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At least 19 recordsLinked to original sources
PubMed1987

Opioids and hibernation. II. Effects of kappa opioid U69593 on induction of hibernation in summer-active ground squirrels by "hibernation induction trigger" (HIT).

A "Hibernation Induction Trigger" (HIT) isolated from plasma of winter-hibernating woodchucks induced hibernation in summer-active ground squirrels (Citellus tridecemlineatus). Effects of kappa opioid U69593 on the HIT-induced hibernation were examined. U69593 alone did not elicit marked behavioral alteration or hibernation in summer-active ground squirrels. U69593, however, antagonized hibernation induced by HIT in summer active ground squirrels. In the guinea pig ileum myenteric plexus-longitudinal muscle preparation, woodchuck HIT depressed the electrically-induced contraction. The depression was, however, neither reversed nor blocked by naloxone even when naloxone was used at high doses. This study demonstrates that kappa opioid, at least in the case of U69593, was unable to induce hibernation in the summer-active ground squirrels. The results also demonstrate that woodchuck HIT, like the bear HIT, did not act directly at opioid receptors. Together with our previous observation that naloxone blocked summer hibernation induced by HIT (Bruce et al., Life Sci.., this issue), it is tempting to suggest that HIT may not mediate its effects through kappa opioid receptors but may do so through other types of opioid receptors such as mu or delta. U69593 may antagonize HIT-induced hibernation as a mu or delta receptor antagonist.

Animals↗
PubMed1993

Hibernation-associated gene regulation of plasma proteins with a collagen-like domain in mammalian hibernators.

In mammals, hibernation is expressed by only a limited number of species, and the molecular mechanisms underlying hibernation are not well understood. Recently, we have found plasma proteins which disappear from blood specifically during hibernation in a mammalian hibernator, the chipmunk. Here, we report the cDNA cloning of these chipmunk hibernation-related proteins, HP-20, -25, and -27, and analyses of their expression. All three proteins contain a collagen-like domain near the N terminus and are highly homologous to each other. Their mRNAs were detected only in liver in nonhibernating chipmunks, and in hibernating chipmunks, the amounts were reduced to less than 1/10 of those in nonhibernating chipmunks, indicating that HP-20, -25, and -27 mRNA expression is regulated similarly in association with hibernation. Southern blot analyses of the squirrel family with each of chipmunk HP-20, -25, and -27 cDNA revealed that a nonhibernating species (tree squirrel) as well as another hibernating species (ground squirrel) retained the corresponding genes. However, their transcripts were detected only with the hibernating species, and in hibernating ground squirrels, their levels were greatly reduced compared with those in nonhibernating animals, as were the cases with the chipmunk. These observations are the first line of evidence for occurrence of hibernation-associated gene regulation. The results would indicate the commitment of HP-20, -25, and -27 to hibernation and support the idea that genetic controls are involved in mammalian hibernation.

Amino Acid Sequence↗
PubMedDate not supplied

Impact of delayed reperfusion of myocardial hibernation on myocardial ultrastructure and function and their recoveries after reperfusion in a pig model of myocardial hibernation.

UNLABELLED: This study examined the effect of delayed reperfusion of myocardial hibernation from 24 hours to 7 days on myocardial ultrastructural and functional changes and their recoveries after reperfusion. BACKGROUND: We have previously shown in pigs that after reperfusion the functional and structural alterations in short-term myocardial hibernation which was reperfused in 24 hours can recover in 7 days. The effect of delayed reperfusion of hibernating myocardium on the extent and severity of cellular and extracellular structural changes of hibernating myocardium, and their recoveries after reperfusion is not known. METHODS AND RESULTS: A severe LAD stenosis was created in 27 pigs, reducing resting flow by 30-40% immediately after placement of the stenosis and producing acute ischemia as evidenced by regional lactate production, a decrease in regional coronary venous pH, reduced regional wall thickening (from 38.5 +/- 5.1% to 10.4 +/- 8.0%) and a 33% reduction of regional oxygen consumption. The stenosis was maintained either for 24 hours in 9 pigs (group 1) with LAD flow of 0.65 +/- 0.13 ml/min/g (38% reduction), or for 7 days in 17 pigs (group 2) with LAD flow of 0.67 +/- 0.14 ml/min/g (36% reduction). There were no differences (p = NS) in the reduction of wall thickening, rate-pressure product, lactate production, or regional oxygen consumption between group 1 and group 2. Quantitative morphometric evaluation of the ultrastructure on electromicrographs revealed a greater decrease in sarcomere volume and a higher incidence of myocytes with reduced sarcomere volume in 7-day than in 24-hour hibernating regions (53 +/- 19% versus 33 +/- 14%, p < 0.05). Patchy myocardial necrosis with replacement fibrosis was common, but 6 of the 18 pigs had no myocardial necrosis or replacement fibrosis in the 7-day hibernating group, and 4 of 9 pigs had no patchy myocyte necrosis in the 24 hour hibernating group. In 6 pigs in group 1 in which the stenosis was then released and hibernating myocardium reperfused in 24 hours, regional wall thickening recovered to 30 +/- 6% (p = NS compared to baseline) after one week of reperfusion. In 12 pigs in group 2 in which the stenosis was released and hibernating myocardium reperfused in 7 days, regional wall thickening recovered slowly, from 10.1 +/- 7.2% to 18.1 +/- 8.3% at one week (n = 5) and to 28.0 +/- 3.6% at 3-4 weeks of reperfusion (n = 7, p < 0.05 compared to baseline). Similarly, the sarcomere volume or myofilament recovered significantly (p < 0.01) and was not different compared to the normal region (p = NS) in the 24-hour hibernating region of group 1, but the recovery was much slower and was incomplete at 4 weeks (p < 0.01) compared to baseline in the 7-day hibernating region of group 2. Recovery of regional wall thickening correlated with ultrstructural recovery (p < 0.01). By multivariate stepwise regression analysis, the degree of LAD flow reduction, the extent of fibrosis, and myofilament loss were independent predictors of the extent of functional recovery. CONCLUSIONS: In a porcine model of myocardial hibernation with myocardial hypoperfusion, systolic dysfunction, and metabolic adaptations, a longer period of myocardial hibernation with delayed reperfusion was associated with more severe abnormalities of myocytes. an increasing interstitial fibrosis, and more protracted myofibrillar and functional recoveries after reperfusion. The extent of functional recovery is related to the degree of coronary flow reduction, the severity of the ultrastructural changes, and the extent of interstitial fibrosis.

Animals↗
PubMed2002

Role of the antioxidant ascorbate in hibernation and warming from hibernation.

Ground squirrels tolerate up to 90% reductions in cerebral blood flow during hibernation as well as rapid reperfusion upon periodic arousal from torpor without apparent neurological damage. Thus, hibernation is studied as a model of tolerance to cerebral ischemia and other types of brain injury. Metabolic suppression likely plays a primary adaptive role that allows hibernating species to tolerate dramatic fluctuations in blood flow. Several other aspects of hibernation physiology are also consistent with tolerance to ischemia and reperfusion suggesting that multiple neuroprotective adaptations may work in concert during hibernation. The purpose of the present work is to review evidence for enhanced antioxidant defense systems during hibernation, with a focus on ascorbate, and discuss potential roles of these antioxidants during hibernation. In concert with dramatic decreases in blood flow, nutrient and oxygen delivery, plasma concentrations of the antioxidant ascorbate [(Asc)p] increase 3-5-fold during hibernation. In contrast, during re-warming, [Asc]p declines at a relatively rapid rate that peaks at the time of maximal O(2) consumption. This peak in O(2) consumption also coincides with a brief rise in plasma urate concentration consistent with a surge in reactive oxygen species production. Overall, data suggest that elevated concentration of plasma ascorbate is poised for distribution to metabolically active tissues during the surge in oxidative metabolism that accompanies re-warming during hibernation. This pool of ascorbate, as well as increased expression of other antioxidant defense systems, may protect vulnerable tissues from oxidative stress during hibernation and re-warming from hibernation. Better understanding of the role of ascorbate in hibernation may guide use of ascorbate and other antioxidants in treatment of stroke, head trauma and neurodegenerative disease.

Animals↗
PubMed1988

Further studies on opioids and hibernation: delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels.

To examine the possible involvement of multiple opioid receptors in animal hibernation, we infused opioids selective for mu, kappa, and delta opioid receptors into summer-active ground squirrels (Citellus tridecemlineatus). The effects of those opioid treatments on the hibernation induced by HIT (Hibernation Induction Trigger) were also examined. Mu opioids morphine (1.50 mg/kg/day) and morphiceptin (0.82 mg/kg/day) and kappa opioid peptide dynorphin A (0.82 mg/kg/day) did not induce hibernation. On the contrary, morphine, morphiceptin and dynorphin A antagonized HIT-induced hibernation in summer-active ground squirrels. Infusion of delta opioid DADLE (D-Ala2-D-Leu5 enkephalin; 1.50 mg/kg/day), however, induced summer hibernation in a manner comparable to that induced by HIT. It is concluded therefore that delta opioid receptor and its ligand may be intimately involved in animal hibernation. In view of the fact that HIT was obtained from winter hibernating animals and might therefore be responsible for natural hibernation, our results also suggest that naturally occurring mu and kappa opioids may play an important role in the arousal state of hibernation.

Analgesics↗
PubMed1992

Plasma lipoprotein cholesterol concentrations in the golden-mantled ground squirrel (Spermophilus lateralis): a comparison between pre-hibernators and hibernators.

1. The concentrations of total cholesterol (free cholesterol plus cholesteryl ester) in the plasma and in two lipoprotein fractions of golden-mantled ground squirrels (Spermophilus lateralis) were measured during pre-hibernation and compared to those values measured during hibernation. 2. Hibernating ground squirrels had significantly higher (P less than 0.005) very low density lipoprotein plus low density lipoprotein cholesterol (VLDL + LDL-C) concentrations than did pre-hibernating ground squirrels. 3. Hibernating squirrels additionally exhibited significantly higher (P less than 0.005) total plasma cholesterol concentration per high density lipoprotein cholesterol concentration (TPC/HDL-C) ratios than did pre-hibernating squirrels. 4. The significant differences in the lipoprotein cholesterol concentrations observed in this study suggest that lipoprotein metabolism in pre-hibernators was significantly different from that in hibernators and was a reflection of the marked biochemical and physiological adjustments these animals must undergo during their transition from pre-hibernation to hibernation.

Animals↗
PubMed1999

Determination of striatal extracellular gamma-aminobutyric acid in non-hibernating and hibernating arctic ground squirrels using quantitative microdialysis.

This study determined extracellular concentrations of gamma-aminobutyric acid ([GABA](ecf)) in striatum of non-hibernating and hibernating arctic ground squirrels to test the hypothesis that an increase in [GABA](ecf) was associated with profound CNS depression during hibernation. Quantitative microdialysis procedures were employed to circumvent the effects of low temperature on the relative recovery of the analyte across the dialysis membrane and yielded for the first time quantitative in vivo estimates of [GABA](ecf) in any brain region or any species. Laboratory housed, wild caught Arctic ground squirrels (Spermophilus parryii) were implanted intraperitoneally with radio transmitters that enabled the telemetric monitoring of activity and core body temperature (T(b)) and bilaterally implanted with cranial guide tubes that enabled the implantation of microdialysis probes into the striatum. Striatal [GABA](ecf) was determined in unrestrained, non-hibernating ground squirrels (T(b) range 34.7-38.9 degrees C) and hibernating ground squirrels (T(b) range 2.9-3.9 degrees C) using extrapolation to zero flow and very slow flow microdialysis techniques. The results show that [GABA](ecf) in non-hibernating squirrels was 73 nM and this level was decreased by approximately 50% during hibernation thereby suggesting that an increase in [GABA](ecf) does not play a major role in CNS depression during hibernation. The reduction of [GABA](ecf) parallels a decrease in plasma and CSF [glucose] and may be related to a decrease in GABA synthesis or reduced voltage dependent release. This paper demonstrates that measurement of extracellular concentrations of neurotransmitters in animals with vastly different body temperatures is possible using microdialysis techniques of extrapolation to zero flow or very slow flow rates that enable 100% recovery. Such quantitative techniques may prove valuable in the study of the neurochemistry of the cerebral mechanisms of hibernation and tolerance to cerebral ischemia exhibited by hibernating animals.

Adaptation, Physiological↗
PubMed2000

Induction of unseasonable hibernation and involvement of serotonin in entrance into and maintenance of its hibernation of chipmunks T. asiaticus.

Chipmunks that had been housed at 22 degrees C under a light-dark cycle of 14L:10D for at least one year were exposed to a short photoperiod (10L:14D) and low temperature to induce unseasonable hibernation. We were able to induce hibernation at any time of year and there was no significant difference in the duration of the hibernation bout, the duration of interbout euthermia and duration of bouts of torpor throughout the year; however entrance into hibernation took about 60 days in summer but only about 30 days in any other seasons. In addition, interbout euthermia predominantly occurred during the light phase in winter, whereas in spring interbout euthermia occurred equally in the light and dark phases. These results suggest that both the circadian and circannual systems are linked to hibernation in chipmunks. Subcutaneous infusion of a serotonin antagonist, para-chlorophenylalanine (PCPA), facilitated entrance into and interrupted hibernation in aroused and hibernating chipmunks in summer, respectively. On the other hand, opioid antagonist, naloxone, did not affect hibernation, but extended the period of interbout euthermia. These results suggest that the role of serotonin in entrance into and maintenance of hibernation in chipmunks is independent of the circannual system, and that opioid system may not be involved in hibernation in chipmunks.

Animals↗
PubMed2000

The carvedilol hibernation reversible ischaemia trial, marker of success (CHRISTMAS) study. Methodology of a randomised, placebo controlled, multicentre study of carvedilol in hibernation and heart failure.

BACKGROUND: Carvedilol reduces mortality and improves symptoms and ejection fraction in ischemic heart failure, but its mode of action is not well defined and not all patients respond to treatment. The aim of the CHRISTMAS (Carvedilol Hibernation Reversible Ischaemia Trial, Marker of Success) study is to examine whether hibernation may be a significant factor determining this response. This paper describes the methodology and the rationale for the choice of the nuclear cardiology and echocardiography imaging techniques used in the study. METHODS AND RESULTS: The CHRISTMAS study is a double-blind, randomised, parallel group, multinational study of oral carvedilol versus placebo in patients with chronic stable heart failure due to left ventricular systolic dysfunction from coronary artery disease. The study aims to randomise 400 patients who are on optimal treatment. Two parallel groups will be randomised to carvedilol or placebo, namely 200 with hibernating myocardium at baseline and 200 matched patients without. The presence of hibernation is defined from a mismatch between regional contractile function and regional viability, measured by echocardiography (severe segmental asynergy) and nitrate prepared resting Tc99m-MIBI myocardial perfusion imaging (segmental activity >60%). The primary treatment-related end-point of the study is the comparison of the mean change, from baseline to the final visit, in radionuclide-determined left ventricular ejection fraction in patients on placebo with those on carvedilol, between the groups designated as hibernating and non-hibernating. Other end-points being examined include the prevalence of hibernation in heart failure, the relationship between the volume of hibernating myocardium and the ejection fraction response, the prevalence of reversible ischemia in heart failure, and the comparison of echo with gated SPECT. To date, 303 patients have been screened and 251 patients randomised in the study. The study aims to report in 2000. CONCLUSIONS: The CHRISTMAS study addresses the issue of whether the presence of hibernation is a predictor of the ejection fraction response to carvedilol in heart failure. It also examines the potential role of medical therapy in hibernation as well as a number of other end-points. The study may potentially lead to an important new role for nuclear cardiology in heart failure, and demonstrates important synergy between cardiac imaging and the pharmaceutical industry.

Adrenergic beta-Antagonists↗
PubMed1988

Cholecystokinin (CCK) and vasoactive intestinal peptide (VIP) in the cerebral cortex of the non-hibernating and hibernating golden mantled ground squirrel.

1. The effect of hibernation on cerebral cortical concentrations of cholecystokinin and vasoactive intestinal peptide was investigated in the golden mantled ground squirrel (Citellus lateralis). 2. During hibernation, cortical brain weight decreased to 83% of the non-hibernating weight. 3. The concentration of the small form of CCK was significantly reduced. The concentration of the large forms of immunoreactive CCK did not significantly change during hibernation. The molecular forms of CCK appeared the same both before and during hibernation. 4. Of note, the concentration of vasoactive intestinal peptide significantly increased during hibernation. 5. Since there was a three-fold reduction in the ratio of large to small forms of CCK during hibernation, this suggests that post-translational processing of the precursor peptides are markedly reduced during hibernation.

Animals↗
PubMed1978

Isolation of a hibernation inducing trigger(s) from the plasma of hibernating woodchucks.

Plasma from hibernating woodchucks was desalted utilizing a hollow fiber device having a M. W. cut-off of 5,000. This preparation was fractionated by isoelectric focusing (IEF) in a pH gradient extending from 3.5 to 10.0 resulting in protein components having isoelectric points (pIs) of 4.5, 5.2, 5.5, 6.3, and 7.0. Fraction I (comprised of proteins having pIs of 4.5 and 5.2) induced hibernation within 2 to 6 days in 8 out of 10 summer-active ground squirrels. Fraction II (pI 5.5) and Fraction III (pI 6.3 and 7.0) failed to induce any summer hibernation in 10 animal test groups at identical sample concentrations. Polyacrylamide gel electrophoresis of Fraction I indicated that albumin was a major constituent of this still heterogeneous preparation. Thus, in order to more clearly define the plasma locus of this hibernation inducing trigger(s) (HIT) molecule, whole plasma and/or Fraction I was fractionated by 3 distinct resolving techniques. These included sub-fractionation of Fraction I by isoelectric focusing utilizing a narrower pH gradient extending from 3.5 to 6.0, isotachophoresis of whole plasma and affinity chromatography of Fraction I and whole plasma. A total of 40 summer-active ground squirrels were injected and assayed for HIT activity with fractionated preparations derived by the three previously cited separation techniques. A total of 18 of these summer-active ground squirrels hibernated. However, a much more impressive figure is that 16 out of 21 animals hibernated when injected with resolved hibernating plasma fractions in which albumin was the predominant plasma protein. A total of 8 control animals were injected with vehicle and none of these hibernated.

Animals↗
PubMed2000

[Pharmacological aspects of mammalian hibernation: central thermoregulation factors in hibernation cycle].

Hibernation in mammalians such as hamsters is a physiological state characterized by an extreme reduction of various functions such as body temperature and metabolism. Under such severe conditions, the central nervous system (CNS) activity is maintained at a functionally responsive level. Although hibernation is an interesting behavioral state, the physiological mechanisms of the introduction to and/or the arousal from hibernation have not been clearly defined. Intracerebroventricularly (i.c.v.) injected adenosine produces hypothermia in various animals. The effect of adenosine is generated by A1-receptors and is caused by the suppression of the thermogenesis center of the posterior hypothalamus. At on ambient temperature of 5, i.c.v. injected N6-cyclohexyladenosine (CHA) adenosine A1-receptor agonist induces profound hypothermia in hamsters. Although the time course of the descent of body temperature coincided with that of entry into natural hibernation, the effect was not antagonized by 8-cyclopentyltheophyllin (CPT), an adenosine A1-receptor antagonist. However, i.c.v. injection of CPT elevated the body temperature and interrupted hibernation, albeit the deep-phase (post-entry 30 h) was unaffected. This result suggests that a different system may suppress the thermogenesis center in the deep hibernation phase. Interestingly, i.c.v. injected thyrotropin releasing hormone (TRH) elevated the body temperature in both hibernation phases in hamsters. These findings suggest that the central adenosine and TRH play important roles in thermoregulation and that the new thermogenesis system, activating in low-body temperature, is induced in naturally hibernating animals.

Adenosine↗
PubMed1987

Opioids and hibernation. I. Effects of naloxone on bear HIT'S depression of guinea pig ileum contractility and on induction of summer hibernation in the ground squirrel.

Summer hibernation in ground squirrels (Citellus tridecemlineatus) can be induced by intravenous injection of hibernation-induction trigger (HIT) from winter bear plasma or its albumin fraction. In this study, we show that bear HIT depresses electrically-induced contraction of the guinea pig ileum myenteric plexus-longitudinal muscle preparation, and that naloxone, at 100, 1,000, or even 4,000 nM, fails to reverse that effect. In a simultaneous study, four sets of ground squirrels were implanted with osmotic minipumps which delivered solutions at a controlled and continuous rate. Two of the groups had pumps delivering naloxone at 1 mg/kg body weight per hour. The other two groups had saline-filled pumps (controls). One set of squirrels from each of the saline- and naloxone-filled pump groups were then injected intravenously with winter bear plasma. The remaining two groups of squirrels were injected with winter bear albumin fraction. Hibernation frequency was determined by measurements of core temperature (from surgically-implanted radio capsules), respiratory rate, and bouts of activity. Squirrels with saline-filled pumps hibernated four times more frequently than the naloxone groups. To confirm these findings, three squirrels from each naloxone group were reinjected with bear HIT after removal of the pumps. These six squirrels then hibernated over four times their previous frequency. Results suggest that bear HIT is not itself an opioid (since naloxone did not reverse bear HIT's depression of electrically-induced contraction of guinea pig ileum). The fact that bear HIT's effect of inducing summer hibernation in ground squirrels is effectively blocked in vivo by naloxone leads to the speculation that HIT may be either a precursor of endogenous opioids or a potent releaser of them, which, in turn, induce hibernation.

Animals↗
PubMed1998

Rapid temperature changes induce adenosine-mediated depression of synaptic transmission in hippocampal slices from rats (non-hibernators) but not in slices from golden hamsters (hibernators).

Disturbances in neuronal communication induced by rapid temperature changes are a risk in the context of accidental hypothermia and would be fatal for hibernators during arousal from hibernation. Therefore, we investigated the effects of rapid temperature changes on synaptically induced CA1 population spikes in hippocampal slices from golden hamsters (hibernators) and rats (non-hibernators). Temperature was changed ramp-like by 0.3 degrees C/min, which corresponds to the rise of body temperature in golden hamsters during arousal from hibernation. During cooling from 35 to 10-15 degrees C, the population spike amplitude increased, reached maximal values at 25-30 degrees C and 20-25 degrees C in hamster and rat slices, respectively, and then decreased with further cooling. During rewarming, hamster slices displayed the same temperature dependence as during cooling. In contrast, in rat slices dynamic effects of the temperature change occurred. These were most obvious in a strong depression of the spike amplitude during rewarming as compared to cooling. Above 26-29 degrees C, the depression was superimposed by an excitatory effect. The depression was largely attenuated by theophylline (100-200 microM) and thus seems to be based on an increase of the concentration of endogenous adenosine, which in turn may result from an imbalance in energy metabolism during warming. The lack of warming-related depression in hamster slices can be explained by a lower sensitivity for adenosine as compared to rat slices. In addition, a better resistance of metabolic balance against rapid temperature changes may prevent large elevations of endogenous adenosine in the hamster hippocampus. For hibernators, the avoidance of temperature change-induced disturbances of neuronal communication may be a prerequisite for safe arousal from hibernation.

Acclimatization↗