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PubMed1998

Antinociception, tolerance, and physical dependence comparison between morphine and tramadol.

The mechanism of action of tramadol includes the activation of opioid receptors, and the potential ability of the drug to induce tolerance and physical dependence has been evaluated in different animal species and humans. This work was designed to study the involvement of opioid receptors in the antinociceptive activity and the potential ability to develop tolerance, crosstolerance, and/or physical dependence of tramadol. The writhes induced by acetic acid administration was used as algesiometric test. After chronic administration of tramadol, tolerance was evaluated by measuring the antinociceptive activity, and physical dependence was measured by naloxone administration. Morphine was used as drug of comparison. The i.p. administration of tramadol produced a dose-dependent antinociception with an ED50 value of 7.82 +/- 1.16 mg/kg, which was unchanged after chronic administration of either tramadol (39.1 or 100 mg/kg) or morphine (1.05 or 100 mg/kg). By contrast, the ED50 for morphine (0.21 +/- 0.08 mg/kg) was significantly reduced only by chronic pretreatment with both doses of morphine (tolerance). Physical dependence was developed only in mice pretreated with morphine, as evidenced by the presence of jumps, wet-dog shakes, tachypnea, piloerection, seizures, diarrhea, and urination after the administration of naloxone (1 mg/kg). These findings suggest that the antinociceptive activity of tramadol in mice is due to activation of opioid and nonopioid mechanisms, and as opposed to morphine, is not likely to induce tolerance and physical dependence.

Analgesics, Opioid↗

PubMed1992

Hormone-dependent aggression in male and female rats: experiential, hormonal, and neural foundations.

Hormone-dependent aggression in both male and female rats includes the distinctive behavioral characteristics of piloerection and lateral attack. In males the aggression is dependent on testicular testosterone and is commonly known as intermale aggression. In females, the aggression is most commonly observed as maternal aggression and is dependent on hormones whose identity is only beginning to emerge. The present review examines the experiential events which activate hormone-dependent aggression, the relation of the aggression to gonadal hormones, and the neural structures that participate in its modulation. In males and females, the aggression is activated by cohabitation with a conspecific of the opposite sex, by competitive experience, and by repeated exposure to unfamiliar conspecifics. In the female, the presence of pups also activates aggression. In both males and females, hormones are necessary for the full manifestation of the aggression. The essential hormone appears to be testosterone in males and a combination of testosterone and estradiol in females. The information available suggests the neural control systems for hormone-dependent aggression may be similar in males and females. It is argued that hormone-dependent aggression is behaviorally and biologically homologous in male and female rats.

Aggression↗

PubMed1994

Methamphetamine toxicity prevented by activated charcoal in a mouse model.

STUDY OBJECTIVE: To determine the effectiveness of activated charcoal in preventing toxicity from oral methamphetamine HCI. DESIGN: Randomized, prospective, nonblinded, controlled animal study. SETTING: Animal care facility. PARTICIPANTS: CD-1 male mice. INTERVENTIONS: Mice were given 100 mg/kg methamphetamine HCI (lethal dose 60) in water by oral gavage. Within 1 minute of methamphetamine administration, mice received either 1 g/kg activated charcoal or an equivalent volume of water as control. MEASUREMENTS AND MAIN RESULTS: Mice were observed for time to onset of symptoms (piloerection, agitation, and tremor) and mortality at 1, 24, and 48 hours. Activated charcoal delayed onset of symptoms (5.53 +/- 1.25 minutes versus 4.27 +/- 1.22 minutes, P < .002) and decreased mortality compared to controls at 1 hour (1 of 20 versus 10 of 20, P < .003) and 24 hours (five of 20 versus 12 of 20, P < .05). There was no difference between groups in mortality at 48 hours. CONCLUSION: A single dose of activated charcoal given after oral methamphetamine delayed onset of toxicity and decreased early mortality in mice. There was no effect on overall mortality.

Animals↗

PubMed2000

Single-unit responses of serotonergic medullary and pontine raphe neurons to environmental cooling in freely moving cats.

Brain serotonin has long been implicated in the regulation of body temperature, although its precise role is not completely understood. The present study examined the effects of environmental cooling (4-8 degrees C for 2 or 4h) on the single-unit activity of serotonergic neurons recorded in the medullary raphe nuclei obscurus and pallidus and in the pontine dorsal raphe nucleus of freely moving cats. These neuronal groups have primarily descending projections to the spinal cord and ascending projections to the forebrain, respectively. Cold exposure induced shivering and piloerection, but no appreciable changes in core temperature. Of the medullary serotonergic cells studied (n=14), seven were activated and seven were unresponsive to cold exposure. For the responsive cells, the mean increase and peak effect in unit activity relative to baseline were 31% and 46%, respectively. Of the seven cold-responsive cells, the activity of four was monitored when the animals were transferred back to room temperature (23 degrees C). Within 15-30 min, the activity of these cells returned to baseline. In contrast, none of the dorsal raphe nucleus cells studied (n=14) displayed a significant change in neuronal activity during cold exposure, suggesting that these neurons do not receive afferent input from cold-sensitive cutaneous receptors or participate in thermoregulatory responses evoked by low ambient temperatures.Overall, these results suggest that a subset of medullary serotonergic neurons play a role in physiological mechanisms underlying cold defense (e.g. increases in motor output and/or autonomic outflow). On the other hand, the lack of responsiveness of serotonergic dorsal raphe nucleus neurons to cold exposure does not support a specific role for these cells in thermoregulation.

Action Potentials↗

PubMed2002

Behavioral and neurochemical characterization of alpha(2A)-adrenergic receptor knockout mice.

Genetic manipulation of mice now provides new tools to evaluate the biological functions of the alpha(2)-adrenergic receptor (alpha(2)-AR) subtypes (alpha(2A), alpha(2B), and alpha(2C)). To investigate the role of the alpha(2A)-AR in the modulation of mouse primary behavioral characteristics and brain neurochemistry, mice with targeted inactivation of the gene for the alpha(2A)-AR were compared with wild-type C57BL/6 control animals. First, a comprehensive behavioral screen was employed to provide a detailed characterization of basic neurologic functions. Thereafter, the mice were analyzed in three models of anxiety, i.e. the elevated-plus maze test, the marble burying test and the open field test. The diurnal activity pattern of the mice was assessed in a 24-h locomotor activity test. Furthermore, receptor autoradiography of the brain was performed using the subtype-non-selective alpha(2)-AR antagonist radioligand [(3)H]RS-79948-197. Lack of the alpha(2A)-AR was associated with alterations in autonomic functions, including increased heart rate and piloerection. The mutant mice also exhibited impaired motor coordination skills, increased anxiety-like behavior and an abnormal diurnal activity pattern. In addition, neurochemical analysis of monoamine neurotransmitters revealed a considerable increase in brain norepinephrine turnover in mice lacking alpha(2A)-AR. Our results provide further support for the crucial role of the alpha(2A)-AR in modulating brain noradrenergic neurotransmission and many aspects of mouse behavior and physiology.

Animals↗

PubMed2000

Isolation of hypotensive compounds from Solanum sisymbriifolium Lam.

The crude hydroalcoholic root extract (CRE) of Solanum sisymbriifolium Lam. has formerly been shown to have hypotensive activity both in normo-and hypertensive rats. Hypotensive activity-guided fractionation of the CRE was performed in anaesthetized normotensive rats, which led to the isolation of the active principles. The intravenous (i.v.) and intraperitoneal (i.p.) values of the CRE in mice were found to be, respectively, 343 and 451 mg/kg, and no lethal effect was caused by doses up to 5.0 g/kg when administered by oral route. Depression of locomotion, increase of breathing rate and piloerection was observed in a general behavior test with doses up to 200 mg/kg i.p., and 1000 mg/kg p.o., respectively. Increase in the gastrointestinal transit was found using 0.1 g/kg, whereas at doses of 0.5 and 1 g/kg, no significant activity was observed in comparison with the control mice. Hexanic and butanolic fractions induced a remarkable hypotension in anaesthetized normotensive rats in doses of 1, 5, 7.5 and 10 mg/kg i. v. Two compounds isolated from the butanolic fraction induced a significant decrease of the blood pressure, HR, amplitude of the ECG and breathing rate when injected in a dose of 1 mg/kg i.v; and both systofic and diastolic, blood pressures were affected in a proportional mode. The hypotensive effect of the two compounds were not influenced by pretreatment with atropine and propranolol; and the pressor response to noradrenaline was not affected by any of them which suggests that neither a direct muscarinic activity, beta-adrenoceptor activation nor decrease of sympathetic vascular tone (sympatholitic activity) are probably involved in the mechanism of hypotension. The present study shows that the CRE of S. sisymbriifolium contains at least two hypotensive compounds whose characterization is under way.

Animals↗

PubMed2002

Fetal toxicity of Solanum lycocarpum (Solanaceae) in rats.

Lobeira (Solanum lycocarpum) is a Brazilian plant used as a hypoglycemic agent. In this study, the toxic effects of lobeira were evaluated during the fetogenesis period. Twenty pregnant Wistar rats were randomly allocated into two groups: control and treated, which received, via oral gavage, 0.5 ml of distilled water or 100 mg of the lobeira powder/kg of body weight, respectively, during days 17-20 of pregnancy. Maternal toxicity was evaluated by body weight, food intake, piloerection, locomotor activity, diarrhoea and vaginal bleeding. Euthanasia was done on 21st day, when ovaries, fetuses and their respective placentas were removed. Resorptions, live and dead fetuses were recorded. External malformations and fetal body, brain, liver, lung and kidneys were also weighed. No clinical signs of maternal toxicity were observed. The placenta weights of the treated rats were lower than those of the control (P<0.01). Lungs (P<0.01) and kidneys (P<0.02) of the fetuses treated with lobeira were also significantly reduced, suggesting a fetotoxic effect of this plant.

Animals↗

PubMed1999

Acute toxicity and general pharmacological effect on central nervous system of the crude rhizome extract of Kyllinga brevifolia Rottb.

Acute toxicity and general pharmacological activities of the crude hydro-alcoholic rhizome extract of Kyllinga brevifolia Rottb., a popular medicine used in Paraguay, were investigated on mice. The intraperitoneal LD50 was found to be 575 mg/kg. Oral administration of doses up to 3.0 g/kg did not provoke any toxic symptoms. Oral administration of 100 mg/kg of the extract induced a significant increase in gastrointestinal transit. In open field studies, a decrease of spontaneous locomotor activity, piloerection, passivity, palpebral ptosis, catatonia and a stereotyped behaviour was produced by the extract when administered orally (1, 10 and 100 mg/kg). A significant decrease in respiration rate was observed (1, 10 and 100 mg/kg, p.o.) using a continuous flow respiration system. Lastly, doses of 1, 10 and 100 mg/kg, p.o. of the extract produced a significant increase in the hypnotic effect induced by pentobarbital in a dose-dependent manner. The latest effects could probably explain its rational use in traditional medicine to alleviate stress or as a sedative agent.

Animals↗

PubMed1987

[Disclosure of a fatal pheochromocytoma during general anesthesia].

A case is reported of a phaeochromocytoma revealed during a general anaesthesia by a sudden hypertensive crisis associated with acute pulmonary oedema and signs of extreme sympathetic stimulation (bilateral mydriasis, piloerection, peripheral vasoconstriction). Aortic angiography revealed the tumour lying in an ectopic retroperitoneal situation and spasm in the superior mesenteric arterial territory. The patient died at the thirtieth hour from septic shock due to necrotizing colitis.

Adrenal Gland Neoplasms↗

PubMed1998

Protective effect of Crassostrea gigas extract on audiogenic seizures in magnesium deficient mice.

Audiogenic seizures associated with loss of weight, prostration, piloerection, palpebral ptosis and motor deficiency were induced after sound stimulation of determined frequency and amplitude in magnesium-deficient DBA/2 mice. These symptoms were maintained when standard diet conditions (1700 ppm Mg2+) were restored. In contrast, mice were protected from audiogenic seizure in a dose related manner when Crassostrea gigas extract (JCOE) were added to the diet for 10 consecutive days. Although a rational explanation for this protective effect has not yet been determined, it is assumed that it might be due to a chelating complex formed between Mg2+ and taurine, which enhance the uptake of Mg2+.

Acoustic Stimulation↗

PubMed1998

A primate model of anxiety.

Pentylenetetrazol (PTZ; 30 mg/kg, i.m.) produced an acute anxiogenic effect on the behaviour of a social colony of rhesus monkeys acclimatized to laboratory conditions. The animals exhibited hypervigilance, aggressiveness, tachypnea, piloerection and frequent change of posture and also had raised plasma cortisol levels. These effects of PTZ were antagonized by benzodiazepines (diazepam; 1 mg/kg, i.v. and alprazolam; 0.05 mg/kg, p.o.). Non-benzodiazepine anxiolytic drug (buspirone; 10 mg/kg, p.o.) blocked the behavioural effects but not the rise in plasma cortisol concentration. On the other hand, pretreatment with hypnosedative (promethazine; 5 mg/kg, i.m.) or anticonvulsant (sodium valproate; 40 mg/kg, p.o.) agents did not attenuate the effects of PTZ indicating the specificity of its anxiogenic response. The model, thus, seems suitable for evaluation of potential anxiolytic agents.

Animals↗

PubMed2003

Pilomotor seizures in frontal lobe epilepsy: case report.

We report a 27-year-old man with pilomotor seizures originating in the right frontal lobe. Subtracted ictal SPECT coregistered with MRI showed multifocal hyperperfused areas in the anterior medial frontal area, mainly involving the cingulate gyrus. Chronic electrocorticography with subdural electrode arrays during the piloerection demonstrated that the pilomotor seizures were originating in the anterior medial frontal region. After resection of the focus, the patient became seizure free.

Adult↗

PubMed2006

Orbital frontal cortex ablations of rock squirrels (Spermophilus variegatus) disinhibit innate antisnake behavior.

The antisnake behavior of rock squirrels (Spermophilus variegatus) was examined to determine the role of the orbital frontal cortex in regulating physiological arousal and behavioral excitability during encounters with a rattlesnake predator. Rock squirrels with orbital frontal cortex ablations and sham-surgery control squirrels were presented with a caged rattlesnake pre- and postsurgery. Orbital frontal cortex ablations had no substantial effect on the expression of gross motor behavior in dealing with the rattlesnake, but they augmented the speed of snake recognition and clearly disinhibited sympathetic arousal as manifested by increased tail piloerection and tail-flagging activity, which is a specific antisnake behavior. Natural selection from snakes has probably shaped the neural organization of the orbital frontal cortex to afford adaptive behavioral flexibility during snake encounters.

Animals↗

PubMed1997

Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.

Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose tissue occurs in response to cold and overeating (diet induced), and there is an inverse relationship between diet-induced thermogenesis and obesity both in humans and in animal models. As a potential model for obesity, we generated mice that cannot synthesize noradrenaline or adrenaline by inactivating the gene that encodes dopamine beta-hydroxylase. These mice are cold intolerant because they have impaired peripheral vasoconstriction and are unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP1). The mutants have increased food intake but do not become obese because their basal metabolic rate is also elevated. The unexpected increase in basal metabolic rate is not due to hyperthyroidism, compensation by the widely expressed uncoupling protein UCP2, or shivering.

Adipose Tissue↗

PubMed1998

Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol.

Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.

Analysis of Variance↗

PubMed2004

Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice.

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg(-1), s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg(-1), intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 micrograms) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg(-1), i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal.

Animals↗

PubMedDate not supplied

Successful treatment of retrograde ejaculation with the alpha1-adrenergic agonist methoxamine: case study.

We treated two patients affected by retrograde ejaculation (RE) with the pure alpha1-adrenergic agonist methoxamine; the drug was self-administered intramuscularly by the patients 30 min prior to intercourse or masturbation. A previous trial with oral imipramine had been ineffective in both patients. Sperm count increased substantially, particularly in the first patient who had insulin-dependent diabetes and was seeking fertility. In this patient, total ejaculated sperm increased from 22 millions to 488 and 419.5 millions on two different occasions, with good motility; two clinical pregnancies were obtained in the partner of this patient after 3 and 4 months of treatment, respectively. The second patient did not desire fertility. In both patients, no side effects were seen except for slight piloerection; blood pressure values increased slightly, and heart rate was unchanged. We conclude that self-administered methoxamine can be a useful, noninvasive and inexpensive treatment of RE, when oral agents are ineffective.

Adrenergic alpha-Agonists↗

PubMed2001

Reflexes and somatic responses as predictors of ejaculation by penile vibratory stimulation in men with spinal cord injury.

STUDY DESIGN: Retrospective chart review. OBJECTIVE: To identify factors in addition to level of injury (LOI) that may predict ejaculation by penile vibratory stimulation (PVS) in spinal cord injured males. SETTING: Major urban medical school and teaching hospital. MATERIALS AND METHODS: Presence of a bulbocavernosus response (BCR) and a hip flexor response (HR) before PVS (n=123 patients), and somatic responses during PVS (n=204 trials performed on a subset of 44 patients) were evaluated for their frequency of occurrence on trials with and without ejaculation. RESULTS: Overall ejaculation success rates for cervical, T1-T6, and T7-T12 LOI were 71%, 73%, and 35%, respectively. Eighty per cent of patients who were positive for both BCR and HR ejaculated with PVS, while only 8% of patients who were negative for both BCR and HR ejaculated with PVS. For cervical injuries, BCR and HR were no more predictive of ejaculation by PVS than LOI alone. T1-T6 patients were more likely to ejaculate when at least one reflex was present. T7-T12 patients with no BCR were unlikely to ejaculate by PVS. Except for abdominal contractions, somatic responses were not present in the majority of PVS trials. When they were present, however, they occurred in a high percentage of ejaculation trials: withdrawal response (hip flexion, knee flexion and thigh adduction) (90%), piloerection (84%), extremity spasms (83%), thigh abduction (80%), and thigh adduction (72%). CONCLUSION: We recommend that patients with cervical injuries initially undergo PVS. Patients with T1-T6 LOI with at least one reflex present, and patients with T7-T12 LOI with both reflexes, or only BCR present, may undergo PVS. Certain somatic/autonomic responses, when seen, may help in deciding whether to continue with a given trial, or give a repeat trial, of PVS. SPONSORSHIP: The Miami Project to Cure Paralysis and the State of Florida Specific Appropriations.

Adult↗