Physical dependence on morphine fails to develop during the hibernating state.

Physical dependence on morphine occurs in a typical fashion during the active state of the mammalian hibernator Citellus lateralis, but does not occur when morphine exposure is confined to the hibernating state. Morphine exposure during hibernation can produce stereotyped behavior, thus demonstrating partial responsiveness of the central nervous system to opioids during this natural state.

Spinal cord immunoreactive TRH is altered after local traumatic injury.

The effect of impaction-induced spinal trauma on the concentration of immunoreactive TRH (TRH-ir) in the spinal cord was studied. Samples were obtained from tissues proximal to, distal to, and at the site of injury at 30 min, 1 hr, 4 hr, and 6 weeks after impaction. After an initial 38% depletion of TRH-ir at the injury site at 30 min, concentrations were progressively elevated over time at all sites. These elevations reached statistical significance in the proximal and distal segments by 4 hr posttrauma. By 6 weeks, a rostral-caudal gradient of TRH-ir concentration was observed, indicating that axoplasmic transport was restricted. The gradient was characterized by a significant TRH-ir elevation proximal to, and a 60% depletion distal to, the injury. The short-term TRH-ir elevation measured indicates that the ability of exogenously administered TRH to reduce the incidence of posttraumatic functional deficit stems from a restoration of endogenous TRH action. The role of the raphe-spinal tract in the development of traumatic paralysis is considered.

Antagonism of brain opioid peptide action reduces hibernation bout duration.

The effect of continuous intracerebroventricular (i.c.v.) administration of naloxone on the duration of individual bouts of hibernation was investigated in the golden-mantled ground squirrel (Citellus lateralis). Following entrance into hibernation, naloxone was continuously administered by an osmotic minipump at a rate of 1 microliter/h through a chronically implanted unilateral i.c.v. cannula guide. Naloxone (1, 5 and 7.5 micrograms/microliter) produced a dose-dependent reduction in hibernation bout duration ranging from 1 to 4 days (13.9-62.3% of expected bout duration). These data suggest that selected endogenous opioid system neurons may contribute to the CNS maintenance of the hibernating state and, consequently, to the overall conservation of energy in this species.

In vivo analysis of dopamine and its metabolites in the caudate nucleus during euthermia and hibernation.

Golden-mantled ground squirrels (Citellus lateralis) were chronically implanted with a unilateral push-pull cannula in the caudate nucleus. Perfusates obtained in these unanesthetized, unrestrained animals during the euthermic (non-hibernating) and hibernating states were analyzed for dopamine (DA) and its metabolites (homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3-methoxy-4-hydroxyphenethanol (MOPET) using high performance liquid chromatography with electrochemical detection. The data revealed clear differences in the performance of the caudate DA system in the two states. During the euthermic state, DA metabolism was indicative of a constant and high turnover rate. Free DA was not detectable in the majority of samples, HVA was detected at consistently high levels, and DOPAC and conjugated DA were present at low levels. By contrast, DA metabolism was sharply altered during hibernation. Free DA was present at high concentrations and HVA concentrations were low. DOPAC was not detected in any sample whereas MOPET was present in all samples. Conjugated DA was present at high concentrations during the second half of the hibernation bout. The shift in the post-release disposition of DA could enhance the stability of DA receptors (i.e. prevent supersensitivity) during the prolonged periods of reduced neural activity typical of hibernation.

Reduction of hibernation bout duration by intraventricular infusion of met-enkephalin.

The potential of brain met-enkephalin (met-enk) systems to modulate central nervous system (CNS) activity during periods of general depression (modeled by the mammalian hibernation state) was studied in the ground squirrel (Citellus lateralis). Following entrance into hibernation, continuous met-enk infusion into the lateral ventricle (1 microliter/h; 0.2, 1 and 5 micrograms/microliter) produced a dose-dependent reduction in bout duration ranging from 1.2 to 3.9 days (13.8-44.6% of baseline bout duration). We suggest that the activity of met-enk-releasing neurons may serve to increase the excitability of the depressed CNS, thus accelerating the termination of the hibernation bout.

Morphine distribution following infusion into lateral ventricle during hibernation and euthermia.

The intracerebral pattern of diffusion of 3H-morphine was studied autoradiographically following continuous infusion (4, 9, and 18 hr; 1 microliter/hr) into the lateral ventricle during hibernation and euthermia (i.e., not hibernating) in ground squirrels (Citellus lateralis). Morphine diffusion into the parenchyma during both states was extensive, resulting in increased autoradiographic optical density of 34 structures examined. The zone of radiolabeled tissue was primarily ipsilateral, and it expanded with increasing duration of infusion. Diffusion into contralateral regions was more evident in hibernation, although the total area of radiolabeled tissue was not significantly greater than that of euthermic animals. The average optical densities of autoradiographs from hibernating brains were significantly greater than those from euthermic animals, suggesting greater accumulation of labeled material during hibernation. These data suggest that neuroactive compounds released into the ventricular space can achieve widespread distribution within the brain during hibernation (in which all physiological parameters are profoundly depressed) as well as during euthermia. Thus, the apparent lack of development of physical dependence to morphine during hibernation is not due to a restricted distribution of morphine in the hibernating brain.

Monoaminergic responses to spinal trauma. Participation of serotonin in posttraumatic progression of neural damage.

The monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their major metabolites were measured in the spinal cord of rabbits following laminectomy or impact injury to the thoracic cord. Samples were taken 30 minutes, 60 minutes, 4 hours, and 6 weeks after injury. Utilization ratios (metabolite/transmitter) were calculated from the data. Turnover rates for NE and DA were also calculated at 30 minutes using the alpha-methylparatyrosine method. Trauma resulted in rapid and sustained elevations in 5-HT concentration at and around the injury site. The catecholamines were depleted slightly at the injury site. Levels of 5-hydroxyindole-3-acetic acid were elevated at 30 minutes but fell to baseline by 4 hours, resulting in a decrease in the 5-HT utilization ratio. The utilization and turnover of NE was increased at the injury site, while DA function was not affected. The large short-term increase in 5-HT levels may have been due to extravasation of platelet 5-HT stores into spinal tissue, rather than due to changes in neuronal 5-HT metabolism. At 6 weeks after injury, each monoamine and metabolite appeared to accumulate in spinal cord tissue proximal to the insult. Distal to the injury, depleted amine stores displayed augmented utilization. The data are discussed in terms of a serotonergic hypothesis of the progression of neural damage after trauma, with the interaction of 5-HT with raphe-spinal nerve terminals as a principal event.

Seasonal variation of morphine physical dependence.

The characteristics of morphine physical dependence in ground squirrels (Citellus lateralis) were examined during each of the four annual seasons. The results showed that this rodent hibernator exhibits a strong and characteristic naloxone-precipitated abstinence syndrome during its non-hibernation state, irrespective of the season. Although qualitatively unchanged throughout the year, the abstinence syndrome showed clear quantitative seasonal differences. These differences were evident in terms of both the number of occurrences of particular signs and the percentage of the morphine-dependent population exhibiting them.

Differential effect of environmental temperature on morphine physical dependence and abstinence.

1) Ambient temperature (Ta) significantly influenced the display of 4 of the 14 naloxone-precipitated withdrawal signs (nesting, flat posture, vocalization, dyspnea) in morphine-dependent, non-hibernating ground squirrels (Citellus lateralis). 2) Analysis of variance performed on the six quantified signs revealed that Ta during withdrawal, but not during the development of physical dependence, was a significant factor in determining the expression of two signs (nesting and vocalization). 3) The interaction between the influence of Ta during the periods of morphine administration and abstinence was a significant factor in determining the expression of nesting behavior, a finding that is consistent with the natural role of nesting as a behavioral thermoregulatory response. 4) We conclude that environmental temperature modulates the expression of selected components of the naloxone-precipitated abstinence syndrome in C. lateralis without exerting a measurable influence on the development of morphine physical dependence itself.

Treatment of experimental spinal trauma with thyrotropin-releasing hormone: central serotonergic and vascular mechanisms of action.

The sites and mechanisms by which thyrotropin-releasing hormone (TRH) may ameliorate the effects of spinal cord contusion were studied in the rabbit. We have examined the actions of an effective intravenous TRH infusion on the spinal content and utilization of the monoamine neurotransmitters (norepinephrine [NE], dopamine [DA], and serotonin [5-HT]) in both control and injured animals. The ability of TRH to penetrate the blood-brain barrier was determined by the measurement of spinal cord TRH immunoreactivity and the effect of TRH upon the development of traumatic edema was evaluated. TRH was found to enter the spinal cord to a large extent in approximately half the animals, but to a lesser degree in the remainder. This indicates the potential for a central site of action. In this regard, TRH induced a significant increase in the metabolism or utilization of 5-HT above the injury site. This effect was not observed in control animals. Finally, TRH was able to cancel the formation of edema at the injury site. These results are correlated with previously described mechanisms and are discussed in terms of the co-existence of TRH and 5-HT in raphe-spinal neurons descending from the medulla.