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Amitriptyline and femoxetine, but not clomipramine or citalopram, antagonize hyperthermia induced by directly acting 5-hydroxytryptamine-like drugs in heat adapted rats.

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist--m-CPP and quipazine. Pirenperone and --to a lesser degree--amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.

Adaptation, Physiological↗

Involvement of the 5-HT(2) receptor in hyperthermia induced by p-chloroamphetamine, a serotonin-releasing drug in mice.

The effects of a serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine (PCA), on body temperature were investigated in mice. PCA induced hyperthermia in mice. PCA-induced hyperthermia was inhibited by the 5-HT(2A/2B/2C) receptor antagonist, 4-isopropyl-7-methyl-9-(2-hydroxy-1-methyl-propoxycarbonyl)-4,6A,7 , 8,9,10,10A-octahydro-indolo[4,3-FG]quinolone maleate (LY53857). The 5-HT(2A) receptor antagonist, ketanserin, reduced the PCA-induced hyperthermia, while the 5-HT(2B/2C) receptor antagonist, N-3-pyridinyl-3,5-dihydro-5-methyl-benzo[1,2-b:4, 5-b']dipyrrole-1(2H)-carboxamide (SB 206553), enhanced it. LY 53857, ketanserin and SB 206553 did not affect hyperactivity in mice treated with PCA. These results suggest that PCA-induced hyperthermia in mice is mediated by 5-HT(2A) receptors and is not related to changes in locomotor activity.

Animals↗

Peripheral cholinergic pathway modulates hyperthermia induced by stress in rats exposed to open-field stress.

Exposure to an open field is psychologically stressful and leads to an elevation in core temperature (T(c)). Methyl scopolamine (MS), a muscarinic antagonist, and pyridostigmine (PYR), a carbamate that inhibits acetylcholinesterase, do not cross the blood-brain barrier and have little effect on T(c) in resting, nonstressed animals. However, we have found that MS has an antipyretic effect on T(c) that is caused by handling and cage-switch stress. PYR should act pharmacologically to reverse the effects of MS. To this end, we assessed the effects of MS and PYR on stress-induced hyperthermia. Male Sprague-Dawley rats at 90 days of age were housed individually at an ambient temperature of 22 degrees C. T(c) and motor activity were monitored by radiotelemetry in an open-field chamber. Rats were dosed intraperitoneally at 1200 with 1.0 mg/kg MS, 0.1 mg/kg PYR, a combination of MS and PYR, or saline and placed immediately inside the open-field chamber for 60 min. Stress-induced hyperthermia was suppressed immediately by MS and enhanced by PYR. T(c) only increased by 0.3 degrees C in the MS-treated animals. The hyperthermic response in the PYR group was nearly 0.6 degrees C above that of rats dosed with saline. Coadministration of PYR and MS led to a stress-induced hyperthermia response nearly identical to that of rats injected with saline. Overall, open-field stress exacerbated the effects of MS and PYR on body T(c) and provides support for a peripheral cholinergic mechanism that mediates stress-induced hyperthermia.

Analgesics, Non-Narcotic↗

Interactions of radiofrequency radiation-induced hyperthermia and 2-methoxyethanol teratogenicity in rats.

Radiofrequency (RF) radiation is used in a variety of workplaces. In addition to RF radiation, many workers are concurrently exposed to numerous chemicals; exposed workers include those involved with the microelectronics industry, plastic sealers, and electrosurgical units. The developmental toxicity of RF radiation is associated with the degree and duration of hyperthermia induced by the exposure. Previous animal research indicates that hyperthermia induced by an elevation in ambient temperature can potentiate the toxicity and teratogenicity of some chemical agents. We previously demonstrated that combined exposure to RF radiation (10 MHz) and the industrial solvent, 2-methoxyethanol (2ME), produces enhanced teratogenicity in rats. The purpose of the present research is to determine the effects of varying the degree and duration of hyperthermia induced by RF radiation (sufficient to maintain colonic temperatures at control [38.5], 39.0, 40.0, or 41.0 degrees C for up to 6 h) and 2ME (100 mg/kg) administered on gestation day 13 of rats. Focusing on characterizing the dose-response pattern of interactions, this research seeks to determine the lowest interactive effect level. Day 20 fetuses were examined for external and skeletal malformations. The results are consistent with previous observations. Significant interactions were observed between 2ME and RF radiation sufficient to maintain colonic temperatures at 41 degrees C for 1 h, but no consistent interactions were seen at lower temperatures even with longer durations. These data indicate that combined exposure effects should be considered when developing both RF radiation and chemical exposure guidelines and intervention strategies.

Abnormalities, Drug-Induced↗

Effects of various neuroleptics on rabbit hyperthermia induced by N, N-Dimethyltryptamine (DMT) and d-amphetamine.

The effects of various neuroleptics were studied on N, N-dimethyltryptamine (DMT, 3.2 mg/kg) and d-amphetamine (3.2 mg/kg) induced hyperthermia in the rabbit. Complete dose-effect curves were obtained. The order of potency for antagonism of DMT-induced hyperthermia was: methiothepin greater than octoclothepin greater than or equal to oxyprothepin greater than perathiepin greater than dokloxythepin greater than mianserine greater than loxapine greater than oxypertine greater than chlorpromazine greater than pipamperone greater than fluphenazine greater than thiothixene greater than haloperidol greater than molindone. The order of potency for antagonism of d-amphetamine hyperthermia was: haloperidol greater than chlorpromazine greater than oxypertine greater than octoclothepin and methiothepin. For these five drugs, the order of potency for antagonism of amphetamine hyperthermia was the reverse of the order for antagonism of DMT hyperthermia. Methiothepin reduced d-amphetamine-induced hyperthermia effectively at a very high dose (0.32 mg/kg) and variably at lower doses. The results indicate that neuroleptics differ markedly in their specificity of antagonism of DMT and d-amphetamine which may act through different neurotransmitter mechanisms (tryptaminergic vs. adrenergic).

Animals↗

Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism.

We investigated the involvement of the sympatho-adrenal axis in the hyperthermia induced by methamphetamine by using a biotelemetric system. The intraperitoneal injection of methamphetamine (1 mg/kg) induced hyperthermia preceded by an increase in oxygen consumption in freely moving rats. The hyperthermic effect of methamphetamine was completely blocked by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.p.). Adrenalectomy, but not adrenal demedullation, prevented the hyperthermia. In adrenalectomized rats, dexamethasone supplementation (0.5 mg/kg, s.c.) restored the methamphetamine-induced hyperthermia. Furthermore, dantrolene (1 or 2 mg/kg, i.v.), which blocks Ca2+ release from the sarcoplasmic reticulum in skeletal muscle, attenuated the hyperthermia. These results suggest that methamphetamine stimulates norepinephrine release from sympathetic nerve terminals, which then enhances thermogenesis in skeletal muscle under the permissive action of glucocorticoids.

Adrenal Glands↗

Use of potentiation of thyrotrophin releasing hormone (TRH)-induced hyperthermia as a test for screening antidepressants which activate alpha-adrenoceptor systems.

1 The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40 mg/kg i.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general, the more sensitive test. 3 A correlation seems to exist between the alpha-adrenergic effect of antidepressants and the potentiation of TRH- induced hyperthermia. Those antidepressants which do not act on alpha-adrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test. 4 This property may be used to select antidepressants that activate alpha-adrenoceptor systems.

Adrenergic alpha-Agonists↗

[Effect of radio wave-induced hyperthermia on microflora of the prostate in the treatment of prostatitis associated with infertility].

The influence of hyperthermia induced by radiowaves on the microflora of the prostate in cases of male sterility was studied. The use of hyperthermia was shown to produce a stable decrease in bacteriospermia and the persistence potential of bacteria isolated from sperm. Hyperthermia produced a bactericidal effect not only on microorganisms contained in sperm but also on the microflora of prostatic tissues 1 cm deep. The study gave grounds for treating male sterility with the use of hyperthermia induced by radiowaves and a subsequent course of antibiotics to achieve the stable decrease of bacteriospermia and the restoration of the reproductive function.

Adult↗

Thermal tolerance reduces hyperthermia-induced disruption of working memory: a role for endogenous opiates?

Previous reports indicate that microwave-induced hyperthermia can impair learning and memory. Here, we report that preexposure to a single 20-min period of hyperthermia can produce thermal tolerance and, thereby, attenuate future physiological and behavioral reactions to heating. Because endogenous opioids have been implicated in thermoregulation and reactions to microwave exposure, we also determined how opioid receptor antagonism might modulate these effects. In an initial experiment, rats were exposed daily, over 5 successive days, to 600-MHz microwaves (at a whole-body specific absorption rate of 9.3 W/kg) or sham exposed. In animals exposed to microwaves, thermal tolerance was evidenced by declining rectal temperatures over time. Temperature reductions following microwave exposure were prominent after a single previous exposure. Therefore, in a second study, a single hyperthermic episode was used to induce thermal tolerance. On Day 1, rats were either exposed, over a 20-min period, to 600-MHz microwaves (at a whole-body specific absorption rate of 9.3 W/kg) or sham exposed. Just prior to radiation/sham-radiation treatment, rats received either saline or naltrexone (0.1 or 10 mg/kg, intraperitoneally (i.p.)). The following day (Day 2), rats were either microwave or sham exposed and tested on a task which measures the relative time subjects explore a familiar versus a novel stimulus object. Normothermic rats spend significantly more time in contact with new environmental components and less time with familiar objects. Brain (dura) and rectal temperatures were recorded on both days of the study. Microwave exposure produced a reliable hyperthermia which was significantly lower (on Day 2) in rats receiving repeated treatments (tolerant group). On the behavioral test, rats exposed only once to microwave-induced hyperthermia (nontolerant group) exhibited significantly different patterns of object discrimination than did tolerant or sham-exposed animals. Sham-exposed and tolerant animals showed a distinct preference for the new object whereas the nontolerant animals did not. Naltrexone (10 mg/kg) antagonized the hyperthermia-induced disruption of the object discrimination task (in nontolerant rats) and produced patterns of object exploration that were similar to those of sham-irradiated and thermal-tolerant rats, suggesting that endogenous opioids play a role in the organism's response to heating. Taken together, these data are consistent with the conclusions that 1) microwave-induced hyperthermia can cause a dose-dependent disruption of the normal discrimination between new and familiar objects, 2) physiological reactions to a single hyperthermic episode can produce a thermotolerance that expresses itself in both reduced levels of hyperthermia and attenuated behavioral disruptions following microwave exposure, and 3) opioid antagonism can partially reverse some of the behavioral effects of microwave-induced hyperthermia.

Acclimatization↗

Role of interleukin-1 beta, interleukin-6 and macrophage inflammatory protein-1 beta in prostaglandin-E2-induced hyperthermia in rats.

The purpose of this study was to investigate the role of pyrogenic cytokines, such as IL-1 beta, IL-6 and MIP-1 beta, in the mechanisms underlying the hyperthermic response of rats to central injection of PGE2. Thus, specific murine neutralizing antibodies against these cytokines were micro-injected directly into the anterior hypothalamic, preoptic area (AH/POA) of unrestrained rats just before intracerebroventricular injection of PGE2. The significant hyperthermia induced by PGE2 was markedly suppressed by micro-injection of anti-IL-6 and partially attenuated by anti-IL-1 beta. However, the micro-injection of anti-MIP-1 beta failed to alter the hyperthermic response. The results indicate that PGE2-induced hyperthermia is presumably mediated through actions of IL-6 on the thermosensitive cells of the AH/POA and confirm that distinct and alternate pathways exist in the rat brain for the induction of fever.

Animals↗

d-Amphetamine antagonizes prostaglandin E1-induced hyperthermia and suppression of fixed interval operant behavior in rats.

The experiments reported herein were designed to study the effects of prostaglandin F2 alpha (PGF2 alpha) and PGE1 on operant behavior and rectal temperature of rats. A solution containing PGF2 alpha or PGE1 was infused intracerebroventricularly into rats trained to press a lever for food reward on a fixed interval 75 second (FI 75 sec) schedule. PGF2 alpha (10, 100 or 1000 ng/min) had no effect on FI 75 sec operant behavior. Only the highest dose increased temperature. PGE1 (100 ng/min) had no effect, whereas higher doses (250 and 500 ng/min) produced a rate-dependent effect on behavior, increasing low rates and decreasing high rates. The two higher doses also produced convulsions after about 25 min or 20 min infusions, respectively. PGE1 also increased temperature in a dose-dependent manner. Systemic administration of a low dose of d-amphetamine (0.5 mg/kg IP) had little or no effect on behavior or temperature. d-Amphetamine did not alter hyperthermia induced by the highest dose of PGF2 alpha, but antagonized the PGE1-induced hyperthermia. d-Amphetamine also antagonized all of the behavioral effects of PGE1, including convulsions. The results are discussed in relation to the actions of PGs and d-amphetamine on catecholamine neurons in the central nervous system.

Alprostadil↗

Isatin (Indole-2, 3-dione) inhibits natriuretic peptide-induced hyperthermia in rats.

The effects of an endogenous indole, isatin (indole-2, 3-dione), on the hyperthermia induced by atrial natriuretic peptide (ANP-28), brain natriuretic peptide (BNP-32), and C-type natriuretic peptide (CNP-22) were investigated in rats. Intracerebroventricular administration of each peptide in a dose of 1 microg caused elevations in colon temperature 30 and 60 min after injection. An intraperitoneal (i.p.) injection of isatin (50 mg/kg) abolished the natriuretic peptide-induced hyperthermia. These data reinforce the possible involvement of natriuretic peptides in thermoregulatory processes in the central nervous system, and suggest that isatin might counteract their hyperthermic effect in vivo.

Analysis of Variance↗

The effect of repeated treatment with antidepressant drugs on the thyrotropin-releasing hormone (TRH)-induced hyperthermia in mice.

The effect of acute (single dose) or repeated (twice daily, for 14 days) administration of 10 mg kg-1 p.o. of imipramine, amitriptyline, citalopram or mianserin has been examined on the hyperthermia induced by thyrotropin-releasing hormone (TRH) (40 mg kg-1 i.p., 2, or 2 and 72 h after single or last dose of antidepressants, respectively) in mice. Both imipramine and amitriptyline, given repeatedly, potentiated the TRH response, though the effect was observed 2 but not 72 h after the last dose of those drugs. Potentiation was also found after the single dose of imipramine or amitriptyline. On the other hand, citalopram and mianserin, administered either acutely or repeatedly, did not affect the TRH-induced hyperthermia.

Amitriptyline↗

Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) in conscious rabbits.

3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") increases body temperature. This process could be associated with increased cutaneous blood flow, as normally occurs with exercise-induced hyperthermia. Alternatively, an MDMA-induced fall in cutaneous blood flow could contribute to the hyperthermia by diminishing normal heat transfer from the body to the environment. We investigated these possibilities by administering MDMA (1.5-6 mg/kg, i.v.) to conscious freely moving rabbits, determining effects on body temperature, cutaneous blood flow (measured by a Doppler ultrasonic probe that was chronically implanted around the ear pinna artery), and other cardiovascular parameters. MDMA caused a dose-dependent increase in body temperature (from 38.3 +/- 0.3 to 41.2 +/- 0.4 degrees C after 6 mg/kg; p < 0.01; n = 5), preceded and accompanied by a dose-dependent cutaneous vasoconstriction (from 29 +/- 6 to 5 +/- 1 cm/sec after 6 mg/kg; p < 0.01; n = 5). MDMA (3 mg/kg) did not change blood flow to the mesenteric vascular bed. Prior unilateral cervical sympathectomy reduced the increase in body temperature elicited by MDMA (6 mg/kg) from 2.0 +/- 0.2 to 1.3 +/- 0.2 degrees C (p < 0.01; n = 5). On the denervated side, ear pinna blood flow after MDMA injection was 13 +/- 3 cm/sec, compared with 3 +/- 1 cm/sec on the sympathetically intact side (p < 0.05; n = 5). Thus, sympathetically mediated cutaneous vasoconstriction is one mechanism whereby MDMA causes hyperthermia. Reversal of cutaneous vasoconstriction by appropriate pharmacological means could be of therapeutic benefit in humans suffering from life-threatening hyperthermia induced by MDMA.

Animals↗

An adrenergic link in the hypothalamic pathways which mediates morphine- and beta-endorphin-induced hyperthermia in the rat.

The mechanism underlying the hyperthermia induced by intrahypothalamic administration of either morphine or beta-endorphin has been investigated in conscious rats. Direct administration of morphine (1--8 micrograms in 1 microliter) or beta-endorphin (1--3 micrograms in 1 microliter) into the anterior hypothalamus caused hyperthermia in rats at the ambient temperature (8, 22 and 30 degrees C) studied. The hyperthermia in response to opiods was brought about by both increased metabolism and cutaneous vasoconstriction. This hyperthermia, unlike the hypothermia induced by intraventricular administration of opiods was not blocked by naloxone nor did tolerance develop to the response. However, the hypothermia induced by intrahypothalamic administration of opioids was greatly reduced by pretreatment with intrahypothalamic administration of either yohimbine (a blocking agent of alpha-adrenergic receptors) or DL-propranolol (a blocking agent of beta-adrenergic receptors) in the rat. These observations suggest that an adrenergic link occurs in the hypothalamic pathways which mediate morphine- and beta-endorphin-induced hyperthermia in the rat.

Animals↗

Ultrasound-Induced hyperthermia increases cellular uptake and cytotoxicity of P-glycoprotein substrates in multi-drug resistant cells.

PURPOSE: Localized hyperthermia has been shown previously to augment the cytotoxicity of some lipophilic anticancer drugs. Because many of the substrates for the multi-drug resistance (MDR) transporter P-glycoprotein (P-gp) are lipophilic in nature, studies were conducted to test the hypothesis that hyperthermia induced by ultrasound could also increase cellular uptake and cytotoxicity of P-gp substrates by P-gp-expressing cells. METHODS: To test this hypothesis, we studied the effects of hyperthermia and ultrasound on cellular accumulation of putative P-gp substrates, rhodamine 123 (R123) and doxorubicin (DOX), and cytotoxicity of DOX in the parent and MDR variants of two human cancer cell lines. RESULTS: Treatment of cells with hyperthermia or ultrasound (20 min at 41 degrees C) both caused a significant increase over controls (no ultrasound treatment) in R123 and DOX accumulation in the parent and MDR lines of MV522 and KB cells. Ultrasound also substantially increased the antiproliferative effects of DOX in both the parent and MDR variants of MV522 and KB cell lines when compared with controls. Our results also indicated that ultrasound exerted a much greater effect on cellular accumulation of R123 and DOX and cytotoxicity enhancement of DOX in the MDR variants than putative P-gp antagonist such as verapamil. CONCLUSION: The present results point to the potential use of ultrasound-induced hyperthermia as a much safer alternative to P-gp antagonist for reversal of MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

p-Chloroamphetamine-induced hyperthermia pharmacologically distinct from fenfluramine-induced hyperthermia.

The influence of various drug pretreatments upon the responses of rabbits to the putative indirect 5-hydroxytryptaminergic agonists p-chloroamphetamine (PCA) and fenfluramine were examined. In naive rabbits PCA evoked hyperthermia, behavioural excitation and prominent forepaw clonic activity, while fenfluramine produced only hyperthermia and behavioural stimulation. The hyperthermic and behavioural responses of both agents were reduced by the 5-hydroxytryptamine (5-HT) uptake inhibitor, fluoxetine, potentiated by the monoamine oxidase inhibitor, pheniprazine, and unaltered by the dopaminergic antagonist, haloperidol. Pretreatment with the 5-hydroxytryptaminergic receptor blockers cinanserin, cyproheptadine or D-2-bromolysergic acid diethylamide markedly attenuated the effects of fenfluramine but only slightly influenced the responses to PCA. Depeletion of central 5-HT stores with p-chlorophenylalanine also affected responses to fenfluramine more than responses to PCA. The tryptaminergic receptor blocker methergoline abolished both PCA-induced hyperthermia and forepaw clonus--but not behavioural stimulation--while the effects of flenfluramine were only partly reduced. We interpret these data to mean that PCA- and fenfluramine-induced drug effects have different underlying mechanisms, the PCA responses relying possibly upon tryptamine while the fenfluramine responses are 5-hydroxytryptaminergic.

Amphetamines↗

Ultrasound-induced hyperthermia in the treatment of cutaneous leishmaniasis.

Local hyperthermia induced by ultrasound was delivered two or three times weekly to twenty-eight lesions of acute cutaneous leishmaniasis in eighteen patients. Twenty-two lesions (78.5 percent) in thirteen patients resolved completely five to ten weeks after the start of treatment. Our results are explained by the thermosensitivity of the parasite and its inability to survive at supranormal temperatures. Ultrasound hyperthermia was tolerated by most of the patients. The results of this study indicate that topical heat is safe and effective for the treatment of patients with acute cutaneous leishmaniasis.

Adolescent↗