naloxone and Hypothermia

Long-acting neuraxial opioids such as morphine and diamorphine, administered via spinal or epidural routes, are staple components of a multimodal approach to postoperative analgesia following cesarean delivery. The widespread use of neuraxial opioids is due largely to their significant analgesic efficacy and favorable safety profile. The most common side effects of neuraxial opioids are pruritus, nausea and vomiting. These symptoms appear to be dose-related. The most serious complication of neuraxial opioids is respiratory depression, which occurs in 0-0.9% of cases. Hypothermia has also been reported in association with neuraxial morphine use at cesarean delivery. This article will review recent advances in prophylaxis, treatment and monitoring of the side effects of long-acting neuraxial opioids.

Topics: Analgesics, Opioid; Cesarean Section; Female; Humans; Hypothermia; Morphine; Naloxone; Pain, Postoperative; Postoperative Nausea and Vomiting; Pregnancy; Pruritus; Respiratory Insufficiency; Serotonin Antagonists

Topics: Adult; Anaphylaxis; Cardiac Tamponade; Cardiopulmonary Resuscitation; Emergency Medical Services; Fat Emulsions, Intravenous; Female; Heart Arrest; Humans; Hypothermia; Naloxone; Near Drowning; Percutaneous Coronary Intervention; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Water-Electrolyte Imbalance; Wounds and Injuries

Topics: Animals; Climacteric; Clonidine; Estrogens; Female; Haplorhini; Humans; Hypothalamic Hormones; Hypothermia; Menopause; Naloxone; Neurotransmitter Agents; Ovary; Rats; Sulpiride; Vasomotor System

After an uneventful caesarean delivery under spinal anaesthesia (hyperbaric bupivacaine 10mg, sufentanil 5μg and morphine 50μg), hypothermia (nadir 34°C) was recorded in a ASA 1 patient. Partial recovery was rapidly obtained with 400μg of naloxone but full recovery was obtained after seven hours of active rewarming with a forced-air warming blanket. Suggested pathophysiology and incidence of this hypothermia are described.

Topics: Adult; Analgesics, Opioid; Anesthesia, Spinal; Cesarean Section; Female; Humans; Hypothermia; Infant, Newborn; Injections, Spinal; Morphine; Naloxone; Narcotic Antagonists; Pregnancy; Rewarming

The aim of the present investigation was to study the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on morphine withdrawal-induced behavioral changes and hypothermia in male CFLP mice. Elevated plus maze (EPM) and jump tests were used to assess naloxone-precipitated morphine withdrawal-induced behavior responses. Different doses of subcutaneous (s.c.) naloxone, (0.1 and 0.2 mg/kg, respectively) were used to precipitate the emotional and psychical aspects of withdrawal on EPM and 1 mg/kg (s.c.) was used to induce the somatic withdrawal signs such as jumping, and the changes in body temperature. In our EPM studies, naloxone proved to be anxiolytic in mice treated with morphine. Chronic intracerebroventricular (i.c.v.) administration of PACAP alone had no significant effect on withdrawal-induced anxiolysis and total activity at doses of 500 ng and 1 μg. At dose of 500 ng, however, PACAP significantly counteracted the reduced motor activity in the EPM test in mice treated with morphine and diminished the hypothermia and shortened jump latency induced by naloxone in mice treated with morphine. These findings indicate that anxiolytic-like behavior may be mediated via a PACAP-involved pathway and PACAP may play an important role in chronic morphine withdrawal-induced hypothermia as well.

Topics: Animals; Hypothermia; Male; Maze Learning; Mice; Morphine; Motor Activity; Naloxone; Pituitary Adenylate Cyclase-Activating Polypeptide; Substance Withdrawal Syndrome

Topics: Aged; Blast Injuries; Emergency Medical Services; Humans; Hypothermia; Naloxone; Research; Wounds and Injuries

The present study used the endpoint of hypothermia to investigate opioid and neuropeptide FF (NPFF) interactions in conscious animals. Both opioid and NPFF systems played important roles in thermoregulation, which suggested a link between opioid receptors and NPFF receptors in the production of hypothermia. Therefore, we designed a study to investigate the relationship between opioid and NPFF in control of thermoregulation in mice. The selective NPFF receptors antagonist RF9 (30nmol) injected into the third ventricle failed to induce significant effect, but it completely antagonized the hypothermia of NPFF (45 nmol) after cerebral administration in mice. In addition, RF9 (30 nmol) co-injected i.c.v. in the third ventricle reduced the hypothermia induced by morphine (5nmol,) or nociceptin/orphanin FQ (N/OFQ) (2 nmol). Neither the classical opioid receptors antagonist naloxone (10 nmol) nor NOP receptor antagonist [Nphe(1)]NC(1-13)NH(2) (7.5 nmol) reduced the hypothermia induced by the central injection of NPFF at dose of 45 nmol. Co-injected with a low dose of NPFF (5 nmol), the hypothermia of morphine (5 nmol) or N/OFQ (2 nmol) was not modified. These results suggest that NPFF receptors activation is required for opioid to produce hypothermia. In contrast, NPFF-induced hypothermia is mainly mediated by its own receptors, independent of opioid receptors in the mouse brain. This interaction, quantitated in the present study, is the first evidence that NPFF receptors mediate opioid-induced hypothermia in conscious animals.

Topics: Adamantane; Analgesics, Opioid; Animals; Area Under Curve; Body Temperature Regulation; Dipeptides; Drug Interactions; Hypothermia; Kinetics; Male; Mice; Morphine; Naloxone; Nociceptin; Opioid Peptides; Receptors, Neuropeptide

Appropriate assessment and resuscitation is an important part of neonatal care provided during the first minutes of life. Midwifery and junior medical staff are often in the frontline of neonatal resuscitation. Appropriate education and training of midwifery staff is therefore essential if the standard of care delivered to babies in the delivery suite is to be improved and maintained. Evaluation of any such educational interventions is necessary to assess their effectiveness.. To assess the effect of a course in neonatal resuscitation introduced in 1995 aimed at midwifery staff, on the standard of care provided to babies immediately after birth. Prior to this, training in neonatal resuscitation was largely theoretical.. Naturalistic design observational study conducted in a maternity unit with a tertiary neonatal intensive care unit in the North of England. We compared two groups of babies born before and after the course was introduced. Use of naloxone in the delivery suite and appropriateness of its use, and temperature on admission to neonatal intensive care unit were used as proxy markers for standard of care and compared in the two groups. We also looked at the use of mask intermittent positive pressure ventilation (IPPV) and tracheal intubation in the delivery suite.. Use of naloxone fell dramatically from 13.2% of all babies born in 1994 to 0.5% in 2003. Inappropriate use of naloxone before other resuscitation measures were initiated declined from 75% of babies given naloxone in 1994 to 10% in 2003. The incidence of hypothermia (<35 degrees C) on admission to neonatal unit declined from 9% of all admissions to 2.3% in 2003. There was a trend towards increased use of mask ventilation in the delivery suite with a corresponding trend towards less tracheal intubation.. We have shown that the intervention has been related temporally to an improvement in the quality of care delivered by midwifery staff to newborn babies. Practical courses in neonatal resuscitation can contribute to improvements in the quality of care provided to babies immediately after birth. These courses are more effective than theoretical teaching alone.

Topics: Drug Utilization; England; Humans; Hypothermia; Incidence; Infant, Newborn; Inservice Training; Intensive Care Units, Neonatal; Intubation, Intratracheal; Masks; Midwifery; Naloxone; Narcotic Antagonists; Patient Admission; Positive-Pressure Respiration; Resuscitation; Retrospective Studies

Mice were forced to swim for 5 min in water at a temperature of 12 degrees C (cold water swim stress) or 32 degrees C (warm water swim stress), and stress-induced analgesia (SIA) was measured using the tail-flick test. The cold water swim stress induced non-opioid SIA as well as hypothermia, whereas the warm water swim stress caused opioid SIA. The in vivo binding of [(3)H]-Ro15-4513 was measured in the stressed mice and compared with that in control mice. The specific binding of [(3)H]-Ro15-4513 in the cerebral cortex, hippocampus, and cerebellum was significantly altered by forced swimming in cold water. Apparent association and dissociation rate of [(3)H]-Ro15-4513 binding were decreased, and the change in the dissociation rate was most pronounced in the hippocampus. In contrast, no significant alterations were observed in in vitro binding. The hypothermia induced by the cold water swim stress seems to be the main reason for alterations in the specific binding of [(3)H]-Ro15-4513. The kinetics of a saturable amount of [(3)H]-Ro15-4513 in the blood and brain were also measured. The relative ratio of the radioactivity concentration in the brain to that in the blood was significantly decreased by forced swimming in cold water, indicating that the cold water swim stress induced changes in the nonspecific binding of [(3)H]-Ro15-4513 in the brain. These results together with previous reports suggested that non-opioid SIA induced by the cold water swim stress might be related to alterations in the rates of general ligand-receptor interactions including GABA(A)/benzodiazepine system. Changes in the nonspecific binding might be also involved in non-opioid SIA.

Topics: Analysis of Variance; Animals; Azides; Benzodiazepines; Binding Sites; Body Temperature; Brain; Cold Temperature; Dose-Response Relationship, Drug; Drug Interactions; Hypothermia; Male; Mice; Naloxone; Narcotic Antagonists; Radioactivity; Stress, Physiological; Swimming; Time Factors; Tissue Distribution; Tritium

Effect of moclobemide, a selective monoamine oxidase-type A enzyme inhibitor, was investigated on the body temperature of male mice. Moclobemide (15-30 mg kg(-1), i.p.) produced significant reductions of body temperature in both normal and yeast-induced hyperthermic male mice. The hypothermic effect of moclobemide was moderate and short-lasting. Moclobemide-induced hypothermia was not antagonized by previous administration of prazosin (10 and 20 mg kg(-1), s.c.), propranolol (5, 10, and 20 mg kg(-1), s.c.), haloperidol (2 and 10 mg kg(-1), s.c.), atropine (10 and 20 mg kg(-1), s.c.), mepyramine (25 and 50 mg kg(-1), s.c.), or methysergide (0.5, 1, and 2 mg kg(-1), s.c.). Pretreatment with the opioid antagonist naloxone (10 mg kg(-1), s.c.), however, was able to reverse the hypothermic effect of moclobemide (30 mg kg(-1), i.p.) in both normal and yeast-induced hyperthermic mice. The present results indicate a possible role for central opioid receptors in the hypothermic effect of moclobemide. Also, a peripheral component for this effect of moclobemide at the mitochondria of peripheral tissues is suspected. The peripheral tissue mitochondria could be considered a common target for moclobemide and opioids actions on body temperature.

Topics: Animals; Body Temperature; Body Temperature Regulation; Dose-Response Relationship, Drug; Fever; Hypothermia; Male; Methysergide; Mice; Moclobemide; Monoamine Oxidase Inhibitors; Naloxone; Narcotic Antagonists; Receptors, Opioid; Saccharomyces cerevisiae; Sex Factors

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. The present study is the first to provide evidence that central endothelin (ET) mechanisms are involved in the modulation of pharmacological actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of endothelin-A (ET(A)) antagonist, BQ123, on morphine-induced analgesia, hyperthermia, and catalepsy was determined in the rat. Morphine produced a significant increase in tail-flick latency as compared to control group. Pretreatment with BQ123 significantly potentiated the effect and duration of morphine (2 and 8 mg/kg, s.c.)-induced analgesia as compared to vehicle-pretreated control rats. The hyperthermic effect of morphine was not only significantly greater in BQ123-pretreated rats but also lasted for more than 6 h. ET antagonist, BQ123, did not affect the pharmacological effect of morphine on cataleptic behavior. These studies demonstrate that BQ123, a specific ET(A) receptor antagonist, significantly potentiated morphine-induced analgesia and hyperthermia in rats without affecting morphine-induced cataleptic behavior. [(3)H]-Naloxone binding was carried out to determine the possibility of BQ123 acting on opiate receptors. It was found that morphine could displace [(3)H]-naloxone but BQ123 did not affect [(3)H]-naloxone binding even at 1,000 nM concentration. Therefore, it can be concluded that BQ123 does not act on opioid receptors. This is the first report suggesting that an ET(A) antagonist, BQ123, significantly potentiates the analgesic effect of morphine, possibly through a nonopioid mechanism.

Topics: Analgesia; Animals; Drug Synergism; Endothelin Receptor Antagonists; Endothelins; Hypothermia; Male; Morphine; Naloxone; Peptides, Cyclic; Rats; Rats, Sprague-Dawley

This study examined the ability of the anti-opioid Neuropeptide FF (NPFF) to modify the endogenous activity of nitric oxide (NO). Antinociceptive and hypothermic effects of 1DMe (D.Tyr-Leu-(n.Me)Phe-Gln-Pro-Gln-Arg-Phe-NH(2)), an NPFF agonist, and of L-NAME (N(omega)nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, were investigated in mice. Intraperitoneal (i.p.) injection of L-NAME induced, in the hot plate test, a dose-dependent antinociception not reversed by naloxone, an opioid antagonist, but inhibited by L-Arg, the NO synthesis precursor. Intracerebroventricular (i.c.v.) injections of 1DMe inhibit the antinociceptive activity of L-NAME in a dose-dependent manner. On the contrary, L-NAME markedly potentiated hypothermia induced by 1DMe injected in the third ventricle. These data show that Neuropeptide FF receptors exert a dual effect on endogenous NO functions and could modulate pain transmission independently of opioids.

Topics: Analgesics, Opioid; Animals; Area Under Curve; Arginine; Body Temperature; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Hypothermia; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Pain; Temperature

The effects of cholecystokinin-8 sulfate (CCK-8), cholecystokinin-8 unsulfate (CCK-8U), cholecystokinin-4 (CCK-4), caerulein and morphine on mice core body temperature have been studied in the present work. Subcutaneous injection of different doses of caerulein (0.05, 0.1 and 0.5 mg/kg), CCK-8 (0.05, 0.1 and 0.25 mg/kg) and morphine (10, 20 and 30 mg/kg) induced hypothermia. CCK-8U and CCK-4 did not elicit any response. The hypothermic response induced by caerulein, a CCK-related decapeptide but not morphine was decreased by selective CCK(A) receptor antagonist MK-329. However, the hypothermia induced by morphine but not caerulein was reduced by opioid antagonist naloxone. When morphine plus caerulein was administered a higher hypothermia was induced. Pretreatment of animals with L-365 260, a selective CCK(B) receptor antagonist did not alter the hypothermia induced by the drugs. The response induced by combination of the both drugs was decreased by MK-329. Administration of CCK antagonists MK-329 and L-365 260 to mice did not exert any effect on temperature. It is concluded that the CCK(A) receptor mechanism may be involved in the hypothermic effect of CCK agonists or morphine, while opioid receptor mechanism is not involved in CCK receptor agonists' response.

Topics: Animals; Body Temperature; Ceruletide; Cholecystokinin; Hypothermia; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Receptors, Cholecystokinin; Time Factors

1. Both L-dopa and low doses of apomorphine potentiated withdrawal symptoms such as jumping, "wet dog" shakes and burrows. L-dopa reduced hypothermia and potentiated body weight loss, whereas apomorphine produced opposite effects. 2. Higher doses of apomorphine attenuated jumping and burrows but had no effect on "wet dog" shakes. On the other hand, and with the exception of sulpiride, all other dopamine (DA) antagonists produced effects opposite those of the agonists with regard to jumping, "wet dog" shakes and burrows. 3. In addition, DA antagonists reduced hypothermia and body weight loss. The effects of DA agonists and antagonists were investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether DA-mediated effects are somehow linked to noradrenergic pathways. 4. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than did untreated mice. 6-OHDA reversed the effects of apomorphine on "wet dog" shakes and burrows while abolishing those of L-dopa on all withdrawal symptoms, the only exception being jumping, which remained unchanged. 5. 6-OHDA also reversed the effects of sulpiride on all withdrawal symptoms while reversing the effects of pimozide on jumping, and it abolished its effect on hypothermia. 6. These findings provide evidence suggesting that the effects of DA agonists and antagonists are dependent at least partly on intact noradrenergic pathways.

Topics: Adrenergic Agents; Analgesia; Analgesics, Opioid; Analysis of Variance; Animals; Apomorphine; Dopamine; Dopamine Agents; Dopamine Antagonists; Hypothermia; Levodopa; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Oxidopamine; Substance Withdrawal Syndrome

This study was designed to assess if opioids or adenosine are involved in the hypometabolism induced by hypoxia in the rat. Accordingly, antagonists such as naloxone (NLX) for opioids or theophylline (THEO) for adenosine were injected into conscious adult rats acutely exposed to either ambient hypoxia (AHx, FIO2: 12%) at ambient temperatures of 26 or 9 degrees C, or to CO hypoxia (COHx, FICO = 0.05%) at an ambient temperature (Ta) of 9 degrees C. Oxygen consumption, ventilation, colonic temperature and shivering were recorded. The results show that with NLX, the degree of hypoxic hypometabolism was reduced with AHx at 26 degrees C and slightly decreased with COHx at 9 degrees C. With THEO, hypoxic hypometabolism was slightly reduced with AHx and COHx at 9 degrees C. The ventilatory response to AHx and COHx was not consistently affected by either NLX or THEO. It is concluded that adenosine and opioids play a minor role, in mediating AHx or COHx hypothermia, especially during cold exposure.

Topics: Adenosine; Animals; Body Temperature; Carbon Monoxide; Hypothermia; Hypoxia; Male; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Oxygen Consumption; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Theophylline

Effects of excitatory aminoacids (EAAs) aspartate (ASP) and glutamate (GLU) in a low (50 ng, i.c.) and high dose (20 micrograms, i.c.), were studied on nociception, catalepsy and rectal temperature in albino rats. Both ASP and GLU altered the tail flick reaction time to thermal stimulation in a dose dependent manner, increasing it with low doses and reduced with high doses. Naloxone (10 micrograms, ic) antagonized the anti-nociceptive effect of EAAs while ketamine (10 micrograms, ic)-a NMDA receptor antagonist antagonized the hyperalgesic effect. These EAAs also antagonized catalepsy induced by haloperidol, chlorpromazine, trifluoperazine and morphine. Both ASP and GLU produced a hyperthermic response in all animals, including those in which hypothermia was induced by reserpine. These EAAs produced a comparable central modulatory effects on nociception, catalepsy and core temperature.

Topics: Adrenergic Uptake Inhibitors; Analgesia; Analgesics, Opioid; Animals; Aspartic Acid; Body Temperature; Catalepsy; Chlorpromazine; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fever; Glutamic Acid; Haloperidol; Hypothermia; Injections, Subcutaneous; Ketamine; Male; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Rats; Reserpine; Trifluoperazine

Topics: Adult; Analgesics, Opioid; Anesthesia, Obstetrical; Anesthesia, Spinal; Anesthetics, Local; Body Temperature Regulation; Bupivacaine; Cesarean Section; Female; Fentanyl; Humans; Hypothermia; Morphine; Naloxone; Narcotic Antagonists; Nerve Block; Pregnancy; Subarachnoid Space

The effects of histamine antagonists on naloxone-precipitated withdrawal symptoms were studied in morphine-dependent mice. Chlorpheniramine (0.5-10 mg/kg), a H1-blocker, given 1P 30 min before naloxone challenge produced a dose-dependent potentiation of withdrawal body weight loss, burrowing, and hypothermia, but did not influence either jumping or wet-dog shakes. On the other hand, cimetidine (10-100 mg/kg), a H2-blocker, produced dose-dependent potentiation of withdrawal hypothermia and jumping. Cimetidine was without effect on wet-dog shakes, burrowing, and body weight loss. The effect of chlorpheniramine was investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether histamine-mediated effects are some-how linked to noradrenergic pathways. Intracerebral injection of 6-OHDA in 5-day-old mice pups resulted in hyperlocomotion by the end of 30 days before initiation of morphine dependence. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than nontreated mice. 6-OHDA (50 micrograms) lesions completely blocked the potentiating effect of chlorpheniramine on burrowing, hypothermia, and even reversed the effect on body weight loss. These findings suggest that both histamine H1- and H2-receptors may be involved in the expression of precipitated withdrawal in morphine-dependent mice and histamine receptors function as modulators of noradrenergic neurotransmission.

Topics: Animals; Behavior, Animal; Chlorpheniramine; Cimetidine; Dose-Response Relationship, Drug; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Hypothermia; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Norepinephrine; Oxidopamine; Substance Withdrawal Syndrome; Sympatholytics; Weight Loss

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Benzazepines; Body Temperature; Cannabinoids; Cyclohexanols; Dopamine Antagonists; Dose-Response Relationship, Drug; Flumazenil; GABA Modulators; Hypothermia; Motor Activity; Naloxone; Narcotic Antagonists; Piperidines; Pyrazoles; Rats; Rimonabant; Vocalization, Animal

Following sensitization to ovalbumin (OA), male Wistar rats were pretreated with naloxone (20 mg/kg i.p.) and subjected to antigen challenge (3 mg OA i.p.). Naloxone exacerbated both systemic and intestinal anaphylaxis when injected 10 and 90 min before the antigen challenge. This was evidenced by a more pronounced drop in rectal temperature, higher hematocrit values, and by an enhanced elevation of basal short-circuit current (an indication of the secretory tone of the small intestine studied in Ussing chambers). Pretreatment with an equipotent does of methylnaloxone (200 mg/kg i.p.), a peripherally acting opiate antagonist, exacerbated the indices of intestinal anaphylaxis but had no apparent effect on indices of systemic anaphylaxis. Thus, our data strongly suggest that in the rat, components of the systemic hypersensitivity reaction are mediated through central opioid receptors, whereas the changes in gut function characterizing intestinal anaphylaxis are mediated through peripheral opioid receptors.

Topics: Anaphylaxis; Animals; Biological Transport; Cell Membrane Permeability; Chlorides; Hematocrit; Histamine Release; Hypothermia; Immunization; Intestinal Absorption; Male; Naloxone; Neuroimmunomodulation; Ovalbumin; Oxymorphone; Rats; Rats, Wistar; Receptors, Opioid; Specific Pathogen-Free Organisms; Water

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PC13), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125.8 and 429.6 mg kg-1. Only at intraperitoneal doses of 100 mg kg-1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5-20 mg kg-1, i.p.) reduced the duration of immobility of mice in the forces swimming test, antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis, and potentiated reserpine (2.5 mg kg-1, i.p.)-induced hypothermia. PC4 and PC13 (20 mg kg-1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg-1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg-1, s.c.). At 200 mg kg-1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg-1, s.c.), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg-1, i.p.) in mice pretreated with pargyline (100 mg kg-1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg-1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg-1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (5.0 < ED50 < 5.5 mg kg-1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Hydroxytryptophan; Analgesia; Animals; Antidepressive Agents; Apomorphine; Behavior, Animal; Blepharoptosis; Citalopram; Clomipramine; Drug Interactions; Fluoxetine; Hypothermia; Imipramine; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Models, Molecular; Motor Activity; Naloxone; Piperazines; Pyridazines; Reserpine; Structure-Activity Relationship; Swimming; Trazodone; Yohimbine

Intraperitoneal administration of the serotonin 5-HT1A agonist, buspirone (1-5 mg/kg), produced dose- and time-related core hypothermia that was coincident with analgesia against a thermally noxious stimulus. Surface body temperature was not altered by buspirone. The 5-HT1A antagonist, NAN-190 (2 mg/kg, s.c.), blocked both hypothermic and analgesic effects, while systemic administration of the opioid antagonist, naloxone (1 mg/kg, s.c.), did not change the pattern of buspirone-induced hypothermia or analgesia. The apparent lack of opioid involvement and the documented role of the 5-HT1A receptor system in neuroendocrine substrates of thermoregulation and pain modulation prompted study of adrenal function in these buspirone-induced effects. Buspirone (5 mg/kg, i.p.) produced significant elevations in plasma epinephrine (EPI) and corticosterone (CST). Bilateral adrenalectomy reduced both control and buspirone-elevated EPI and CST levels and attenuated the antinociceptive, but not hypothermic, effects of buspirone (1-5 mg/kg, i.p.). Administration of the phenylethanolamine-N-methyltransferase (PNMT) inhibitor, dichloromethylbenzylamine (DCMB: 25 mg/kg, i.p.) reduced basal and buspirone-elevated plasma EPI, but not CST levels. This treatment did not affect buspirone-induced hypothermia, while significantly reducing buspirone antinociception. Pretreatment with the CST synthesis inhibitor, aminoglutethemide (AG: 2 x 25 mg/kg, i.p.), reduced plasma CST levels while not significantly affecting EPI. AG pretreatment did not alter the hypothermic effects of buspirone, but attenuated antinociception produced by the highest buspirone dose. The AG-induced reductions of buspirone antinociception were less than those effects produced by DCMB treatment. These data suggest that buspirone-induced antinociception may be a non-opioid, adrenally mediated co- and/or epi-phenomenon to core hypothermia evoked by 5-HT1A receptor agonism.

Topics: Adrenalectomy; Aminoglutethimide; Analgesics; Animals; Benzylamines; Buspirone; Dose-Response Relationship, Drug; Hypothermia; Male; Naloxone; Piperazines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Time Factors

Shapiro's syndrome comprises agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia. We describe a 25-year-old man who is the twentieth case to be reported. There was no evidence of epilepsy, sympathetic nervous system dysfunction or inappropriate vasopressin release. However, investigation demonstrated a central defect in temperature regulation with an abnormally low hypothalamic set-point and normal homeothermic reflexes. Therapy with clonidine, an alpha 2-adrenoceptor agonist, was associated with remission of symptoms: these recurred on four occasions when clonidine was withdrawn. Clonidine therapy was also associated with a return to normal central temperature regulation. We suggest that the efficacy of clonidine reflects an action on hypothalamic thermoregulation rather than on peripheral catecholamine release. These findings have implications for the use of clonidine in other patients with Shapiro's syndrome and in more common disorders of temperature control, including perimenopausal flushing.

Topics: Adult; Agenesis of Corpus Callosum; Body Temperature Regulation; Clonidine; Humans; Hyperhidrosis; Hypothermia; Magnetic Resonance Imaging; Male; Naloxone; Syndrome; Water-Electrolyte Imbalance

The increased metabolic and respiratory demand during naloxone recovery from opioid-based anesthesia could be related to the return of thermoregulation in hypothermic patients and thus be avoided by preventing intraoperative hypothermia. In this study, we measured O2 uptake (VO2) during naloxone-induced recovery in two groups of patients to determine the effect of intraoperative heat loss on postoperative VO2 changes. In seven patients, intraoperative hypothermia was prevented (normothermic group), whereas hypothermia was allowed to develop in seven other patients (hypothermic group). Core and skin temperatures were measured throughout the study to calculate changes in body heat content. Before naloxone antagonism of fentanyl-supplemented anesthesia, core temperature (mean +/- SEM) was 36.8 +/- 0.1 degrees C in the normothermic group and 34.2 +/- 0.2 degrees C in the hypothermic group (P less than 0.001). After titrated administration of naloxone during recovery, VO2 and minute ventilation (VE) increased in the hypothermic group, by 114 +/- 37% and 97 +/- 52% respectively (P less than 0.05), with a three-fold increase in four patients. In the normothermic group, VO2 increased significantly less (25 +/- 5%), without any significant change in VE. The change in VO2 and VE was significantly greater in patients who were hypothermic. VO2 was integrated throughout the recovery period to calculate recovery energy expenditure. Recovery energy expenditure and intraoperative heat loss were highly correlated (r = 0.88; P less than 0.01). This study demonstrates that the metabolic and respiratory stresses associated with naloxone-induced recovery from opioid-based anesthesia depend on the intraoperative heat loss and can therefore be reduced by preventing intraoperative hypothermia.

Topics: Anesthesia Recovery Period; Body Temperature Regulation; Energy Metabolism; Female; Humans; Hypothermia; Intraoperative Complications; Male; Middle Aged; Naloxone; Oxygen; Shivering

1. The effects of intravenous (i.v.) morphine on adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-END), total catecholamines (CA) and histamine (HIS) plasma concentrations, were determined in anaesthetized dogs at 30 degrees C and 37 degrees C. 2. Hypothermia initially increased CA levels by 29%, but the values returned to baseline after 2 h. Morphine (1 mg/kg, i.v.) produced a significant decrease in CA both at 37 degrees C and 30 degrees C (34% and 54%, respectively). Subsequent administration of naloxone (1 mg/kg, i.v.) significantly increased CA levels in both groups. 3. Hypothermia per se had no effect on ACTH, beta-END, and HIS concentrations. Morphine produced a significant increase in pituitary hormones and HIS, in hypothermic but not in normothermic animals. Morphine concentrations were significantly higher at 30 degrees C during the first 45 min. 4. The results suggest that the effects of morphine on hormonal and histamine release observed at 30 degrees C are concentration-dependent and related to changes in morphine pharmacokinetics.

Topics: Adrenocorticotropic Hormone; Anesthesia; Animals; beta-Endorphin; Catecholamines; Dogs; Histamine; Histamine Release; Hormones; Hypothermia; Morphine; Naloxone; Time Factors

Prodynorphin-derived peptides were tested for their effects on body temperature after intracerebroventricular administration to unrestrained male rats. Dynorphin A (Dyn A) (5 and 10 nmol) and Dynorphin A-(1-32) (Dyn A-(1-32) (2.5 and 5 nmol) lowered body temperature with a maximum approximately 30 min after administration. Dyn B (up to 50 nmol) did not induce hypothermia. Lower doses of all peptides did not alter body temperature. The hypothermic effect was significantly, but not completely prevented by MR1452 (30 nmol), a preferential antagonist of the kappa receptor, administered intracerebroventricularly. Naloxone, a mu receptor antagonist, naltrexone, its long acting analog up to doses of 100 nmol, as well as MR1453, the (+)-enantiomer of kappa antagonist MR1452 with no opioid binding properties, did not prevent the hypothermic effect. Moreover, episodic barrel rolling and bizarre postures elicited by Dyn A and Dyn A-(1-32) were reduced in rats pretreated i.c.v. with MR1452 (30 nmol), but not with naloxone (up to 100 nmol). Interestingly, des-Tyr-Dynorphin A (Dyn A-(2-17)), a fragment with virtually no opioid binding potential, was 4 times less potent that Dyn A in inducing hypothermia. These findings are consistent with the hypothesis that prodynorphin-derived peptides effects are not exclusively opioids in nature.

Topics: Animals; Benzomorphans; Body Temperature; Dynorphins; Endorphins; Hypothermia; Kinetics; Male; Motor Activity; Naloxone; Naltrexone; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Opioid

Chronic morphine treatment has been suggested to cause the development of supersensitive dopamine receptors. This increase in sensitivity was detected as a hypersensitivity in direct-acting dopamine agonists and as an increase in the affinity of dopamine receptors. However, these binding studies were performed in animals which had been withdrawn from morphine for a period of 24-48 h prior to killing. In the present study mice were implanted with pellets containing 75 mg of morphine free base. The pellets were left in situ in all experiments. One group of mice exhibited an increased sensitivity to apomorphine 72 h following pellet implantation as evidenced by a decrease in the ED50 of apomorphine for inducing cage climbing behavior. A second matched group of mice was found to have a significant increase in whole brain [3H]spiroperidol binding sites. These results suggest that chronic morphine treatment can cause the development of central supersensitive dopamine receptors. Lithium administered concurrently with the morphine attenuated the increased sensitivity to apomorphine and the increase in the number of [3H]spiroperidol binding sites. Concurrent lithium treatment also facilitated the degree of analgesic tolerance, and naloxone-induced withdrawal hypothermia. The ability of lithium to enhance analgesic tolerance while simultaneously attenuating the increase in dopamine receptors suggests that alterations in dopamine receptors might modify the degree of analgesic tolerance which develops to chronic morphine administration, or might modify the animal's response to thermal stimuli. The mechanism by which lithium enhanced naloxone-induced hypothermia is presently unknown.

Topics: Analgesia; Animals; Apomorphine; Behavior, Animal; Binding Sites; Brain; Drug Implants; Drug Tolerance; Hypothermia; Lithium; Male; Mice; Morphine; Naloxone; Receptors, Dopamine; Spiperone; Substance Withdrawal Syndrome

Topics: Blood Coagulation Disorders; Blood Substitutes; Calcium; Emergencies; Filtration; Fluid Therapy; Gravity Suits; Humans; Hypothermia; Naloxone; Shock, Hemorrhagic; Transfusion Reaction; Vasoconstrictor Agents; Wounds and Injuries

The effects of the three peptides neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors were studied in mice. Intracisternal administration of these peptides to mice prolonged the duration of sleep induced by ethanol (5.2 g/kg). Neurotensin and beta-endorphin also enhanced ethanol-induced hypothermia. None of the peptides, when administered alone, produced sleep. However, all three compounds impaired the aerial righting reflex and induced sleep when followed by an IP dose of ethanol (3.5 g/kg), which alone did not induce sleep. These results, taken together with previous findings, suggest that neuropeptides may be involved in the complex mechanisms of action of ethanol on the CNS.

Topics: Animals; Behavior, Animal; beta-Endorphin; Bombesin; Endorphins; Ethanol; Hypothermia; Male; Mice; Mice, Inbred Strains; Naloxone; Neurotensin; Peptides; Reflex; Sleep; Thyrotropin-Releasing Hormone

Rats subjected to non-noxious, anxiogenic stressors were found to exhibit either hyperthermia or hypothermia depending on the nature of the stressor. The present work examines the effects of naloxone (Nx), diazepam (DZP) and gamma-acetylenic GABA (AcG), an inhibitor of GABA catabolism, on these phenomena. Nx reduced stress hyperthermia and basal temperature by similar amounts; it did not affect stress hypothermia. DZP also reduced basal Tb but was able to completely inhibit and even reverse stress hyperthermia and to reduce stress hypothermia. The effects of AcG were similar to those of DZP. In conclusion, it appears that endogenous opioids are not involved in the thermic responses to our emotional stressors whereas GABA would be an important modulator. It is suggested that DZP, through a GABAergic link might inhibit the release of hyperthermic pituitary factors from the neurointermediate lobe and of hypothermic substances from the anterior lobe.

Topics: 4-Aminobutyrate Transaminase; Alkynes; Aminocaproates; Animals; Body Temperature; Diazepam; Humans; Hypothermia; Male; Naloxone; Rats; Rats, Inbred Strains; Stress, Psychological

Morphine elicited a dose-related increase in the duration of phencyclidine (PCP)-induced motor incoordination. In the open field behavioral observations, morphine enhanced the PCP-induced decrease in the number of ambulation and rearing. Morphine potentiated the PCP-induced decrease in body temperature. The LD50 of PCP was significantly decreased in the presence of morphine. An opiate antagonist, naloxone, antagonized the morphine-induced effects without influencing the pharmacological actions of PCP itself. The levels of hepatic microsomal cytochrome P-450 and cytochrome b5 and the activities of NADPH dehydrogenase and NADPH cytochrome c reductase were unaffected by morphine treatment. The half-lives of PCP in serum and brain were increased by the concurrent administration of morphine. The ratio of the liver weight to body weight and aniline hydroxylase activity in hepatic microsomal fraction were decreased in the morphine-treated group compared with the control group; this is indicative of a possible reduction in the oxidative metabolism of PCP. The results indicate that acute administration of morphine enhances a variety of pharmacological effects of PCP; an inhibition of PCP disposition by morphine may be a mechanism involved in this process.

Topics: Aniline Compounds; Animals; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Fever; Half-Life; Hypothermia; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Morphine; Motor Activity; Naloxone; Phencyclidine

Chlornaltrexamine (beta-CNA) a selective, long-acting irreversible opiate antagonist inhibited the analgesia, hypothermia, hypothermia tolerance and physical dependence produced by delta 9-tetrahydrocannabinol (THC) in rats. The results suggest that there are some common features between cannabis and opiates and some actions of THC may be mediated by opioid related mechanisms in the central nervous system.

Topics: Analgesia; Animals; Dronabinol; Drug Tolerance; Humans; Hypothermia; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nitrogen Mustard Compounds; Rats; Receptors, Opioid; Substance-Related Disorders

Recently it has been suggested that MIF-I can act as an opiate antagonist for analgesia. Therefore, rats kept at 4 degrees C were pretreated with MIF-I in an attempt to extend the observation to a nonanalgesic opiate effect by determining any blockade of the thermal response to beta-endorphin and morphine. MIF-I, at an ip dose of 1.0 mg/kg, was found to block the thermal responses to beta-endorphin injected ip at doses of 0.1 and 1.0 mg/kg. A lower dose (0.1 mg/kg, ip) of MIF-I, or naloxone (10 mg/kg), was also able to block the thermal effects of 30 and 60 mg/kg doses of morphine. However, an ip dose of 1.0 mg/kg MIF-I potentiated the hypothermic effects of morphine but, like naloxone, reduced the magnitude of the decrease in the level of motor activity induced by beta-endorphin or by morphine. The results of this study demonstrate a nonanalgesic situation in which MIF-I can act as an antagonist of opiate effects after peripheral injection.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Endorphins; Hypothermia; Male; Morphine; Motor Activity; MSH Release-Inhibiting Hormone; Naloxone; Rats

Topics: Animals; Blood Pressure; Body Temperature; Body Temperature Regulation; Hypotension; Hypothermia; Laminectomy; Male; Naloxone; Rats; Receptors, Opioid; Respiration; Spinal Cord

The effects of morphine and pethidine upon body temperature and upon the reversal of reserpine hypothermia in the mouse were investigated. Both morphine and pethidine produced a dose-dependent fall in body temperature, that of morphine being totally antagonized by nalorphine and partially by naloxone, while that of pethidine was antagonised by naloxone and enhanced by nalorphine. Both drugs reversed reserpine-induced hypothermia. The reversal by morphine, but not by pethidine, was partially antagonized by naloxone. Adrenalectomy prevented the reversal of reserpine hypothermia by pethidine but morphine produced a partial reversal. Ganglion blockade and alpha-and beta-blockade all prevented reversal of reserpine hypothermia by both drugs. The results are discussed with regard to differences between pethidine and morphine and possible involvement of opiate receptors.

Topics: Adrenalectomy; Animals; Body Temperature; Dose-Response Relationship, Drug; Female; Hypothermia; Male; Meperidine; Mice; Morphine; Naloxone; Pentolinium Tartrate; Phenoxybenzamine; Propranolol; Reserpine; Species Specificity

Naltrexone, in relatively high doses, has been reported to cause a fall in body temperature in human ex-heroin addicts who had been abstinent for at least 6 weeks. The underlying mechanism of this hypothermic effect has been investigated in rats. The first consideration was that the temperature change was a reflection of delayed withdrawal but rats implanted with a morphine pellet 45 days earlier showed no significant change in temperature after a dose of naltrexone that caused marked withdrawal hypothermia in dependent rats implanted 3 days previously. A fall in core temperature was only induced in rats after doses of 80 and 160 mg/kg i.p. of naltrexone. Behavioral thermoregulatory studies revealed that the animals correct the falling body temperature by increased exposure to a radiant heat source indicating that the central thermostats had not been significantly affected by the drug. These data suggest that the major component in the hypothermic effect of naltrexone is activation of efferent heat loss pathways or peripheral heat loss mechanisms. Due to current suggestions that opiate receptors might represent the receptors for an endogenous transmitter the results are discussed in relation to this consideration. When compared to the sites and mechanism of action of opiates on thermoregulation the results with naltrexone lend little support to the hypothesis that the fall in temperature is due to displacement of an endogenous substance from central opiate receptors.

Topics: Animals; Body Temperature Regulation; Dose-Response Relationship, Drug; Humans; Hypothermia; Morphine; Naloxone; Naltrexone; Placebos; Rats; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Apomorphine; Dopamine; Humans; Hypothermia; Male; Morphine; Naloxone; Pimozide; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Body Temperature; Conditioning, Psychological; Humans; Hypothermia; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors