Morphine-induced analgesia in rats withdrawn from concurrent nimodipine and morphine treatment

The effect of repeated administration of dihydropyridine calcium channel antagonist, nimodipine, given concurrently with morphine on the development of tolerance to the antinociceptive actions of morphine in rats was studied. In acute experiments nimodipine (1 mg/kg i.p.) enhanced the antinociceptive effect of morphine (2.5 mg/kg s.c.) in the hot-plate and tail immersion tests. Daily administration of morphine either for 10 days (increasing the daily dose from 20 to 35 mg/kg) or for 24 days (increasing the daily dose from 20 to 70 mg/kg) induced tolerance to the antinociceptive effect of a challenge dose of morphine (10 mg/kg) administered 24 h after the withdrawal from chronic morphine. Concurrent administration of nimodipine (1 mg/kg per day) with morphine for 10 or 24 days augmented the reduction of the antinociceptive effect of morphine. Neither acute nor repeated administration of nimodipine with morphine altered the concentrations of morphine or its metabolite morphine 6-glucuronide in the brain tissue or in the plasma. The observed further reduction in the nociceptive response in morphine tolerant animals pre-treated with nimodipine is, most probably, due to the adaptive changes in the central dihydropyridine calcium channels induced by the withdrawal from repeated nimodipine treatment.     

Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test

The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), which differ in their interactions with high- and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.     

氯胺酮对子鼠学习记忆能力的影响及其机制研究

目的 探究氯胺酮对子鼠学习记忆能力的影响及其机制。方法 选取60只子鼠,使用跳台实验将子鼠分为智力及记忆能力相近的4组,每组各15只,分别为:空白组、低剂量氯胺酮组(25 mg/kg)、中剂量氯胺酮组(50 mg/kg)和高剂量氯胺酮组(100 mg/kg),氯胺酮各组腹腔注射对应剂量的氯胺酮,空白组腹腔注射等量生理盐水,每日1次,连续7 d。使用跳台法和Morris水迷宫法测定子鼠的学习记忆能力;采用HE染色观察子鼠海马体内神经细胞的变化;采用比色法测定子鼠脑组织中乙酰胆碱(Ach)、5-HT含量和乙酰胆碱酯酶(TCh E)活力;使用Western blot检测子鼠海马体内环磷腺苷效应元件结合蛋白(CREB)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)及脑源性神经营养因子(BDNF)的表达情况。结果 相比空白组,使用氯胺酮组处理各组子鼠逃避潜伏时间、出现逃避错误次数、每个象限内停留时间、TCh E活力均显著升高(P <0. 05),120 s内穿台次数、Ach水平、CREB、p-CREB及BDNF表达水平、pCREB/CREB值显著降低(P <0. 05);相比低剂量氯胺酮组,中剂量氯胺酮组和高剂量氯胺酮组子鼠逃避潜伏时间、出现逃避错误次数、每个象限内停留时间、TCh E活力均显著升高(P <0. 05),120 s内穿台次数、Ach水平、CREB、pCREB及BDNF表达水平、p-CREB/CREB值显著降低(P <0. 05);HE染色结果显示,使用氯胺酮处理后子鼠海马区细胞间隙明显增宽,结构组织松散,细胞水肿,以条索状为主,并存在大量的细胞坏死。结论 氯胺酮会损害子鼠的学习记忆能力,其作用机制可能与调控神经递质、减少BDNF表达并抑制CREB信号传导通路相关,并呈剂量依赖性。     

Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats

The pharmacologic specificity of the sensitization to naltrexone induced by acute opioid pretreatment was studied in rats trained to lever-press on a multiple-trial, fixed-interval 3-min schedule of food reinforcement. Cumulative doses of naltrexone were given until responding was suppressed; control naltrexone ED50 values for decreasing response rates ranged from 5.0 to 22 mg/kg. Agonists were administered 4 hr before naltrexone challenge. Pretreatment with morphine (10 mg/kg) initially produced a 4-fold shift to the left of the naltrexone dose-effect curve, but after repeated weekly testing with various agonists, produced a 1700-fold shift. Pretreatment with other millimicrons agonists (i.e., 0.3 mg/kg of levorphanol, 0.06 mg/kg of fentanyl and 3.0 mg/kg of methadone) produced similarly large (100- to 250-fold) increases in sensitivity to the rate-decreasing effects of naltrexone. On the other hand, pretreatment with agonists selective for kappa (1.0 mg/kg of ethylketocyclazocine and 3.0 mg/kg of U-50,488) or sigma (10 mg/kg of [+]-N-allylnormetazocine) receptors, produced smaller (10-fold) changes in sensitization to naltrexone. Neither dextrorphan (3.0 mg/kg) nor pentobarbital (18 mg/kg) pretreatment altered sensitivity to naltrexone. Thus, the sensitization to naltrexone induced by acute opioid pretreatment was a stereoselective, opioid-specific effect, and appeared to be mediated primarily by a mu-opioid mechanism. With repeated testing, the effect of acute morphine pretreatment was comparable to that reported after chronic administration, thus supporting the hypothesis that this phenomenon reflects receptor-mediated changes that underlie the state of opioid physical dependence.     

Immune status and survival of opiate- and cocaine-treated mice infected with Friend virus

In as much as the immunomodulatory effects of opiates and cocaine are known to modify spontaneous host defenses against infection, we investigated the effects of morphine, pentazocine and cocaine on the time course of Friend virus infection in mice. Repeated i.p. injections with increasing doses of morphine hydrochloride (10-100 mg/kg for 10 days before infection, a dose regimen which induced tolerance to the acute antinociceptive effects of the drug, followed by 30 mg/kg for 14 days postinfection) did not increase the mortality due to Friend virus infection. This regimen did not significantly affect the immune response of infected mice assessed in terms of delayed hypersensitivity (ear thickness) and the hemagglutination assay. In contrast, a single challenge with a large dose of morphine (up to 300 mg/kg), which is not lethal in noninfected mice, increased mortality markedly (up to 100%) in infected mice when administered at day 14 or 21 postinfection. Repeated i.p. injections with pentazocine (50 mg/kg b.i.d. for 5 days before infection, followed by 30 mg/kg for 14 days postinfection) had no influence on mortality or immune responses in infected mice; similar results were obtained with a single high-dose injection (up to 100 mg/kg). Lastly, repeated i.p. injections of cocaine, using the same experimental procedure as that for pentazocine, decreased immune responsiveness and slightly increased mortality, whereas a single injection was devoid of lethal effect. These findings suggest that chronic opioid treatment does not lower host resistance to viral infection but that the latter could increase the toxicity of a single high dose of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of treatment with 1-beta-D-arabinofuranosylthymine of experimental encephalitis induced by herpes simplex virus in mice.

1-beta-D-Arabinofuranosylthymine (ara-T) was examined for its therapeutic efficacy against encephalitis in mice inoculated intracerebrally with herpes simplex virus. Intraperitoneal treatment with 100 mg of ara-T per kg twice daily for 4.5 days was as effective as treatment with 50 mg of arabinosyladenine 5'-monophosphate per kg. Under the same conditions, doses of 5-iododeoxyuridine or arabinosylcytosine (50 mg/kg each) were not effective. Even when the virus inoculum was as high as 320 or 3,200 50% lethal doses, ara-T increased the life span significantly. Oral treatment with 27 mg of ara-T per kg produced a modest increase in the mean survival time, equal to that of 50 mg of ara-T per kg administered intraperitoneally or subcutaneously. A single dose of ara-T, 800 mg/kg intraperitoneally or 400 mg/kg orally, was effective. The 50% lethal dose of ara-T administered intraperitoneally and that administered orally were more than 10 and 15 g/kg, respectively. The therapeutic indexes (maximal tolerated dose divided by minimal effective dose) in multiple intraperitoneal treatments and in multiple oral treatments were estimated to be more than 25 and 100, respectively.     

Is Defibrillation Testing Safe?

Determination of defibrillation thresholds (DFTs) and implantable cardioverter defibrillalur (ICD) testing requires repeated inductions of ventricular fibrillation (VF) and defibrillation attempts using known energy outputs. Little is known about the individual and cumulative effects of repetitive brief episodes of VF and hypoperfusion on cerebral function. The potential clinical utility of quantitative electroencephalographic (QEEG) monitoring during intraoperative ICD testing, by using processed 19-channel EEG (0.5–35 Hz bandwidth), was examined in ten anesthetized patients, five males and five females (mean age 62 ± 10 years), who underwent ICD implantation and testing. Ischemic QEEG patterns were defined as those with a 3 standard deviation increase (P < 0.01) in absolute delta (1.5–3.5 Hz) power persisting for ≥ 2.5 minutes. The majority (80%) of the VF episodes (70) were accompanied by QEEG "slowing" (doubling of the pre-VF low frequency delta waves amplitude). All the patients (5/5) experiencing > 6 VF episodes showed a statistically significant increase in the low frequency amplitude. In contrast, this EEG abnormality was apparent in only one of five patients experiencing < 6 VF episodes. These results suggest a cumulative QEEG depression associated with ICD testing. QEEG may provide an objective means for establishing an individualized upper safe limit of DFT testing and the total number of induced VF episodes.     

The effects of the 5-hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin on spontaneous activity, cocaine-induced hyperactivity and behavioral sensitization: a microanalysis of locomotor activity

The influence of the 5-hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) on locomotor hyperactivity induced by the acute and chronic administration of cocaine was assessed. Horizontal activity was measured in the periphery and center of an open field test enclosure equipped with photobeams; vertical activity was also recorded. Peripheral hyperactivity induced by an acute administration of cocaine (10 or 20 mg/kg) was significantly enhanced by 0.2 mg/kg DPAT. In contrast, central and vertical activities were reduced in a dose-related manner by DPAT (0.1 and 0.2 mg/kg); DPAT also suppressed central (0.2 mg/kg) and vertical (0.1 and 0.2 mg/kg) activities when administered alone. Similar observations were made on day 1 of chronic treatment with DPAT (0, 0.1, or 0.2 mg/kg) injected 15 min before an injection of cocaine (0, 10, or 15 mg/kg) administered twice daily for 7 days. By day 7 of repeated DPAT treatment, sensitization of DPAT-evoked peripheral activity developed, which contrasted with tolerance to the central and vertical hypoactivity evoked by DPAT. Sensitization developed to the repeated treatment with 15 mg/kg cocaine but not 10 mg/kg cocaine. Interestingly, enhancements of all activity measures were observed between days 1 and 7 in rats cotreated with DPAT plus either dose of cocaine. This sensitization to DPAT plus cocaine was expressed on challenge with DPAT and cocaine but not with cocaine alone. The present study implies that the stimulation of 5-hydroxytryptamine(1A) receptors is capable of modulating the hyperactivity evoked by cocaine, possibly via modulation of the mesoaccumbens dopamine circuit thought to mediate the behavioral effects of cocaine.     

Treatment of acute Chlamydia pneumoniae infection with telithromycin in C57BL/6J mice

OBJECTIVES: The efficacy of telithromycin, a new ketolide antibiotic, was investigated in the treatment of acute Chlamydia pneumoniae infection in a mouse model. METHODS: C57BL/6J mice were inoculated intranasally, and the effects of three different doses of telithromycin (25, 50 and 100 mg/kg) were assessed after 5 and 10 days of treatment. Lungs for culture, PCR, histopathology, and blood for serum samples were collected immediately after each treatment period and at 3 weeks post-inoculation. C. pneumoniae-specific antibodies were analysed, and the effect of treatment was assessed by culture, detection of C. pneumoniae DNA and determination of histopathological inflammatory changes in mouse lungs. RESULTS: Culture negativity in the lungs was achieved with the higher doses, 50 and 100 mg/kg, after 10 days of treatment. C. pneumoniae DNA was not totally eradicated with the treatments, but the groups treated with 50 and 100 mg/kg doses for 10 days had the lowest DNA positivity rates (10%) 3 weeks after the inoculation. In lung histopathology, the efficacy of telithromycin on inflammatory changes was also dose-dependent: higher doses were more effective in reducing the inflammatory reaction. Overall, the 25 mg/kg dose had a weaker effect compared with the others. CONCLUSIONS: Telithromycin had both time- and dose-dependent effects on the eradication of chlamydia and on reducing infection-induced inflammatory changes in mouse lungs.     

Cross-sensitization to morphine in cocaine-sensitized rats: behavioral assessments correlate with enhanced responding of ventral pallidal neurons to morphine and glutamate, with diminished effects of GABA

Common neurobiological substrates contribute to the progressively increased behavioral effects (i.e., sensitization) that occur with repeated intermittent treatments of cocaine and morphine. Consequently, repeated exposure to cocaine can augment responding to morphine (termed cross-sensitization). Drug-induced sensitization in rats may model aspects of the dysfunction in motivation that are imposed by addiction. The ventral pallidum (VP) is involved in motivated behaviors and its function is altered by acute administration of cocaine and morphine, but the effects of repeated drug exposure remain unknown. Targeting this paucity, the present study evaluated electrophysiological changes in the VP of rats exposed to five once-daily cocaine treatments (15 mg/kg i.p.). This regimen also induced behavioral-sensitization that was expressed 3 days later when the rats received either an acute injection of cocaine (15 mg/kg i.p.) or morphine (10 mg/kg i.p.). VP neurons recorded in vivo 3 days after the repeated cocaine treatment regimen demonstrated increased excitatory responding to microiontophoretic applications of morphine and glutamate. The maximal effect (E(max)) was increased without altering potency, suggesting a change in the functional efficacy of the respective receptor systems. This did not represent a potentiation in transmission in general, for the effects of GABA were diminished. The results provide the first evidence for cellular adaptation in the VP after a sensitizing drug treatment paradigm and reveal that cross-sensitization of drug-induced behaviors temporally correlates with changes in VP neuronal responding. These findings advance an emerging theme that alterations in the VP may contribute to the increased motivation for drug seeking that occurs in drug-withdrawn addicts.     

Treatment of murine cytomegalovirus infections in severe combined immunodeficient mice with ganciclovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, interferon, and bropirimine.

Severe combined immunodeficient (SCID) mice were found to be highly susceptible to murine cytomegalovirus (MCMV) infection. Treatment of infected mice with ganciclovir (12.5, 25, and 50 mg/kg of body weight for 10 days) starting 24 h after virus challenge resulted in delays in death by 2 to 8 days, and no animals survived the infection. (S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) was much more potent, with doses of 1, 3.2, and 10 mg/kg/day (for 10 days) increasing the mean survival time by 15 to 30 days. Twenty-day treatments with HPMPC starting 5 days after virus inoculation increased the mean survival time by 24 to 32 days, with once-weekly (50-mg/kg) treatments being equivalent to daily (10-mg/kg) treatments. Delays in the development of liver, lung, and spleen virus titers in ganciclovir- and HPMPC-treated groups correlated with extensions in the mean survival times relative to the survival times of the placebo controls. The two compounds were approximately equally toxic to uninfected BALB/c mice treated for 10 days, causing 80 to 100% mortality after a dose of 150 mg/kg and 0% mortality after a dose of 75 mg/kg. Thus, the relative therapeutic index of HPMPC was 50-fold greater than that of ganciclovir. Recombinant alpha interferon delta 4 alpha 1/alpha 2 (1 x 10(4) and 5 x 10(4) units per mouse per day) and bropirimine (100 and 300 mg/kg/day) provided no protection from the lethal MCMV infection. The severe combined immunodeficient mouse MCMV infection is an important new model that will permit chemotherapy regimens to be studied over several months.     

Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine‐induced cognitive deficits in mice

This study was undertaken to examine the effects of CDPPB (3‐cyano‐N‐(1,3‐diphenyl‐1H‐pyrazol‐5‐yl)benzamide), a positive allosteric modulator (PAM) of metabotropic glutamate receptor 5 (mGlu₅), on cognitive deficits in mice after repeated administration of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)‐induced cognitive deficits in mice were not improved by a single administration of CDPPB (10 mg/kg/day). However, PCP (10 mg/kg/day for 10 days)‐induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of CDPPB (10 mg/kg/day), but not of CDPPB (1.0 mg/kg/day). This study suggests that PCP‐induced cognitive deficits in mice are improved by subsequent subchronic administration of CDPPB. Therefore, mGlu₅ PAMs would be potential therapeutic drugs for cognitive deficits in schizophrenia.     

Necessary role for ventral tegmental area adenylate cyclase and protein kinase A in induction of behavioral sensitization to intraventral tegmental area amphetamine

In the present study, we investigated the effects of selective activation or inhibition of ventral tegmental area (VTA) adenylate cyclase (AC) and protein kinase A (PKA) on long-term sensitization induced by repeated intra-VTA or peripheral amphetamine (AMPH). Selective inhibition of AC by SQ 22,536 (9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 100 nmol/side bilateral into VTA) had no effect on acute basal locomotion but attenuated the locomotor stimulation induced by acute i.p. AMPH (1.5 mg/kg). Coinjection of SQ 22,536 (100 nmol/side) fully blocked the sensitization induced by repeated intra-VTA AMPH (15 nmol/side) but had no detectable effect on the sensitization induced by repeated i. p. AMPH. Persistent activation of AC by intra-VTA cholera toxin (500 ng/side) modestly increased acute locomotion and induced a robust sensitization to i.p. AMPH challenge 10 days after the last of three repeated VTA microinjections. Selective inhibition of PKA by Rp-adenosine-3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS; 25 nmol/side) had no effect on acute basal or AMPH-stimulated locomotion. Coinjection of Rp-cAMPS (25 nmol/side) fully blocked the sensitization induced by repeated intra-VTA AMPH but had no effect on sensitization induced by repeated i.p. AMPH. Intra-VTA microinjection of the selective PKA activator Sp-adenosine-3',5'-cyclic monophosphothioate triethylamine (Sp-cAMPS; 25-100 nmol/side) dose-dependently stimulated acute locomotion and exerted synergistic effects on locomotor activity when coinfused into the VTA with AMPH but had no detectable effect on acute i.p. AMPH-induced locomotion. Repeated intra-VTA Sp-cAMPS did not induce sensitization to AMPH challenge but potentiated the sensitization induced by repeated i.p. AMPH. These results suggest that VTA cAMP signal transduction is necessary for the induction of persistent sensitization to intra-VTA amphetamine and that peripheral and intra-VTA AMPH may not induce behavioral sensitization by identical mechanisms.     

Activity of minocycline against Toxoplasma gondii infection in mice

The chemotherapeutic activity of minocycline, a semi-synthetic tetracycline analogue, was evaluated in a murine model of toxoplasmosis. A lethal acute toxoplasmosis was produced by injecting 10(5) tachyzoites of the RH strain of Toxoplasma gondii into the peritoneal cavities of Swiss-Webster mice. When infected mice were treated once daily for 12 days, starting 2 h after challenge, the survival and cure rates were 100% and 40% respectively after minocycline alone (100 mg/kg per day), 0% and 0% after pyrimethamine alone (8.5 mg/kg per day), and 100% and 50% after combination of the two drugs at the same dosages. Absolute survival and cure with minocycline were observed when mice were treated with two daily doses of 100 mg/kg for 12 days. Mice chronically infected with a low virulent strain of T. gondii (Me49) showed a significant reduction in the number of brain cysts after three weeks of treatment with 50 mg/kg per day of minocycline. Minocycline serum levels after a single oral administration of 50 mg/kg or 100 mg/kg to normal mice, peaked at 1.8 mg/l and 10 mg/l after 1 h, respectively, and showed an extended half-life.     

Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (> or =100 micro M), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.     

Median Nerve Stimulation as a Nonpharmacological Approach to Bypass Analgesic Tolerance to Morphine: A Proof-of-Concept Study in Mice

Analgesic tolerance to opioids contributes to the opioid crisis by increasing the quantity of opioids prescribed and consumed. Thus, there is a need to develop non-opioid-based pain-relieving regimens as well as strategies to circumvent opioid tolerance. Previously, we revealed a non-opioid analgesic mechanism induced by median nerve electrostimulation at the overlaying PC6 (Neiguan) acupoint (MNS-PC6). Here, we further examined the efficacy of MNS-PC6 in morphine-tolerant mice with neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Daily treatments of MNS-PC6 (2 Hz, 2 mA), but not electrostimulation at a nonmedian nerve-innervated location, for a week post-CCI induction significantly suppressed established mechanical allodynia in CCI-mice in an orexin-1 (OX₁) and cannabinoid-1 (CB₁) receptor-dependent fashion. This antiallodynic effect induced by repeated MNS-PC6 was comparable to that induced by repeated gabapentin (50 mg/kg, i.p.) or single morphine (10 mg/kg, i.p.) treatments, but without tolerance, unlike repeated morphine-induced analgesia. Furthermore, single and repeated MNS-PC6 treatments remained fully effective in morphine-tolerant CCI-mice, also in an OX₁ and CB₁ receptor-dependent fashion. In CCI-mice receiving escalating doses of morphine for 21 days (10, 20 and 50 mg/kg), single and repeated MNS-PC6 treatments remained fully effective. Therefore, repeated MNS-PC6 treatments induce analgesia without tolerance, and retain efficacy in opioid-tolerant mice via a mechanism that involves OX₁ and CB₁ receptors. This study suggests that MNS-PC6 is an alternative pain management strategy that maybe useful for combatting the opioid epidemic, and opioid-tolerant patients receiving palliative care.PerspectiveMedian nerve stimulation relieves neuropathic pain in mice without tolerance and retains efficacy even in mice with analgesic tolerance to escalating doses of morphine, via an opioid-independent, orexin-endocannabinoid-mediated mechanism. This study provides a proof of concept for utilizing peripheral nerve stimulating devices for pain management in opioid-tolerant patients.     

Antitrypanosomal Activity of Fexinidazole Metabolites,Potential New Drug Candidates for Chagas Disease

This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole-treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.     

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on renal excretion of sodium and water, and on body fluid volume in rats.

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on urine volume and urinary sodium excretion, and on plasma volume and extracellular fluid volume were examined in conscious rats. The basal urine volume and urinary sodium excretion were decreased and the increased urine volume and urinary sodium excretion elicited by saline load (25 ml/kg) and by hydrochlorothiazide (10 mg/kg) were inhibited after oral administration of NSAID in doses which inhibited the rat carrageenin-induced hind paw edema (indomethacin, 1--10 mg/kg; tolmetin, 3--30 mg/kg; phenylbutazone, 3--30 mg/kg; aspirin, 30--300 mg/kg), but aminopyrine (30--300 mg/kg) did not show such an effect. The inhibitory activity on renal function was diminished gradually with repeated administration of NSAID. NSAID (indomethacin, 3 mg/kg; tolmetin, 10 mg/kg; phenoxybenzamin, 10 mg/kg; aspirin, 100 mg/kg) increased plasma volume and extracellular fluid volume of rats after repeated medication for 3 or 5 days, but the body fluid volume expansion disappeared with further repeated administration of NSAID. These results suggest that NSAID may inhibit the intrarenal role of prostaglandins and decrease sodium and water excretion in urine with resulting increased body fluid volume. Tolerance to these actions of NSAID developed after repeated administration.     

Efficacy of cethromycin, a new ketolide, against Streptococcus pneumoniae susceptible or resistant to erythromycin in a murine pneumonia model

Cethromycin is a ketolide with in vitro activity against macrolide-sensitive and -resistant strains of Streptococcus pneumoniae. We compared its in vivo efficacy to erythromycin in a mouse model of acute pneumonia induced by two virulent clinical strains: a serotype 3 susceptible strain (P-4241) (MICs: erythromycin, 0.03 microg/ml; cethromycin, 0.015 microg/ml) and a serotype 1 strain resistant to erythromycin (P-6254; phenotypically MLSB constitutive) (MICs: erythromycin, 1,024 microg/ml; cethromycin, 0.03 microg/ml). Immunocompetent mice were infected with 10(5) CFU of each strain. Six treatments given either subcutaneously (s.c.) or per os (p.o.) at 12-h intervals were initiated at 6 or 12 h after infection. Against P-4241, cethromycin given s.c. at 25 or 12.5 mg/kg protected 100% of the animals, with lungs and blood completely cleared of bacteria. Given p.o., cethromycin maintained its efficacy with 100 and 86% survival at 25 and 12.5 mg/kg, respectively. Erythromycin, given s.c. at 50 or 37.5 mg/kg, provided 50 and 38% survival rates, respectively. Against P-6254, cethromycin was effective at 25 mg/kg (100% survival) regardless of the administration route, whereas only 25 and 8% of animals survived after a 75-mg/kg erythromycin treatment given s.c. and p.o., respectively. The serum protein binding levels of cethromycin were 94.8 and 88.5% after doses of 12.5 and 25 mg/kg, respectively. The higher in vivo activity of cethromycin compared to erythromycin could be explained by favorable pharmacokinetic/pharmacodynamic indexes against P-6254 but not against P-4241.