady-state and 30-s postrest-potentiated contractions (PRP; an index of SR Ca2+ release) of left atria. R-PIA did not selectively decrease contractility of PRP compared to steady state in either adult or senescent left atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related characterization of atrial adenosine A1 receptor activation: direct effects on chronotropic and inotropic function in the Fischer 344 rat.

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.

Endogenous opiates: 1990.

This paper, an examination of works published during 1990, is thirteenth in a series of our annual reviews of the research involving the behavioral, nonanalgesic, effects of the endogenous opiate peptides. The specific topics this year include stress; tolerance and dependence, eating; drinking; gastrointestinal, renal, and hepatic functions; mental illness; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; locomotor activity; sex, pregnancy, development, and aging; immunological responses; and other behavior.

Endogenous opiates: 1984.

This paper is the seventh in an annual series of reviews of research involving the endogenous opiate peptides, each installment being restricted to work published during the previous year. As in the past three years, the review this year is limited to non-analgesic and behavioral studies of the opiate peptides. The specific topics this year include: stress, tolerance and dependence, consummatory responses, gastric and renal activity, alcohol, mental illness, learning and memory, cardiovascular responses, respiratory effects, thermoregulation, seizures and neurological disorders, activity, and miscellaneous other topics.

Endogenous opiates: 1985.

This paper is the eighth installment of our annual review of research involving the endogenous opiate peptides. It is restricted to the non-analgesic and behavioral studies of the opiate peptides published in 1985. The specific topics this year include stress, tolerance and dependence, eating, drinking and alcohol consumption, gastrointestinal and renal activity, mental illness, learning and memory, cardiovascular responses, respiration and thermoregulation, seizures and neurological disorders, activity, and some other selected topics.

Endogenous opiates: 1992.

This paper is the fifteenth installment of our annual review of research concerning the opiate system. It includes papers published during 1992 involving the behavioral, non-analgesic, effects of the endogenous opiate peptides. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal and renal function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.

Endogenous opiates: 1993.

This paper is the sixteenth installment of our annual review of research concerning the opiate system. It is restricted to papers published during 1993 that concern the behavioral effects of the endogenous opiate peptides, and does not include papers dealing only with their analgesic properties. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; development; immunological responses; and other behaviors.

Endogenous opiates: 1991.

This paper is the fourteenth installment of our annual review of research concerning the opiate system. It includes papers published during 1991 involving the behavioral, nonanalgesic, effects of the endogenous opiate peptides. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal and renal function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.