Role of benzodiazepine-GABAA receptor complex in attenuation of U-50,488H-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin in mice

In the present study, the role of benzodiazepine-GABAA receptor complex in the attenuation of U-50,488H (U50), a selective kappa opioid agonist-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin (GTS) was investigated using the mice tail-flick test. The intraperitoneal (i.p.) treatment of GTS (100 and 200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently attenuated the U50 (40 mg/kg, i.p.)-induced analgesia. GTS (0.001-10 microg/ml) did not alter binding of [3H]naloxone to mice whole brain membrane. The attenuation effect of GTS (100 mg/ kg) and diazepam (0.5 mg/kg) on U50-induced analgesia was blocked by flumazenil (0.1 mg/kg, i.p.), a benzodiazepine receptor antagonist, and picrotoxin (1 mg/kg, i.p.), a GABAA-gated chloride channel blocker. However, bicuculline (1 mg/kg, i.p.), a GABAA receptor antagonist blocked the attenuation effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on U50-induced analgesia. Chronic treatment (day 4-day 6) of GTS (50-200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently inhibited the tolerance to U50-induced analgesia. Flumazenil (0.1 mg/kg) and picrotoxin (1 mg/kg) on chronic treatment blocked the inhibitory effect of GTS (100 mg/kg) and diazepam (0.5 mg/kg) on tolerance to U50-induced analgesia. On the other hand, chronic treatment of bicuculline (1 mg/kg) blocked the inhibitory effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on tolerance to U50-induced analgesia. In conclusion, the findings suggest that GTS attenuates U50-induced analgesia and inhibits tolerance to its analgesia and this action involves benzodiazepine receptors and GABAA-gated chloride channels.     

Neuromodulatory effects of TRH upon swim and cholinergic analgesia

In addition to short-acting analgesic actions by itself and modulation of analgesic responses induced by endogenous opioids and neurotensin, central administration of thyrotropin-releasing hormone (TRH) potentiates footshock analgesia. The present study evaluated the effects of TRH upon the neurohormonally-mediated though nonopioid analgesia induced by swims in rats. Intracerebroventricular TRH (10 and 50 micrograms) dose-dependently potentiated swim (21, 15, 2 degrees C baths) analgesia on the tail-flick test, an effect which was not due to the hypothermic or basal pain threshold changes. Intravenous (8 mg/kg) TRH potentiated swim (21 degrees C) analgesia; the 600:1 difference in potency between routes strongly suggests central sites of neuromodulatory action. Intracerebroventricular diketopiperazine (50 micrograms), a TRH metabolite, and RX77368 (50 micrograms), a TRH analogue, also potentiated swim (21 degrees C) analgesia, effects also independent of hypothermia and basal reactivity to pain. Finally, given the excitatory interaction between TRH and acetylcholine as well as the cholinergic involvement in swim analgesia, intracerebroventricular TRH potentiated pilocarpine (10 mg/kg, IP) analgesia.     

Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia,tolerance and dependence in mice

The effects of L-Canavanine, a selective inducible nitric oxide synthase (NOS) inhibitor and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, on pain threshold and morphine induced analgesia, tolerance and dependence in mice were investigated and compared. Morphine was administered by subcutaneous implantation of a pellet containing 40 mg free base and withdrawal was precipitated by intraperitoneal (i.p.) injection of naloxone (2 mg/kg). L-Canavanine (200 mg/kg, i.p.) did not affect the pain threshold, morphine-induced analgesia and the induction and expression phases of morphine tolerance and dependence. L-NAME (20 mg/kg, i.p.) significantly (p < 0.05) enhanced the pain threshold, potentiated morphine-induced analgesia and attenuated the expression phase of morphine dependence which has been characterized by withdrawal signs and body weight loss, but did not modify the induction phase of morphine tolerance and dependence. It is concluded that constitutive NOS isoforms which were inhibited by L-NAME may be involved specifically in the mechanisms of morphine induced analgesia, tolerance and dependence.     

Involvement of H2-receptors in the mechanism of analgesic action of Tyr-MIF-1

The antinociceptive effects of H2-agents cimetidine (CIM) and dimaprit (DMP) as well as their effects on the Tyr-MIF-1-evoked analgesia have been studied after intraperitoneal (i.p.) administration in rats. In the paw-pressure (PP) test Tyr-MIF-1 (1 mg/kg), CIM (50 and 100mg/kg) and DMP (5 and 10mg/kg) induced analgesia. Injected before DMP, naloxone (NAL) and CIM diminished or completely prevented the pain-relieving effect of H2-agonist DMP. The antinociceptive effect of Tyr-MIF-1 has been potentiated by DMP dose-dependently. CIM (50mg/kg) decreased the antinociceptive action of the combination Tyr-MIF-1 + DMP, while CIM (100mg/kg) expressed a weaker inhibitory effect on it. The data obtained clearly show that H2-receptor activation is involved in the mechanism of the Tyr-MIF-1 antinociceptive action.     

Environmental and intraperitoneal ethanol influences morphine antinociceptive effect in mice

The ability of acute environmental or intraperitoneal (i.p.) ethanol to influence morphine antinociceptive effect was studied in mice. In order to induce tolerance to morphine analgesia, mice received daily injections of 10 mg/Kg morphine over a period of 10 days. Mice were divided into three groups: i.p. ethanol (E), environmental ethanol (E*), and control saline (M). During the induction of tolerance these groups were treated identically except on days 1 and 11. On these days, 10 minutes prior to morphine injection, mice received either i.p. ethanol (1g/Kg), environmental ethanol (a bottle of 10% ethanol placed next to the animals cage during the experiments), or an equivalent volume of saline. Analgesia was assessed using a standard hot plate protocol and dose-response cumulative curves for morphine analgesia were obtained on days 1 and 11. On day 1, both the i.p. and environmental administration of ethanol showed similar morphine-potentiation effects [Mean Effective Dose: ED50 (M1)=4.5 mg/kg; ED50 (E1)=2.4 mg/kg; ED50 (E*1)=2.1 mg/kg]. On day 11, control group mice showed a reduction of morphine analgesia at test [ED50 (M11)=14.1 mg/kg]. Mice receiving i.p. and environmental ethanol again showed a leftward shift in dose-response cumulative curves for morphine antinociception with respect to controls [ED50 (E11)=9.1 mg/kg; ED50 (E*11)=4.7 mg/kg]. I.p. ethanol administration at non-antinociceptive doses enhances the morphine antinociception effect similarly in tolerant and non-tolerant (naive) mice. The presence of environmental ethanol can also induce a similar pattern of increase in morphine antinociception effect.     

Stereospecific reversal of nitrous oxide analgesia by naloxone

The opiate antagonist naloxone was found to block nitrous oxide analgesia in a stereospecific fashion. Using a modified hotplate test in mice, the (-)-enantiomer of naloxone (which has a KD of approximately 1 nM for opiate receptors) antagonized the analgesic actions of nitrous oxide in a dose-dependent (2.5-20 mg/kg) fashion. In contrast, the (+)-enantiomer (KD approximately 10,000 nM) had no effect on nitrous oxide analgesia at the highest dose tested (40 mg/kg). These data strongly suggest that nitrous oxide analgesia is mediated via opiate receptors and is consistent with the hypotheses that this effect occurs either through the release of endogenous opioids or by physical perturbation of the opiate receptors.     

Chronic administration of clomipramine inhibits morphine hot plate analgesia

Clomipramine, chronically administered in mice, for 3 days, inhibits partially but significantly morphine analgesia in the hot plate test, when used at dose of 10 mg/kg/day, i.p.; 2.5 and 5 mg/kg/day were ineffective. Neither higher doses (20 and 40 mg/kg/day) nor longer duration of pretreatment (8 and 16 days) modified the intensity of this inhibition. Reduction in morphine analgesia was obtained after a 24h delay between the last injection of clomipramine and that of morphine (30 min before testing), while clomipramine did not induce any antinociceptive effect and clomipramine and desmethylclomipramine plasma and brain levels were low or undetectable. These results provide new evidence for the interaction between clomipramine and the endogenous opiate system. A pharmacokinetic interaction between clomipramine and morphine was excluded; involvement of change in opiate and 5 HT2 receptors by chronic administration of clomipramine is discussed.     

Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions

To test whether nitric oxide (NO) participates in cyclosporine A (CsA)-induced neurotoxicity including convulsions, we examined the effect of an NO synthase inhibitor on convulsions induced by combined treatment with CsA and bicuculline in mice and the effect of CsA on NO production in the dorsal hippocampus using an in vivo microdialysis method in rats. CsA (200 mg/kg, i.p.) significantly increased the intensity of convulsions induced by an intracerebroventricular injection of bicuculline (25 pmol) in mice. This facilitation was blocked by N omega -nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, but not by N omega -nitro-D-arginine methyl ester (D-NAME), an inactive form of L-NAME (10 mg/kg, i.p.). CsA (20-50 mg/kg, i.p.) dose-dependently increased NO 2 - levels in dialysates obtained with microdialysis in the rat dorsal hippocampus. This enhanced NO 2 - formation was blocked by L-NAME but not by D-NAME (50 mg/kg, i.p.). These findings suggest that CsA stimulates NO production and induces convulsions as a result of an interaction between NO and the gamma-aminobutyric acid (GABA) system in the hippocampus.     

Anti-diabetic effect of ginsenoside Re in ob/ob mice

We evaluated the anti-diabetic effects of ginsenoside Re in adult male C57BL/6J ob/ob mice. Diabetic ob/ob mice with fasting blood glucose levels of approximately 230 mg/dl received daily intraperitoneal injections of 7, 20 and 60 mg/kg ginsenoside Re for 12 consecutive days. Dose-related effects of ginsenoside Re on fasting blood glucose levels were observed. After the 20 mg/kg treatment, fasting blood glucose levels were reduced to 188+/-9.2 and 180+/-10.8 mg/dl on Day 5 and Day 12, respectively (both P<0.01 compared to vehicle group, 229+/-9.5 and 235+/-13.4 mg/dl, respectively). The EC(70) of ginsenoside Re was calculated to be 10.3 mg/kg and was used for subsequent studies. Consistent with the reduction in blood glucose, there were significant decreases in both fed and fasting serum insulin levels in mice treated with ginsenoside Re. With 12 days of ginsenoside treatment, glucose tolerance of ob/ob mice increased significantly, and the area under the curve for glucose decreased by 17.8% (P<0.05 compared to vehicle treatment). The hypoglycemic effect of the ginsenoside persisted even at 3 days of treatment cessation (blood glucose levels: 198+/-13.1 with ginsenoside treatment vs. 253+/-20.3 mg/dl with vehicle, P<0.01). There were no significant changes in body weight or body temperature. Preliminary microarray analysis revealed differential expression of skeletal muscle genes associated with lipid metabolism and muscle function. The results suggest that ginsenoside Re may prove to be useful in treating type 2 diabetes.     

Effect of methamphetamine on the development of acute morphine tolerance and dependence in mice

The effect of methamphetamine on morphine analgesia (tail-flick assay) was studied in non-tolerant mice and in mice made acutely tolerant to morphine following a single injection of 100 mg/kg morphine. The analgesic potency of morphine was increased in non-tolerant and tolerant mice to the same extent by 3.2 mg/kg methamphetamine (3.3 and 4.4 fold increases, respectively). In contrast, the ED50's for morphine analgesia and naloxone-precipitated jumping in mice pretreated with either 100 mg/kg morphine or both morphine and 3.2 mg/kg methamphetamine were not significantly different, indicating that methamphetamine had no effect on the development of acute morphine tolerance and dependence. Although methamphetamine had no effect on the development of acute tolerance to morphine, 4-day pretreatment with methamphetamine produced cross-tolerance to morphine analgesia. However, cross-tolerance to morphine was not accompanied by enchanced sensitivity to naloxone.     

Tolerance to morphine-induced analgesia in mice: Magnetic fields function as environmental specific cues and reduce tolerance development

Mice receiving daily injection of morphine (10 mg/kg) developed tolerance to morphine-induced analgesia, such that after 5–7 days of treatment their thermal response (paw licking) latencies in the hot plate test were indistinguishable from those of control animals. Exposure to a rotating magnetic field for thirty minutes before the daily morphine administrations significantly reduced the development of tolerance. These magnetic exposure also significantly increased over 7–10 days the basal nociceptive thresholds and paw licking response latencies of saline treated mice. Control and sham exposed mice that were fully tolerant to the analgesic effects of morphine failed to show any tolerance to morphine-induced analgesia when exposed to the magnetic stimuli prior to injection. Likewise, the partial tolerance to morphine shown by mice exposed to the rotating magnetic field pre-injection environmental cues was eliminated when control or sham pre-injection cues lacking the magnetic stimuli were provided. In all cases tolerance to morphine-induced analgesia was evident in the subsequent re-test with the original cues. These results indicate that magnetic field exposure can reduce the development of tolerance to the analgesic effects of morphine. They also show that magnetic stimuli function as significant environmental cues for the development of tolerance to morphine-induced analgesia. This suggests that magnetic stimuli affect both the associative (classical conditioning) and non-associative (physiological, pharmacological) mechanisms involved in the development of opiate tolerance.     

Pharmacological actions of Y-24180: I. A potent and specific antagonist of platelet-activating factor

The ability of Y-24180, 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine to inhibit platelet-activating factor (PAF)-induced reactions was investigated. Y-24180 (0.0003–0.003 mg/kg, i.v.) dose-dependently inhibited PAF-induced bronchoconstriction in guinea pigs, but even at a high dose of 10 mg/kg, i.v., it was either inactive or weakly active against the bronchoconstriction induced by histamine, serotonin, acetylcholine, arachidonic acid, bradykinin, or leukotriene D₄. Oral doses (0.003–0.1 mg/kg) of Y-24180 also prevented hemoconcentration due to PAF in a dosedependent manner and produced a parallel shift of the PAF dose-response curve. Y-24180 (0.0003–0.1 mg/kg, i.v.) and WEB 2086 (0.03–1 mg/kg, i.v.) dose-dependently reversed PAF-induced hypotension in anesthetized rats. In mice, PAF-induced lethality was inhibited by Y-24180 and WEB 2086 with ED₅₀ values of 0.022 and 1.42 mg/kg, p.o., and 0.023 and 0.12 mg/kg, i.v., respectively. This protective effect of Y-24180 given p.o. persisted for at least 6 hr. In actively sensitized mice lethal anaphylactic shock was prevented by oral doses of Y-24180 and WEB 2086 with ED₅₀ values of 0.095 and 0.69 mg/kg, respectively. These results suggested that Y-24180 is an extremely potent and specific PAF antagonist with a good duration of action.     

Non-opioid analgesia of the neuropeptide, neo-kyotorphin and possible mediation by inhibition of GABA release in the mouse brain

The novel neuropeptide, neo-kyotorphin, produced a naloxone-resistant analgesia in the tail pinch test when given (IC) to mice. Pretreatments with implantation of a morphine pellet or with phentolamine (10 micrograms IT) or with reserpine (10 mg/kg SC) did not attenuate this analgesia, yet the analgesia was antagonized by GABA mimetics, such as muscimol (0.1 microgram IC), nipecotic acid (100 mg/kg IP). Neo-kyotorphin inhibited the Ca2+-dependent and depolarization-evoked release of 3H-GABA, from crude synaptosomes of the lower brain stem of rats. These findings suggest that inhibition of GABA in the brain may in part be involved in neo-kyotorphin-induced analgesia.     

Effects of escins Ia, Ib, IIa, and IIb from horse chestnuts on gastrointestinal transit and ileus in mice.

The effects of saponin fraction and its principal constituents escins Ia (1), Ib (2), IIa (3), and IIb (4) from horse chestnuts on gastrointestinal transit (GIT) and ileus were investigated in mice. Ileus was induced by acetic acid peritoneal irritation or by laparotomy with manipulation. One hour after the oral administration, the saponin fraction (12.5-100 mg/kg) and 14 (12.5-50 mg/ kg, except for 3 at 12.5 mg/kg) dose-dependently accelerated GIT. The optimal effects of the saponin fraction (25 mg/kg) occurred 5-240 min (applied intervals between the fraction and the charcoal meal) after the oral administration. The fraction (12.5-100 mg/ kg) and 1-4 (12.5-50 mg/kg, except for 1 and 2 at 12.5 mg/kg) dose-dependently prevented the inhibition of GIT induced by the acetic acid peritoneal irritation. They (12.5-100mg/kg) also dose-dependently prevented the inhibition of GIT induced by the laparotomy with manipulation. Desacylescins I (5) and II (6) (50 mg/kg) showed no such effects. These results demonstrated that the saponin fraction and 1-4 accelerated GIT and prevented the experimental ileus, and indicate that the 21, 22-acyl groups are essential for the accelerative effects of 1-4. The accelerations of GIT by 1-4 were completely abolished by the pretreatment with streptozotocin (100 mg/kg, iv), but not by the pretreatment with capsaicin (75 mg/kg in total, sc) or atropine (10 mg/kg, sc). These results imply that the sympathetic nervous system may be, but neither capsaicin-sensitive sensory nerves nor the cholinergic mechanism, involved in the accelerations of GIT by escins 1-4.     

Dynorphin (1-13): analgesia, hypothermia, cross-tolerance with morphine and beta-endorphin

Intracerebroventricular administration of 20, 40 and 60 nmol of dynorphin (1-13) produced analgesia, as assessed by flinch/jump response to footshock, and hypothermia in the rat. Rats developed tolerance to both the analgesic and thermic effects of the 20 nmol dose of dynorphin. Dynorphin and beta-endorphin showed cross-tolerance with respect to their analgesic but not their thermic effects. Dynorphin and morphine also produced cross-tolerant analgesic effects. Naloxone (10 mg/kg, IP) completely blocked the barrel rolling produced by 20 nmol dynorphin but did not alter its analgesic or thermic effects.     

Structure-related inhibitory activity of oleanolic acid glycosides on gastric emptying in mice

We examined the effects of various oleanolic acid oligoglycosides obtained from traditional herbs on gastric emptying in non-nutrient meal- or nutrient meal-loaded mice. Test samples were given orally to fasted mice 0.5 h before loading of test meals. Oleanolic acid 3-O-monodesmosides [oleanolic acid 3-O-glucuronide (3, 12.5-50 mg/kg), momordin Ic (4, 25 and 50 mg/kg), momordin I (6, 12.5-50 mg/kg), and 28-O-deglucosyl-chikusetsusaponins IV (8, 12.5-50 mg/kg) and V (10, 50 mg/kg)] were found to show inhibitory effects on gastric emptying in 1.5% CMC-Na test meal-loaded mice. 4, 6, and 8 also inhibited gastric emptying in mice given 40% glucose test meal, milk test meal, and 60% ethanol test meal. 3 inhibited gastric emptying in mice given milk test meal or 60% ethanol test meal, but lacked significant inhibition in 40% glucose test meal-loaded mice. 10 (50 mg/kg) also slightly inhibited gastric emptying in milk test meal-loaded mice, but lacked the significant inhibition in mice given 40% glucose or 60% ethanol test meal. Whereas oleanolic acid 3,28-0-bisdesmosides [momordin IIc (5), chikusetsusaponins IV (7) and V (9)], oleanolic acid 28-O-monodesmoside [compound O (2)], and their common aglycon [oleanolic acid (1)] showed no such effects at dose of 50 mg/kg. 28-O-Deglucosyl-chikusetsusaponin V (10) showed a little inhibition in these experiments. These results indicate that both the 3-O-monodesmoside structure and 28-carboxyl group were confirmed to be essential for such activity, and the 28-ester glucoside moiety and 2'-O-beta-D-glucopyranoside moiety reduce the activity.     

IL-18-binding protein protects against lipopolysaccharide- induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice.

IL-18-binding protein (IL-18BP) is a natural IL-18 inhibitor. Human IL-18BP isoform a was produced as fusion construct with human IgG1 Fc and assessed for binding and neutralizing IL-18. IL-18BP-Fc binds human, mouse, and rat IL-18 with high affinity (K(D) 0.3-5 nM) in a BIAcore-based assay. In vitro, IL-18BP-Fc blocks IL-18 (100 ng/ml)-induced IFN-gamma production by KG1 cells (EC(50) = 0.3 microg/ml). In mice challenged with an LD(90) of LPS (15 mg/kg), IL-18BP-Fc (5 mg/kg) administered 10 min before LPS blocks IFN-gamma production and protects against lethality. IL-18BP-Fc administered 10 min before LPS blocks IFN-gamma production induced by LPS (5 mg/kg) with ED(50) of 0.005 mg/kg. Furthermore, IL-18BP-Fc (5 mg/kg) abrogates LPS (5 mg/kg)-induced IFN-gamma production even when administered 6 days before LPS but shows no effect when administered 9 or 12 days before LPS. Given 10 min before LPS challenge to mice primed 12 days in advance with heat-killed Propionibacterium acnes, IL-18BP-Fc prevents LPS-induced liver damage and IFN-gamma and Fas ligand expression. Given at the moment of priming with P. acnes, IL-18BP-Fc decreases P. acnes-induced granuloma formation, macrophage-inflammatory protein-1alpha and macrophage-inflammatory protein-2 production and prevents sensitization to LPS. IL-18BP-Fc also prevents Con A-induced liver damage and IFN-gamma and Fas ligand expression as well as liver damage induced by Pseudomonas aeruginosa exotoxin A or by anti-Fas agonistic Ab. In conclusion, IL-18BP can be engineered and produced in recombinant form to generate an IL-18 inhibitor, IL-18BP-Fc, endowed with remarkable in vitro and in vivo properties of binding and neutralizing IL-18.     

Nω-硝基-L-精氨酸甲酯抑制吗啡镇痛耐受大鼠中脑和脊髓一氧化氮合酶/N-甲基-D-天冬氨酸受体表达上调

采用热甩尾测痛法观察全身应用非特异性一氧化氮合酶（nitric oxide synthase,NOS）抑制剂——N^ω-硝基-L-精氨酸甲酯（L-NAME）对吗啡镇痛耐受形成的影响,并通过观察脊髓和中脑神经元型NOS（nNOS）和N-甲基-D-天冬氨酸（NMDA）受体亚单位表达的变化来阐释NO／NMDA受体在吗啡镇痛耐受形成中的作用。将36只健康成年Sprague-Dawley大鼠平均分为6组（每组6只）：1组为对照组,皮下注射生理盐水1ml;2、3、4、5和6组为处理组,分别皮下注射L-NAME10mg／kg、L-NAME20mg／kg、吗啡10mg／kg、L-NAME10mg／kg＋吗啡10mg／kg、L-NAME20mg／kg＋吗啡10mg／kg,每天2次。在注射前测量大鼠的热甩尾潜伏期（tail-flick latency,TFL）基础值,随后每天第一次给药50min后测量其TFL。第8天最后一次给药80min后（除2组和5组之外）断头取脊髓和中脑,采用RT-PCR技术测量nNOS以及NMDA受体1A（NR1A）和2A（NR2A）亚单位的表达。结果显示,2组大鼠第1天至第7天的TFL与基础值相比无显著差异;3组第7天时的TFL仍显著高于基础值;4组的TFL在第1天时最高,第2至第6天期间逐渐降低,第6天时与基础值相比无显著差异：5组的TFL在实验过程中呈下降趋势,虽然第7天时较第1天有所降低,但是仍然显著高于基础值;6组的TFL变化趋势与5组相同。PT—PCR分析结果显示,与1组相比,3组脊髓和中脑的nNOS mRNA表达显著降低,但NR1A mRNA和NR2A mRNA表达无显著改变;4组的nNOS mRNA、NR1A mRNA和NR2A mRNA表达均显著高于1组。与4组相比,6组的nNOS mRNA、NR1A mRNA和NR2A mRNA表达均显著降低。结果提示,吗啡镇痛耐受大鼠脊髓和中脑的nNOS和NMDA受体表达增加,联合应用L—NAME可抑制长期应用吗啡所致的nNOS表达增加和NMDA受体上调,延缓吗啡镇痛耐受的形成。本研究结果提示,脊髓和中脑的NO／NMDA受体与吗啡镇痛耐受形成密切相关。     

Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice

We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using "four core genotypes" C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3-4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In Experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In Experiment 2 (test of development of tolerance to morphine), mice were injected twice daily with 10 mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP (3-(2-carboxypiperazin-4yl) propyl-1-phosphonic acid) (10 mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10 mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In Experiment 3, mice were injected with morphine (10 mg/kg) or saline, 15 min before intraplantar injection of formalin (5%/25 microl). XX mice licked their hindpaw more than XY mice within 5 min of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.     

Effects of ethanol on plasma corticosterone and rectal temperature modification by U50488H and WIN 44441-3

Endogenous opiates are believed to subserve various behaviors and physiological functions. We have examined the effect of U50488H (0-12 mg/kg), a kappa agonist, and WIN 44441-3 (0-4.0 mg/kg), a kappa antagonist, on ethanol (ET)-induced changes in rectal temperature and in plasma corticosterone (CS) levels in rats. The 12 mg/kg dose of U50488H produced marked hypothermia, the other doses either produced hyperthermia comparable to that seen in control animals, or had no effect. The 0.5 mg/kg of WIN44441-3 had a small hypothermic effect while the 4.0 mg/kg produced hyperthermia. U50488H potentiated and the low dose of WIN 44441-3 reversed the hypothermic effect of ethanol. By contrast, neither WIN 44441-3 nor U50488H pretreatments affected the ethanol-induced elevation in plasma CS. These results indicate that kappa agonists increase plasma CS concentration and affect thermoregulatory mechanisms. Furthermore, our data indicate a possible role of endogenous kappa opioids in the hypothermic effect of ethanol, but not in the elevation of plasma CS.