Ambient temperature related sleep changes in rats neonatally treated with capsaicin

Ambient temperature related sleep changes in rats neonatally treated with capsaicin. PHYSIOL BEHAV 00(0) 000-000, 2004. The study was conducted on adult male Wistar rats, neonatally treated with capsaicin to destroy the peripheral warm receptors. The sleep-wakefulness was recorded for 5 h at an ambient temperature (T(amb)) of 18, 24, 30 and 33 degrees C on different days. The rectal temperatures (T(r)) of the rats were studied on exposure to 6 and 37 degrees C for 2 h to assess their thermoregulatory ability. The changes in the behavioral thermoregulation were assessed by noting the thermal preference of rats when they were placed in an environmental chamber with 3 interconnected compartments maintained at 24, 27 and 30 degrees C. Slow wave (SWS) and rapid eye movement (REM) sleep were decreased at 18 degrees C and increased at 30 degrees C, in control rats. There was a decrease in REM sleep and no change in SWS when T(amb) was raised from 30 to 33 degrees C. However, in neonatally capsaicin treated rats, sleep was increased even at 33 degrees C, though there was no significant change in sleep when T(amb) was increased from 18 to 24 degrees C. Capsaicin treated rats showed thermoregulatory deficiency at 37 degrees C but the thermal preference was unaltered in these rats. The results suggest that the central warm receptors can produce alteration in sleep at different T(amb), even in absence of peripheral warm receptors. The behavioral thermoregulation was unaffected in these rats, though their ability to defend the body temperature in warm environment was affected.     

Self-stimulation,salicylate and ambient temperature

Effects of sodium salicylate and of cold or warm environment on intracranial self-stimulation and on colonic temperature of rats were assessed. Colonic temperature at the end of intracranial self-stimulation sessions was significantly lower after salicylate than after saline in 33 out of 36 animals. Self-stimulation rate was either decreased or increased by one or several of the three independent variables (salicylate, warm environment, cold environment), at only some scattered sites. These effects were frequently independent of one another. These results that only some rewarding sites are related to temperature regulation and, that each rewarding site operates as a discrete elementary reinforcing unit with its particular pattern of susceptibilities to distinct drives or substances.     

Intrinsic heart rate in the dog determined by pharmacologic denervation

Intrinsic heart rate was measured in 19 dogs in 76 experiments after autonomic blockade, using various forms of anesthesia. Measurements were made in conscious dogs (n = 16) and in dogs in neuroleptanesthesia (n = 54) or under pentobarbital sodium (n = 6). Temperature, arterial pH, and blood gases were kept within narrow limits. Adrenergic blockade was achieved by phenoxybenzamine (2 mg X kg-1) and propranolol (2 mg X kg-1, followed by 2 mg X kg-1 X h-1). The parasympathetic system was blocked either by atropine (0.5 mg X kg-1, followed by 0.5 mg X kg-1 X h-1) and hexamethonium (20 mg X kg-1, followed by 10 mg X kg-1 X h-1) or by atropine and bilateral cervical vagotomy. Administration of hexamethonium or vagotomy was needed to block the vagal cardioacceleration unmasked by the administration of muscarinic blocking agents in conscious dogs and in dogs in neuroleptanesthesia. The mean denervated heart rate was 142.8 beats/min. This value is higher than that reported for surgically denervated hearts, the difference very likely reflecting the activity of the intact parasympathetic intrinsic cardiac innervation in surgical preparations. The estimated intraindividual and interindividual SD were 9.7 and 19.4 beats/min, respectively. The highly significant interindividual variation (P less than 0.01) contradicts the concept of an intrinsic heart rate as a practically constant species-dependent quantity.     

Behavioral self warming and cooling of spinal canal by rats

Rats with a chronic thermode implanted in their spinal canal could bar-press to warm or cool their spinal cord. With a “cold” lever, they cooled their spinal canal less in a cold environment than in a warm environment. With a “warm” lever they behaved in the same way, i.e., warmed their spinal canal more in a warm than in a cold environment. In a two-lever situation they pressed the cold and the warm levers alternately in warm environment, but did not press either in cold environment. These results suggest that cold and warm spinal cord provided the rats with rewards of a different nature.     

Capsaicin pretreatment modifies hydrogen sulphide-induced pulmonary injury in rats.

One of the major target organs of hydrogen sulphide gas is the lung. Exfoliation of upper respiratory epithelia and pulmonary edema are prominent effects. Various neuropeptides contained in afferent C-fibres are intimately associated with the epithelia of the conducting airways and are liberated upon exposure to noxious gases. We sought to determine their role in the pathogenesis of hydrogen-sulphide-induced pulmonary injury by pretreating rats with the neurotoxin, capsaicin, which is known to ablate a subpopulation of vagal afferent C-fibres. Groups of capsaicin and saline (control) pretreated Fischer 344 rats were exposed to an edemogenic concentration of hydrogen sulphide (525-559 mg/m3) for 4 hr. Mortality was significantly greater (p less than 0.01) in the capsaicin treated rats (12/12) compared to the control animals (2/12). Pulmonary injury was also more severe in the capsaicin pretreated animals as assessed by lung water content, histological grade of pulmonary edema and protein in the broncho-alveolar fluid. Animals depleted of substance P exhibited a significantly greater (p less than 0.01) degree of bronchial epithelial cell exfoliation and ulceration following exposure to hydrogen sulphide. These experiments indicate that capsaicin sensitive sensory nerves may play a major role in pulmonary defense against the effects of inhaled toxic gases such as hydrogen sulphide.     

Capsaicin-induced excitation of locus coeruleus neurons

The noradrenergic pontine nucleus locus coeruleus (LC) seems to be involved in sensory processing. In the present study, the effect of capsaicin, a drug which specifically interferes with chemosensitive primary afferents, on LC firing rate was analysed, utilizing electrophysiological techniques. In control rats, low doses of capsaicin (1-8 micrograms kg-1 i.v.) caused a marked excitation of LC units. The effect was instantaneous in onset but short-lasting and no signs of tachyphylaxis were observed. The excitation was maintained in adult rats treated as neonates with high doses of capsaicin (50 mg kg-1 s.c.) but almost totally prevented by pretreatment of adult rats with high doses of capsaicin (300 mg kg-1 s.c.). According to our histological data, using selective silver impregnation techniques, the LC seems not to receive innervation by sensory primary afferents. It is proposed that the capsaicin-induced excitation of LC neurons is a centrally mediated effect and might, in part, be involved in the analgetic effect induced by the drug.     

Effect of p-chlorophenylalanine on thermoregulation in unrestrained rats

p-Chlorophenylalanine (PCPA), a serotonin depletor, was used to investigate thermoregulation of unrestrained unanesthetized rats exposed to warm (approximately 32 degrees C) and cold (approximately 3 degrees C) environments. PCPA (300 mg/kg, ip) was administered approximately 48-96 h prior to the experimental trials. After 60 min of warm exposure, PCPA-treated rats had a significantly smaller increase in mean tail temperature (3.05 degrees C) and a greater increase in mean core temperature (1.47 degrees C) than did the control rats (6.13 and 1.20 degrees C, respectively) as measured via chronically implanted thermistors. A noninvasive method, infrared photography, was also used to monitor skin temperatures following heat exposure. Changes were qualitatively similar to those seen with thermistors, although differences between control and PCPA-treated groups were not statistically significant. During cold exposure, thermistor measurements indicated that the decrease in mean core temperature of the PCPA-treated rats (0.62 degrees C) did significantly differ from that of the controls (1.11 degrees C), whereas tail temperatures did not. These data confirm other studies implicating serotonin in the thermoregulation of rats. In particular, these results show that in a warm environment, PCPA may alter, albeit subtly, peripheral vasodilation in unrestrained rats.     

The effect of capsaïcin on temperature regulation of the rat

1. Subcutaneous injection of capsa?cin (6-11 mg, or 21-66 mg cumulative), permanently reduced the capacity of rats to withstand a hot environment, as described by Jancsó-Gábor et al. (1970). 2. The treated rats thermoregulatory behaviour was not different from that of control rats, both in hot and cold environments. 3. Saliva secretion was decreased in a hot environment, and the weight of the submaxillary glands was reduced in capsa?cinized rats. 4. It is concluded that hyperthermia present in treated rats when subjected to a warm environment is not due to a disruption of sensu stricto temperature regulation, but rather to a decreased salivary secretion. Whether this decrease has a central or a peripheral origin is not known.     

LPS fever in old rats depends on the ambient temperature

In earlier work, we found that following lipopolysaccharide (LPS) injection at an ambient temperature (Ta) of 23 degrees C, old rats developed blunted fevers compared with those of young rats. However, the old rats did become febrile if placed in a thermally graded alleyway: they spent more time in the warm end of the gradient and developed a significantly higher body temperature (Tb) than they did following saline injections. In the present experiments, we maintained old and young rats for 3 days at 20 or 31 degrees C (the Ta preferred by the old rats given LPS). After LPS (50 microg/kg ip), the young rats developed equivalent fevers at both Ta's. The old rats developed fevers that were equivalent to those of the young rats at 31 degrees C. At 20 degrees C, their fever was significantly lower. These results suggest that Ta plays a decisive role in the ability of old rats to mount febrile responses.     

Cold increases and warmth diminishes stress-induced rise of colonic temperature in rats.

It is generally believed that the rise of core temperature of rats induced by handling is due to a shift of set-point temperature as in fever. Changes in core temperature due to set-point shifts should not be affected by changes in the ambient temperature. Nevertheless, when the colonic temperature of rats was taken in a cold environment the usual emotional rise was higher and when the colonic temperature was taken in a warm environment the emotional rise was lower. These results contradict the hypothesis that the emotionally induced rise in temperature of rats is a fever.     

The effect of ambient temperature on rectal temperature,food intake and short term body weight in the capsaicin desensitized rat

1. .Subcutaneous injections of capsaicin (mean cumulative dose: 80.1±3.6 mg·kg^?1) permanently reduced the capacity of rats to withstand a hot environment when deprived of water. With water available, hyperthermia was discrete or absent in capsaicinized rats in hot environment.
2. Desensitization was followed by a significant decrease in both food intake and body weight. Treated rats recovered normal body weight after 3 weeks.
3. In a hot environment, compared to controls, food intake was significantly increased in capsaicin desensitized rats which maintained their body weight. In cold environment, food intake was decreased in capsaicin desensitized rats which lost body weight. At normal ambient temperature, food intake and body weight were similar in the 2 groups.
4. Caloric intake adjustment at high and at low temperatures was therefore disturbed in capsaicin desensitized rats. It is concluded that hypothalamic thermodetectors implicated in both thermoregulation and food intake behaviour could be partially damaged by capsaicin.

     

Thermoregulation in adult rats which have been treated with capsaicin as neonates

1. Subcutaneous or intrahypothalamic injections of capsaicin produce hypothermia in the neonate rat. Repeated injections with increasing doses of capsaicin result in unresponsiveness to this drug (capsaicin-desensitization).
2. Young rats aged 8–10 days which had received serial injections of capsaicin solution (a cumulative dose of 4.63 mg per animal) or of the solvent alone were subsequently tested as adults for their ability to thermoregulate.
3. On exposure to an ambient temperature of 41° C, adult rats which had been capsaicin-desensitized as neonates were unable to thermoregulate against overheating by means of autonomic responses whereas control littermates could maintain normal rectal temperature. However, autonomic thermoregulation against cold was unimpaired in the desensitized rats.
4. Skin-cooling operant behavior in heat stress was impaired in adult rats which had been capsaicin-desensitized as neonates whereas their skin-heating behavior was not different from that of control littermates.
5. These results suggest that the central and peripheral warm-receptors responsible for thermoregulation in the neonate rat are functionally mature at least inasmuch as they form a part of thermoregulatory system involved in lowering body temperature and can be desensitized by capsaicin. Moreover, such receptors, once desensitized 8–10 days after birth, apparently do not regain their function and are not regenerated or replaced during subsequent maturation of the animal.

     

Effects of diethylcarbamazine and cromolyn sodium on hypoxic pulmonary vasoconstriction in dogs

Evidence has recently been accumulated that leukotrienes might be involved in the still unknown biochemical mechanism of hypoxic pulmonary vasoconstriction. We therefore investigated the effects of i.v. cromolyn sodium, which prevents the release of leukotrienes from mast cells by a membrane stabilizing effect, and of i.v. diethylcarbamazine citrate (DEC), a leukotriene synthesis inhibitor, in 13 dogs challenged with the inhalation of 10% O2 in nitrogen (FIO2 0.1) during 10 min. The dogs were anaesthetized with pentobarbital, paralysed with pancuronium, ventilated with a FIO2 of 0.4 and equipped with catheters for the purpose of pulmonary and systemic vascular pressure measurements and thermodilution cardiac output determinations. Thirty minute infusions of DEC at respectively 100 mg, 400 mg, 2 g, 5 g, 10 g and 15 g (one dosage per dog) did not alter the hypoxic pulmonary pressor response. Dosages of 10 g and 15 g DEC were associated with systemic hypotension, and one additional dog given 20 g died in refractory shock. A continuous infusion of cromolyn sodium inhibited hypoxic pulmonary vasoconstriction, partially at 3 and 4.5 mg X kg-1 X min-1 (2 dogs) and completely at 6 mg X kg-1 X min-1 (3 dogs). A lower dosage of 1 mg X kg-1 X min-1 cromolyn sodium (one dog) had no circulatory effect. These results do not support the hypothesis that hypoxic pulmonary vasoconstriction is mediated by vasoconstricting leukotrienes in the dog. The mechanisms accounting for the inhibition of the pulmonary hypoxic pressor response by cromolyn sodium are uncertain.     

The effect of an intraperitoneal injection of capsaicin on the thermopreferendum in the frog (Rana esculenta)

In 7 frogs (Rana esculenta) weighing 70 to 180 g, thermopreferendum (Thp), measured by recording cutaneous temperature (Ts) in the animal placed in the warm end of an aqueous temperature gradient (0 degree C-40 degrees C), equalled 25 +/- 2 degrees C. After an intraperitoneal (IP) injection of 20 mg/kg of capsaicin, Thp was significantly decreased and equalled 3 +/- 1 degree C. The frogs then remained in the cold end of the gradient for 60 minutes. When the time of observation was extended to 3 hours, one frog died from hypothermia. Seven to 24 days after the capsaicin injection, Thp was still decreased in 4 surviving frogs (Thp = 15 +/- 2 degrees C). Capsaicin or isotonic saline solution injected in frogs maintained at 25 degrees C ambient temperature had no effect on Ts or on cloacal temperature. According to results previously obtained in homeothermic species, small doses of capsaicin activated heat-loss responses in the frog.     

Suppression of norepinephrine-induced thermogenesis in brown adipose tissue by fasting

Fasting-induced changes in thermogenic responses to norepinephrine (NE, 4.0 micrograms X kg-1 X min-1 iv) were studied in anesthetized rats previously cold acclimated. The rats were divided into five groups at the end of 30-40 days of cold acclimation (5 degrees C). The five groups were kept for 5 days at 25 degrees C and fed (intact fed), fasted (intact fasted), fasted with daily treatment with thyroxine (T4, 2 micrograms/kg sc), thyroidectomized and fed, or thyroidectomized and fasted. In the intact fasted group, in which the weight of brown adipose tissue decreased, NE-induced increases in oxygen consumption, colonic temperature (T col), and temperature of the interscapular brown adipose tissue (TBAT) were markedly suppressed. The two thyroidectomized groups also showed a reduction in thermogenic response. In these three groups, TBAT was lower than Tcol throughout NE infusion. In the T4-treated fasted group, fasting-induced suppression of thermogenic response to NE was largely prevented. In the intact fed and the T4-treated fasted groups, TBAT attained higher values than Tcol during NE infusion. Plasma levels of thyroid hormones were significantly lower in the intact fasted group than in the intact fed or the T4-treated fasted group. These results suggest that fasting-induced suppression of the thermogenic response to NE is largely due to the reduced thermogenic response of brown adipose tissue to NE. The lowering of the levels of the thyroid hormones induced by fasting may be one of a number of causes of the reduction in the thermogenic response of brown adipose tissue.     

The role of preoptic area and anterior hypothalamus and median raphe nucleus on thermoregulatory system in freely moving rats

To clarify the role of the preoptic area and anterior hypothalamus (PO/AH) on thermoregulatory system and the effects of serotonergic innervation from the median raphe nucleus (MRN) on body temperature (Tb), we perfused tetrodotoxin (TTX) solution into the PO/AH or MRN by using a microdialysis technique at different ambient temperatures (5, 23 and 35 degrees C) in freely moving rats. Tb was continuously monitored by using a telemetry system. In the MRN, perfusion of TTX solution induced significant hypothermia in the normal environment, a greater decrease in Tb during cold exposure and had no effect on Tb during heat exposure. In the PO/AH, perfusion of TTX solution induced significant hyperthermia in normal environment, a greater increase in Tb during heat exposure and had no effect on Tb during cold exposure. Our results indicate that the PO/AH regulates mainly heat loss or inhibits the loci regulating heat production. Furthermore, heat production appears to be regulated by other loci receiving serotonergic innervation from the MRN.     

Enhanced responsiveness to insulin in sheep exposed to cold

The effects of cold exposure on tissue sensitivity and responsiveness to insulin were determined by the euglycemic insulin clamp technique. Insulin was infused at rates of 0.2, 0.5, 1.0, 6.0, and 30.0 mU x kg-1 x min-1 into five adult sheep in a warm environment and after cold exposure (0 degree C) from 7 to 23 days. Cold exposure increased basal plasma glucose concentration and basal glucose irreversible loss. Glucose metabolic clearance rate (MCR) was significantly increased by cold exposure at all rates of insulin infusion, with increases ranging from 44 to 72%. The insulin concentration causing half-maximal stimulation of glucose MCR was unchanged by environment (warm, 42 microU/ml; cold, 36 microU/ml). Combined alpha + beta-adrenergic blockade did not affect the increased response to insulin during cold exposure. Endogenous (hepatic) glucose production was inhibited by insulin to a similar extent in the two environments and was less sensitive to insulin than was glucose utilization or MCR. The results suggest that cold exposure increases the responsiveness to insulin of a postreceptor event in peripheral tissues.     

Early capsaicin intervention for neurogenic bladder in a rat model of spinal cord injury

We explored capsaicin pretreatment, prior to spinal trauma, as a method to prevent the development of neurogenic detrusor overactivity (NDO) and urethral-bladder dyssynergia reflex after spinal cord injury (SCI). In addition, the duration of effect of capsaicin therapy on NDO in a rat model of SCI was investigated. Two sets of experiments were performed on female Sprague Dawley rats transected at the T9-T10 spinal level. First, SCI rats received capsaicin (125 mg/kg s.q.) 3-4 days before and 4-5 days after SCI. Cystometrograms (CMG) was performed 4 weeks after injury. In the second set of experiments, serial CMG in the same SCI animal was performed after one time injection of capsaicin (125 mg/kg s.q.) 4 weeks after spinalization. There were no differences in intercontraction intervals, voiding efficiency, or voiding pressure between the capsaicin pretreated and control SCI rats. However, the number of uninhibited detrusor contractions decreased 4 weeks after injury. We found that a single dose of capsaicin suppressed uninhibited detrusor contractions for 34 days in the chronic SCI animals. Early therapy with capsaicin was able to prevent/reduce detrusor hyperreflexia in spinal cord injured animals 4 weeks after injury. Early vanilloid therapy may prevent development of urologic sequelae after SCI.     

Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats.

The influence of dopamine receptor blockade and synthesis inhibition on natriuresis induced by isotonic saline volume expansion was investigated in anaesthetized spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. The aim of the study was to elucidate the mechanisms underlying the phenomenon of exaggerated natriuresis during volume expansion that has been observed in spontaneously hypertensive rats. Volume expansion, at 5% of body weight, resulted in a larger and faster natriuretic response in spontaneously hypertensive rats than in Wistar-Kyoto rats. Sixty minutes after commencement of volume expansion the natriuretic response (accumulated sodium excretion) in Wistar-Kyoto rats (n = 8) was only 24% of that in spontaneously hypertensive rats (n = 17). When spontaneously hypertensive rats were pretreated with the dopamine receptor blockers haloperidol (n = 14, 1 mg kg-1), SCH23390 (n = 8, 30 micrograms h-1 kg-1) or the dopamine synthesis inhibitor benserazide (n = 8, 50 mg kg-1; n = 5, 100 mg kg-1), the natriuretic response to volume expansion was only 16, 35, 59 and 42%, respectively, of that in untreated SHR. The corresponding proportion in the haloperidol-treated (n = 8) compared with untreated Wistar-Kyoto rats was 22%. In conclusion, isotonic volume loading results in more pronounced natriuresis in spontaneously hypertensive than in Wistar-Kyoto rats. Dopamine receptor blockade and synthesis inhibition attenuate the expansion of exaggerated natriuresis in spontaneously hypertensive rats and reduces the volume expansion natriuresis in Wistar-Kyoto rats, indicating that the dopamine system plays an important role.     

Rapid tolerance to focal cerebral ischemia in rats is induced by preconditioning with electroacupuncture: window of protection and the role of adenosine

The aim of the present study was to investigate the first protective window of preconditioning with electroacupuncture (EA) against focal cerebral ischemia, and to explore whether adenosine is involved in the rapid tolerance phenomenon. Sixty-four male Sprague-Dawley rats were randomly assigned to eight groups (n=8 in each). Animals in the control group received no treatment, and animals in EA1-EA4 groups received EA at 0.5, 1, 2 and 3 h before induction of focal cerebral ischemia, respectively. Rats in DPCPX group were intraperitoneally injected with 1 mg kg-1 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 3 h before induction of focal cerebral ischemia. Animals in vehicle group and EA+DPCPX group were pretreated with 1 ml kg-1 dimethyl sulfoxide (DMSO, the solvent of DPCPX) and 1 mg kg-1 DPCPX 30 min before preconditioning with EA, respectively. All rats were anesthetized with 40 mg kg-1 pentobarbital sodium intraperitoneally. Animals that required EA preconditioning, received EA with intensity of 1 mA and frequency of 15 Hz at the Baihui acupoint (GV 20) for 30 min. The focal cerebral ischemia was produced by the right middle cerebral artery occlusion (MCAO) for 120 min. The neurologic deficit scores (NDS) and brain infarct volumes were evaluated at 24 h after reperfusion. All rats survived until 24 h after reperfusion. Preconditioning with EA at 2 h before induction of focal cerebral ischemia improved neurologic outcome (P<0.05 versus control) and reduced the infarct volume (P<0.01 versus control) at 24 h after reperfusion. These beneficial effects were reversed by pretreatment with 1 mg kg-1 DPCPX, whereas this agent itself did not affect the NDS and volume in drug-ischemic controls after ischemia. The results show that preconditioning with single EA session induces rapid tolerance to focal cerebral ischemia. The rapid ischemic tolerance appears at 2 h (but not at 0.5, 1, or 3 h) after preconditioning, and is possibly mediated through an adenosine A1 receptor-related mechanism.