The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 78 , Issue 4
Showing 1-19 articles out of 19 articles from the selected issue
Review
  • Yasunobu Okuma, Yasuyuki Nomura
    1998 Volume 78 Issue 4 Pages 399-404
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    To elucidate the fundamental mechanism of age-related deficiencies of learning and to develop effective drugs for intervention in age-related diseases such as learning dysfunctions, pertinent animal models that have characteristics closely similar to human dysfunctions should be established. SAM (senescence-accelerated mouse) has been established as a murine model of the SAM strains, groups of related inbred strains including nine strains of accelerated senescence-prone, short-lived mice (SAMP) and three strains of accelerated senescence-resistant, long-lived mice (SAMR). SAMP-strain mice show relatively strain-specific age-associated phenotypic pathologies such as shortened life span and early manifestation of senescence. Among the SAMP-strain mice, SAMP8 mice show an age-related deterioration in learning ability. Here, the neuropathological, neurochemical and pharmacological features of SAM are reported, especially for SAMP8. Moreover, the effects of several drugs on the biochemical and behavioral alterations in SAMP8 and the etiologic manifestation of accelerated senescence are also discussed.
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  • Kazuhide Inoue
    1998 Volume 78 Issue 4 Pages 405-410
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The inhibitory effects of extracellular adenosine 5′-triphosphate (ATP) are reviewed in the present paper. ATP inhibits the release of the excitatory transmitter glutamate and stimulates the release of the inhibitory transmitter GABA from hippocampal neurons. Also, ATP activates potassium conductance directly through G protein, resulting in hyperpolarization of membrane potential. ATP activates microglia to secrete plasminogen that promotes the development of mesencephalic dopaminergic neurons and enhances neurite outgrowth from explants of neocortical tissue. Moreover, ATP may protect hippocampal neurons from excitotoxic cell death by preserving mitochondrial function. Thus, ATP may have a role in the protection of the function of hippocampus from over-stimulation by glutamate.
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  • Yasuhito Shirai, Norio Sakai, Naoaki Saito
    1998 Volume 78 Issue 4 Pages 411-417
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    To clarify the subspecies-specific functions of protein kinase C (PKC), we constructed cDNAs encoding γ-, ε- and δ-PKC fused with green fluorescent protein (GFP). All fusion proteins had enzymological and immunological characteristics similar to those of native PKCs. When expressed in CHO-K1 cells, each fusion protein showed a specific subcellular localization. Their translocations induced by various stimulation were also diverse. For example, ATP translocated γ-, ε- and δ-PKC-GFP in the cytoplasm to the plasma membrane within 30 sec with a return to the cytoplasm in 3 min, whereas TPA induced slow and irreversible translocation of all subspecies to the plasma membrane. Fatty acids also induced the translocation of γ- and ε-PKC-GFP, but the two PKC subspecies showed distinct translocation and sensitivity to various fatty acids. Furthermore, we revealed that the PKC translocation requires neither the kinase activity of PKC nor its association with cytoskeletal proteins such as F-actin. These results indicate that each subspecies has a spatially and temporally different targeting mechanism that depends on the extracellular and intracellular signals, contributing to the subspecies-specific functions of PKC. These remarkable findings also indicate that a system for monitoring the PKC translocation is a powerful tool for investigating the subspecies-specific functions of PKCs and mechanism of its translocation.
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Regular Papers
  • Er-Qing Wei, Yasuyuki Irie, Che-Hui Kuo, Yun Ding, San-Yong Niu, Eunju ...
    1998 Volume 78 Issue 4 Pages 419-427
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    ssCRE-BP/Purα is a single stranded DNA-binding protein and may be involved in gene replication and transcription and in the development of morphine dependence. We found a ssCRE-BP/Purα (45 kDa) in rat lung that was larger than those (40 kDa) identified in rat and mouse brains and mouse lung. Immunohistochemistry showed that ssCRE-BP/Purα is primarily distributed in the lung epithelium. As allergic inflammation induces various gene expressions, we investigated the changes of Purα during airway inflammation. Ovalbumin-sensitized rats were used for inducing allergic airway inflammation. The expression and DNA-binding activity of 45-kDa ssCRE-BP/Purα were significantly increased in the sensitized rat lungs 24 hr after antigen challenge, but not in those of rats nonsensitized or sensitized with ovalbumin and challenged with saline. Immunohistochemistry and in situ hybridization demonstrated that the vascular endothelial cells and numerous infiltrated eosinophils around the airways were stained with anti-Purα antibody. These data suggest that rat lung and the eosinophils contain a 45-kDa ssCRE-BP/Purα that is increased when airway inflammation occurs.
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  • Shinji Teramoto, Masashi Suzuki, Takeshi Matsuse, Yasuyoshi Ouchi
    1998 Volume 78 Issue 4 Pages 429-434
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the effect of ambroxol and age on oxygen radical production and generation with stimulation of phorbol-myristate acetate (PMA) by bronchoalveolar lavage (BAL) cells. Lung free cells including pulmonary alveolar macrophages were harvested from young (4-month-old) and aged (28-month-old) male guinea pigs using BAL. The oxygen radicals produced by BAL cells with or without stimulation of PMA were measured by the lucigenin-dependent chemiluminescence method using a photon counter. Oxygen radical production and generation by BAL cells were not different between young and aged guinea pigs. However, the oxygen radical generation after stimulation with PMA was greater than the oxygen radical spontaneous production both in young and aged animals. Ambroxol solution given into culture media containing BAL cells inhibited oxygen radical production and generation by BAL cells harvested from both young and aged guinea pigs in a concentration-dependent manner. Approximately 16 - 20 μM of ambroxol inhibited 50% of the production of oxygen radicals in vitro by BAL cells in young and aged guinea pigs, whereas a slightly greater amount of ambroxol was necessary to inhibit 50% of the PMA-induced oxygen radical generation in vitro by BAL cells in guinea pigs. These results indicate that ambroxol inhibits oxygen radicals produced by BAL cells from young and aged guinea pigs, and they suggest that ambroxol may be a possible therapeutic modality for ameliorating oxidant associated pulmonary disorders in young and aged patients.
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  • Yoshinori Suzuki, Masashi Ishihara, Tetsuya Segami, Mikio Ito
    1998 Volume 78 Issue 4 Pages 435-441
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    When free radical-scavenging activities of quercetin, α-tocopherol, nifedipine and tetracycline were measured by an electron spin resonance technique, all test compounds (10-5 to 10-3 M) scavenged both superoxide anions and hydroxyl radicals. The oral administration of quercetin (50 and 100 mg/kg), α-tocopherol (8 and 16 mg/kg), nifedipine (20 and 40 mg/kg) or tetracycline (10 and 20 mg/kg) markedly prevented the HCl plus ethanol-induced gastric mucosal injury and the increase in the content of thiobarbituric acid-reactive substances in the injured mucosa in rats. In addition, quercetin (25, 50 and 100 mg/kg), α-tocopherol (4, 8 and16 mg/kg), nifedipine (10, 20 and 40 mg/kg) and tetracycline (5, 10 and 20 mg/kg), given orally, twice daily for 14 consecutive days from the day after acetic acid injection, dose-dependently promoted the ulcer healing and inhibited the increase in the content of thiobarbituric acid-reactive substances in the ulcerated mucosa. These results indicate that quercetin, α-tocopherol, nifedipine and tetracycline possess gastric cytoprotective and gastric ulcer healing-promoting actions. In addition, the free radical-scavenging properties of these compounds may be partly related to their anti-ulcer effects.
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  • Jodie J. Rady, Jennifer M. Gorny, James M. Fujimoto
    1998 Volume 78 Issue 4 Pages 443-454
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a μ- to δ-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained μ. Heroin and 6 MAM responses involved δ1 (inhibited by 7-benzylidenenaltrexone) and δ2 (inhibited by naltriben) receptors, respectively. These δ-agonist actions did not synergize with the μ-agonist action of morphine in the diabetic mice. The expected synergism between the δ agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported μ/δ-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different μ-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these μ actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.
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  • Yuko Fukunaga, Norihiro Inoue, Masahiko Miyamoto, Shiroh Kishioka, Hir ...
    1998 Volume 78 Issue 4 Pages 455-461
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the involvement of enkephalins in the caudal periaqueductal gray (cPAG) in morphine withdrawal in rats. Rats were treated with increasing doses of morphine (20 - 30 mg/kg/day, s.c., for 5 days) to develop morphine dependence. Morphine withdrawal was induced by naloxone (5 mg/kg, s.c.) 24 hr after the final morphine injection. The level of preproenkephalin (PPE) mRNA in the cPAG was estimated by quantitative in situ hybridization. PPE mRNA in the cPAG was increased 4 - 24 hr after naloxone in morphine-treated rats. A mixture of peptidase inhibitors (0.5 μl of a solution of amastatin, captopril and phosphoramidon, 3×10-3 M each) microinjected into the cPAG suppressed morphine withdrawal (a decrease in the number of jumping, chin rubbing, paw rubbing and teeth chattering). Antiserum to methionine-enkephalin (1:10 dilution) microinjected into the cPAG did not significantly aggravate morphine withdrawal with or without the mixture of peptidase inhibitors. However, [D-Ala2, Met5]-enkephalinamide (20 nmol), an enkephalin analog, injected into the cPAG decreased the number of jumping without any influence on the other withdrawal signs. These results suggest that the increase in enkephalins in the cPAG may participate in the alleviation of morphine withdrawal ( jumping behavior).
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  • Masato Nanri, Hidekazu Miyake, Yukihisa Murakami, Kinzo Matsumoto, Hir ...
    1998 Volume 78 Issue 4 Pages 463-469
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the effects of GTS-21 [3-(2, 4-dimethoxybenzylidene)-anabaseine dihydrochloride], a nicotinic agonist, on histopathological changes of the brain and radial maze learning performance in rats with permanent occlusion of the bilateral common carotid arteries (2VO) and elucidated whether this compound has a protective effect against the neuronal degeneration and spatial cognitive deficit caused by chronic ischemia. Rats were administered GTS-21 (1 and 10 mg/kg, p.o.) or vehicle 24 hr and 30 min before the 2VO operation and then once daily for 2 months after the operation. The 2VO rats given vehicle had multiple infarctions in the cerebral cortex, hippocampus and striatum and rarefaction in the white matter at 2 months after the operation, although the number and distribution of infarctions varied among individual animals. In addition, the 2VO rats given vehicle showed a higher rate of errors in the acquisition trials of the 8-arm radial maze task than sham-operated controls. However, 2VO rats treated with GTS-21 (1 and 10 mg/kg, p.o.) showed significantly decreased neuropathological changes and less errors in the acquisition trials compared to the vehicle-treated 2VO rats. These results indicate that GTS-21 attenuates impairment of spatial cognitive deficit and progressive neuronal degeneration induced by 2VO and suggest that this compound is beneficial for the treatment of neurodegenerative diseases following chronic cerebral hypoperfusion.
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  • Shinjiro Kobayashi, Mizuki Fukuta, Hitoshi Kontani, Sumino Yanagita, I ...
    1998 Volume 78 Issue 4 Pages 471-478
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Angiogenesis of cultured choroids was quantitatively assayed in spontaneously diabetic GK and a bolus-treated streptozotocin (STZ)-diabetic Wistar rats. The number and total length of microvessels budded from cultured choroidal explants were measured to use as angiogenic indices. Both indices in 10-week-old Wistar rats were increased in parallel by 5% fetal bovine serum (FBS) from days 2 to 7 in culture. These indices in STZ-rats (10 weeks of age) were increased by 5% FBS to a greater extent than those in age-matched normal rats. These enhanced actions of FBS were concentration-dependent. The explants of 16-week-old GK rats also increased these indices to a greater extent than those of age-matched Wistar rats. Aging to 18 weeks of age also increased choroidal angiogenesis in the normal rats. In conclusion, the assay model of choroidal angiogenesis was established by determining the number and length of microvessels in cultured choroidal explants. The diabetic states of STZ-Wistar and GK rats enhanced FBS-induced choroidal angiogenesis. This assay model is useful for determining angiogenic activity of growth factors and effective drugs in diabetic choroidopathy and retinopathy.
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  • Dale W. Quest, Thomas W. Wilson
    1998 Volume 78 Issue 4 Pages 479-486
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Ridogrel is a dual acting thromboxane synthase inhibitor/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B2 or 6-keto-prostaglandin F, although ex vivo serum thromboxane B2 was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200±6.1 to 173±6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B2 and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B2 excretion (from 103±7 ng/day to 49±10 ng/day, P<0.01) while preserving 6-keto-prostaglandin F excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F in addition to attenuating serum and urine thromboxane B2. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.
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  • Takao Taniguchi, Xin-Tian Fan, Ken Kitamura, Tetsuo Oka
    1998 Volume 78 Issue 4 Pages 487-492
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The intra-third-ventricular (i.t.v.) administration of [Met5]-enkephalin (enk) to rats pretreated i.t.v. with three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, inhibited the tail-flick response. The enk-induced inhibition was augmented by increasing the doses of the three PIs, with the maximum inhibition being attained at the doses of 10 nmol each. The enk-induced inhibition in rats pretreated with any combination of two PIs, however, were markedly smaller than that in rats pretreated with all three PIs, indicating that three kinds of enzymes all played important roles in the inactivation of enk. The inhibitory effect of enk on the tail-flick response in rats pretreated with the three PIs at doses of 10 nmol each was approximately tenfold higher than that of morphine. The relative anti-nociceptive potencies of enk and morphine were similar to the relative inhibitory potencies obtained previously with the isolated guinea pig ileum pretreated with the three PIs, indicating that the hydrolysis of the i.t.v. administered enk was largely prevented by the three PIs. However, the magnitude of the enk-induced inhibition in rats pretreated s.c. with the three PIs indicated that the hydrolysis of enk injected i.t.v. was not largely prevented by the s.c. administration of three PIs at doses up to 10 μmol each/kg.
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  • Miho Kasama, Yasuyuki Furukawa, Takeshi Oguchi, Yuji Hoyano, Shigetosh ...
    1998 Volume 78 Issue 4 Pages 493-499
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We investigated the effects of hypothermia (25°C) on the chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, If), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, IKr) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the If and inward Ca2+ current are sensitive to hypothermia in the heart.
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Short Communications
  • Ming-Tsuen Hsieh, Fu-Yu Chueh, Shui-Mu Lin, Fu-Shin Chueh, Chieh-Fu Ch ...
    1998 Volume 78 Issue 4 Pages 501-504
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Intraperitoneal administration of magnolol (25 - 100 mg/kg) produced a dose-related fall in rats’ colonic temperature. The magnolol-induced hypothermia was attenuated by pretreatment with intracerebroventricular 6-hydroxydopamine (200 μg/rat). The L-DOPA (200 mg/kg, i.p.) plus benserazide (50 mg/kg, i.p.)-induced hyperthermia was attenuated by magnolol. On the other hand, the α-methyltyrosine (100 mg/kg, i.p.)-induced hypothermia was potentiated by magnolol. Furthermore, magnolol (50 mg/kg, i.p.) decreased the dopamine and norepinephrine release in the hypothalamus, but did not change the concentrations for their metabolites (3, 4-dihydroxyphenylacetic acid and homovanillic acid). The data suggest that magnolol decreases colonic temperature by reducing catecholaminergic activity in rat hypothalamus.
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  • Takayuki Ishii, Nobuyuki Kibushi, Takashi Nakajima, Tae Kakuta, Noriko ...
    1998 Volume 78 Issue 4 Pages 505-509
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The local anti-inflammatory activity and systemic side effects of NM-135 (6α, 9-difluoro-11β-hydroxy-16α-methyl-21[[2, 3, 4, 6-tetrakis-O-(4-methylbenzoyl)-β-D-glucopyranosyl]oxy]-pregna-1, 4-diene-3, 20-dione) in croton oil-induced granuloma pouches and ear edema in rats were studied. The local anti-inflammatory activity of NM-135 was stronger than that of betamethasone 17-valerate (BV). As to systemic side effects, BV and diflucortolon valerate (DFV) caused thymolysis at the doses required for the anti-inflammatory activity. In contrast, no clear systemic side effect was observed in rats administered NM-135 at the dose producing the anti-inflammatory activity. These results suggest that NM-135 is a drug exhibiting a high degree of dissociation between the local anti-inflammatory activity and systemic side effects.
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  • Jun Takagi, Norifumi Yonehara
    1998 Volume 78 Issue 4 Pages 511-514
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the effects of intravenous injection of several serotonin (5-HT) antagonists on the inhibitory action of electro-acupuncture (EAP) against the nociceptive responses in the trigeminal nucleus caudalis in rabbits. The inhibitory effect of EAP was suppressed by pindolol, methysergide and ICS 205-930, whereas NAN-190 and ketanserin amplified the EAP effect. These results suggest that 5-HT1, except 5-HT1A; 5-HT2, except 5-HT2A; and 5-HT3 receptors are positively involved in EAP-induced analgesia, whereas the activation of 5-HT1A and 5-HT2A receptors suppressively act on EAP-induced analgesia.
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  • Michihisa Tohda, Hiroshi Watanabe
    1998 Volume 78 Issue 4 Pages 515-517
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The effects of repeated oral administration of antidepressants on the serotonin 2C receptor subtype (5-HT2CR) mRNA level in the rat brain were examined. Imipramine (20 mg/kg, p.o.) enhanced the hybridization signal in a time (days)-dependent manner, reaching a maximum at day 4 and maintaining a high level until day 14. Desipramine and mianserin, which have 5-HT2CR antagonistic activity, also stimulated the mRNA expression to about same extents as imipramine, but nomifensine, which has no effect on 5-HT2CR, was ineffective. These results suggest that long-term treatment with antidepressants, which act as 5-HT2CR antagonists, stimulates 5-HT2CR mRNA expression.
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  • Keiji Nishida, Yoshiji Ohta, Isao Ishiguro
    1998 Volume 78 Issue 4 Pages 519-522
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined whether the increasing action of teprenone (TP) on mucus synthesis and content in rat gastric mucosa is related to nitric oxide (NO) formation via NO synthase (NOS) in the tissue. TP (200 mg/kg)-induced increases in levels of gastric mucosal hexosamine and adherent mucus were inhibited with decreased gastric mucosal NOS activity and nitrite/nitrate concentration by co-administration of NG-monomethyl L-arginine (100 mg/kg), a NOS inhibitor, but not its D-isomer. These results suggest that TP exerts an increasing action on gastric mucus synthesis and content possibly under the condition of maintained NO production via NOS in gastric mucosal tissues, although the precise mechanisms for the action of TP is still unclear.
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  • Sonja Vuckovic, Milovan Ivanovic, Milica Prostran, Zoran Todorovic, Zo ...
    1998 Volume 78 Issue 4 Pages 523-527
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The influence of higher environmental temperature (HET=30±1°C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P<0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22±1°C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2 - 0.5 mg/kg) was significantly (P<0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P<0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. HET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.
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