Inhibitory effects of MPEP,an mGluR5 antagonist,and memantine,an <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate receptor antagonist,on morphine antinociceptive tolerance in mice

Abstract Rationale. Inhibition of N-methyl-D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. Objective. In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. Methods. Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose–response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. Results. MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. Conclusions. The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance. Electronic Publication     

Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice

Rationale: Opioid withdrawal is known to facilitate aggressive behavior in laboratory rodents. Aggression develops as the somatic signs disappear and thus may reflect protracted withdrawal-related behavioral alterations. Antagonists acting at the NMDA receptor are known to attenuate the expression of morphine withdrawal syndrome in laboratory animals. Objective: The present study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine withdrawal in mice. Methods: Significant increases in aggressive behavior were observed 48 h after repeated morphine administration (8 days, b.i.d., 10–80 mg/kg, SC) was discontinued. Separate groups of mice were treated intraperitoneally with vehicles or different doses of memantine (1, 3, 10 or 30 mg/kg) or MRZ 2/579 (1, 3 or 10 mg/kg) 48 h after the last morphine injection. Results: Both compounds dose-dependently reduced the expression of aggressive behavior while having no significant effect upon the intensity of non-aggressive social contacts. Memantine significantly diminished the occurrence of all recorded components of aggressive behavior (attacks/bites, threats, tail rattling) while MRZ 2/579 affected mainly the appetitive events of aggressive bursts (threats, tail rattling). For both compounds, anti-aggressive effects occurred at dose levels that did not produce motor impairment in the Rotarod test. Conclusions: Taken together with the evidence on the lack of selective anti-aggressive effects of these drugs in morphine-naive mice, attenuation of the aggression observed in the present study may be due to specific interaction with morphine withdrawal-triggered processes. Received: 2 May 1999 / Final version: 17 November 1999     

Vigabatrin attenuates the development and expression of tolerance to morphine-induced antinociception in mice

The efficacy of opioids is limited in chronic pain treatment, as a result of development of opioid tolerance. Based on previous demonstration of the effect of anticonvulsant drugs on morphine antinociception, the present study investigated the effects of vigabatrin (VGB) on the development and expression of morphine tolerance in mice. 101 male NMRI mice weighing 20-25 g were used in these experiments. To evaluate the VGB effects on the development or expression of morphine tolerance, animals received VGB (5, 10 or 20 mg/kg; i.p.), 30 min before morphine (50 mg/kg; s.c.) during induction period once daily for 3 days; or 30 min before challenge dose of morphine (5 mg/kg) before and after morphine-induced tolerance, respectively. The analgesic effect of VGB was evaluated at 30-time intervals (30, 60, 90 and 120 min) by tail-flick analgesiometer. The results showed that VGB at the dose of 20 mg/kg significantly attenuated the development and expression of morphine tolerance. Additionally, VGB alone did not affect the tail-flick latency times. Therefore, while VGB alone has no antinociceptive effect, it can prevent the development of morphine tolerance in mice.     

GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice

The effects of the N-methyl- -aspartate (NMDA) receptor/glycine site antagonist, GV196771A (E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt), on mechanical allodynia and on tolerance to the antinociceptive effects induced by morphine were evaluated. Its antiallodynic properties were studied in a model of chronic constriction injury applied to rat sciatic nerve. GV196771A (0.3–10 mg/kg, p.o.) dose-dependently inhibited established mechanical allodynia when tested 14 or 21 days after nerve ligation. In the formalin test in mice, GV196771A (10 or 20 mg/kg, p.o.), administered for 8 days together with morphine 10 mg/kg, i.p. inhibited morphine tolerance development in both early and late phases of the test. This finding reinforces the key role of the NMDA receptors in the plastic event, such as allodynia, which develops in some conditions of painful neuropathy. Moreover, the capability to strongly reduce morphine-induced tolerance suggests that GV196771A could be an alternative agent for the treatment of difficult pain states not only when given alone, but also in combination, in order to prolong the analgesic effects of the opiates.     

Role of morphine maintenance dose in the development of tolerance and its attenuation by an NMDA receptor antagonist

Rationale: Current research shows that N-methyl-d-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance in rodent antinociceptive assays. Objective: The purpose of this study was to determine the role of morphine maintenance dose in the attenuation of morphine tolerance by the competitive NMDA receptor antagonist, LY235959. Methods: A rat warm-water tail-withdrawal procedure was used to measure the antinociceptive effects of morphine and LY235959. In this procedure, the distal 8 cm of each rat’s tail is immersed in 40° (non-noxious) and 55°C (noxious) water, and the latency to remove the tail is recorded. Results: Morphine (0.3–10 mg/kg, SC) produced dose-dependent increases in tail-withdrawal latencies from the 55°C water. Following determination of the morphine dose-effect curves, rats were administered chronically one of three doses of morphine (10, 20, or 40 mg/kg) either alone or in combination with LY235959 (1.0, 3.0, or 5.6 mg/kg, SC) twice daily for 7 days. Chronic administration of 10, 20, and 40 mg/kg morphine produced rightward shifts in the morphine dose-effect curves of approximately 3-, 6-, and 12-fold, respectively. When LY235959 (1.0–5.6 mg/kg) was co-administered with 10 mg/kg morphine, the development of morphine tolerance was attenuated in a dose-dependent manner, with complete prevention observed following 3.0 mg/kg LY235959. LY235959 (1.0, 3.0 mg/kg) also attenuated the development of tolerance to 20 and 40 mg/kg morphine; however, tolerance was not completely prevented. Administering 3.0 mg/kg LY235959 along with 20 and 40 mg/kg morphine was functionally equivalent to treating rats with half the amount of morphine. Conclusion: These data suggest that the maintenance dose of morphine, and thus the magnitude of tolerance, can determine the effectiveness of an NMDA receptor antagonist to attenuate morphine tolerance. Received: 5 April 1999 / Final version: 23 July 1999     

Effects of low-affinity NMDA receptor channel blockers in two rat models of chronic pain

In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.     

Dissociation in the modulatory effects of environmental novelty on the locomotor,analgesic, and eating response to acute and repeated morphine in the rat

Rationale. We have previously shown that environmental novelty can potentiate the activating effects of morphine and the development of sensitization to this effect. Objectives. Our main goal was to determine whether environmental novelty can also modulate the prophagic (time spent eating and food intake; experiment 1) and/or the analgesic (tail-flick test; experiments 2 and 3) effect of morphine, as well as the development of tolerance or sensitization to these effects. Methods. In experiment 1, two groups of rats were administered seven intraperitoneal (i.p.) injections of either saline or morphine (4.0 mg/kg) either in their home cages (home groups) or in a distinct environment (novelty groups). After 7 days of withdrawal, both groups underwent a morphine challenge (4.0 mg/kg, i.p.). In experiment 2, home and novelty rats were administered four doses of morphine (0.0, 2.0, 4.0, and 8.0 mg/kg, i.p.) following a counterbalanced order. In experiment 3, home and novelty rats were administered eight intraperitoneal (i.p.) injections of either saline or morphine (8.0 mg/kg) and then given a morphine challenge (4.0 mg/kg). Results. Environmental novelty enhanced the locomotor activating effect of morphine and the expression of sensitization to this effect (even after a period of withdrawal). Environmental novelty had relatively little effect on morphine-induced eating, and no effect on morphine-induced analgesia. Conclusions. Environmental context can have very different consequences on distinct drug effects as well as on distinct neurobehavioral adaptations to the same drug treatment (e.g., psychomotor sensitization versus analgesic tolerance). Electronic Publication     

Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats

The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10 mg/kg) at set intervals of 12 h for 10 days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2 h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30 min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.     

Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane

Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.     

Effects of antagonists at the NMDA receptor complex in two models of anxiety

The effects of an antagonist at the strychnine insensitive glycine site (5,7-dichlorokynurenic acid, i.c.v.), and of noncompetitive (MK-801, i.p.) and competitive (CGP 37849, i.p.; CGP 39551, i.p.; AP-7, i.c.v.) NMDA antagonists were compared with diazepam (i.p.) in two animal models of anxiety (the open field exploratory behavior of non-habituated rats, and the Vogel conflict test). All drugs when applied in appropriate doses increased punished drinking in the Vogel test, without producing any significant changes in free drinking and the stimulus threshold at their lowest anticonflict doses. The effective doses were as follows: diazepam 1.5 and 2.5 mg/kg; MK-801 0.005 and 0.01 mg/kg; CGP 39551 5.0 and 20.0 mg/kg; CGP 37849 1.0 and 2.5 mg/kg; 5,7-dichlorokynurenic acid 5.0 μg (i.c.v); AP-7 0.5 μg (i.c.v.). In the open field diazepam (0.05 mg/kg), MK-801 (0.1 mg/kg), CGP 37849 (0.01, 0.1, 1.0 mg/kg), and AP-7 2.5 μg (i.c.v.) significantly increased exploratory activity in the central sectors of the open field (anti-neophobic reaction), without changing motor activity of the rat. MK-801 at the highest tested dose of 0.2 mg/kg significantly stimulated animal locomotor activity. CGP 37849 in the largest dose examined (10 mg/kg) significantly depressed the motor behavior of rats. Overall, it appeared that different NMDA antagonists showed an anxiolytic-like profile, similar to that of the benzodiazepine diazepam. Among different NMDA receptor complex antagonists studied, CGP 37849 was characterized by the largest distinction between the doses showing an anxiolytic-like action in the open field test, and changing rat motor behavior.     

Effects of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of ethanol tolerance in C57BI mice

The effect of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of environment-dependent ethanol tolerance was studied in C57B1 mice. Ethanol tolerance was produced by daily injections of ethanol (3.5 g/kg, IP) in the same experimental environment and measured as ethanol-produced sleep-time during 5 consecutive days. The non-competitive NMDA receptor antagonist, dizocilpine (MK-801; 0.1 mg/kg, IP), and the competitive NMDA receptor antagonist, CGP 39551 (5 mg/kg, IP), both given 120 min after the administration of ethanol, inhibited the development of tolerance to the hypnotic actions of ethanol. In contrast, the development of ethanol tolerance was not altered by administration of the specific AMPA/KA receptor blocking agents, NBQX (10 mg/kg, IP), and LY326325 (2.5 mg/kg, IP), respectively. Modulation of NMDA receptor activity by drugs like NMDA,d-cycloserine, and milacemide, which are known to enhance learning and memory in rodents, had no significant effect on the development of ethanol tolerance. Our present data confirm and extend previous findings which indicate that NMDA, but not non-NMDA, glutamate receptors may play an important role in the neuroadaptive processes associated with the development of ethanol tolerance.     

Effects of NMDA receptor antagonists and sigma ligands on the acquisition of conditioned fear in mice

Recent studies have shown that several compounds known to act as competitive or non-competitive antagonists of NMDA receptors can disrupt learning in rodents. The present study was carried out to investigate the effects of a range of NMDA antagonists, acting at several sites in the NMDA receptor complex, on the acquisition of learned fear in mice. Dose-related disruptions of learning were produced by the non-competitive antagonists phencyclidine, dizocilpine, dextromethorphan and (+) and (–)N-allylnormetazocine. The (+) enantiomer of N-allylnormetazocine was approximately twice as potent as the (–) enantiomer. The competitive NMDA receptor antagonist, CGS 19755, also blocked the acquisition of learned fear as did the non-specific glutamate antagonist riluzole. In contrast, the antiischaemic drugs ifenprodil and SL 82.0715, which probably act as NMDA antagonists through an effect on the polyamine site, had no effect on learning up to doses which substantially reduced locomotion. The sigma receptor ligand DTG was also inactive. These results confirm that both competitive and non-competitive NMDA antagonists disrupt learning but indicate that the extent to which such an effect is observed may depend on the site at which the compounds act within the receptor complex. Activity at sigma receptors is unrelated to the effect on learning.     

Effects of calcium channel blockers on behaviors induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats.

The present study assessed the ability of voltage-sensitive calcium channel (VSCC) blockers to affect the behavioral effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine, in male Wistar rats. Dizocilpine produced dose-dependent increases in locomotor activity. Nimodipine, verapamil, and flunarizine suppressed dizocilpine-facilitated vertical activity, while horizontal activity was attenuated by verapamil and nimodipine but not flunarizine. Repeated dizocilpine injections resulted in the development of sensitization to its locomotor stimulating properties. Development of sensitization was not context specific, and was observed following repeated exposures to 0.1 but not 0.056 or 0.3 mg/kg of dizocilpine. Nimodipine retarded the development of sensitization to dizocilpine's stimulating effects on horizontal activity, while verapamil suppressed sensitization to the vertical stimulating effects of dizocilpine. Flunarizine had no significant effects on sensitization to dizocilpine's locomotor stimulating properties. In rats trained to discriminate between injections of 0.056 mg/kg of dizocilpine and vehicle, none of the tested VSCC blockers was able to completely antagonize the discriminative stimulus properties of dizocilpine. Nimodipine, when administered in combination with the training dose of dizocilpine, modestly decreased the dizocilpine-lever selection. Dizocilpine dose dependently decreased the self-determined stimulation threshold implanted in rats with electrodes into the ventral tegmental area. Nimodipine exhibited some tendency to block the facilitating effects of dizocilpine, while verapamil and flunarizine had no effects. In summary, in the present experiments VSCC blockers exerted only modest interactions with the behavioral effects of dizocilpine, and it is unlikely that VSCC blockers have remarkable potential as adjunct treatment aimed at correcting the negative side effects of NMDA receptor antagonists (e.g., dizocilpine).     

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the -opioid agonists morphine (0.1–10.0 mg/kg) and levorphanol (0.1–3.0 mg/kg), the -opioid agonist ethylketazocine (0.03–3.0 mg/kg), the mixed -/-opioid agonist metkephamid (0.1–10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0–100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.     

Effects of repeated injections of naltrexone on antagonism of rate decreases by morphine in the pigeon

Responding of three pigeons was maintained under a multiple schedule of food presentation in which key-pecks produced access to grain under a fixed-interval schedule in the presence of one stimulus and a fixed-ratio schedule in the presence of another stimulus. Repeated daily injections of 1 mg/kg naltrexone had no systematic effect on overall response rate during either schedule component, and the naltrexone continued to antagonize rate decreases of periodic single injections of 10 mg/kg morphine for seven weeks. Tolerance did not occur to the antagonistic effects of naltrexone on rate decreases generally produced by morphine.     

The effects of cholinergic compounds on the development of morphine tolerance,dependence and increased naloxone potency in mice

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Futhermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependendence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependen on, morphine in mice.     

Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice

The effects of NMDA antagonists on passive avoidance learning, shock sensitivity and locomotor activity were examined. Pre-training administration of the antagonists 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) in mice and rats resulted in impaired performance in a retention test 24 h later. No such impairment resulted from immediate post-training administration of either compound in either species. In addition neither compound, given only before the retention test, reduced the retention latencies of mice. In rats CPP was similarly ineffective whereas MK-801 reduced retention latencies, but only at a dose which significantly elevated locomotor activity at the time of the retention test. As assessed by vocalization threshold in mice and by the proportion of animals vocalizing in response to the passive avoidance training shock, neither compound produced analgesia. The vocalization threshold was, in fact, slightly reduced by both compounds. MK-801, but not CPP, stimulated locomotor activity in mice. These results indicate that in the passive avoidance task activation of NMDA receptors is involved in memory formation, but is not critical for the maintenance of memory or its retrieval.     

Attenuating effect of adenosine receptor agonists on the development of behavioral sensitization induced by sporadic treatment with morphine

The aim of the study is to investigate the effect of adenosine receptor agonists on the development of morphine-induced sensitization to the locomotor activity of mice. Selective A1 (N⁶-cyclopentyladenosine - CPA) and A2A (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride - CGS 21680) adenosine receptor agonists or non-selective A1/A2A (5'-N-ethylcarboxamidoadenosine - NECA) adenosine agonists as representatives of adenosinergic drugs have been used in the experiment. Behavioral sensitization has been obtained by sporadic treatment with morphine (10.0 mg/kg, i.p.). We have shown that adenosine receptor agonists co-administered with morphine significantly attenuates increase in the locomotor activity of mice evoked by challenge dose of morphine. These effects have been observed after stimulation of the selective A1 or A2A and non-selective A1/A2A adenosine receptors, namely both receptors were involved in morphine-induced sensitization. Thus, we have demonstrated that adenosine agonists are able to inhibit behavioral sensitization induced by sporadic applications of morphine.     

Co-administration of ultra-low dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords

Although mechanisms underlying ultra-low dose naloxone-induced analgesia have been proposed, possible interactions with glutamatergic transmission and glial cell activation have not been addressed. In the present study, we examined the effect of ultra-low dose naloxone on spinal glutamatergic transmission and glial cell activity in rats chronically infused with morphine.In male Wistar rats, intrathecal morphine infusion (15 μg/h) for 5 days induced (1) antinociceptive tolerance, (2) downregulation of glutamate transporters (GTs) GLT-1, GLAST, and EAAC1, (3) increasing of NMDA receptor (NMDAR) NR1 subunit expression and phosphorylation, (4) upregulation of protein kinase C gamma (PKCγ) expression, and (5) glial cell activation. On day 5, morphine challenge (15 μg/10 μl) caused a significant increase in the concentration of the excitatory amino acids (EAAs) aspartate and glutamate in the spinal CSF dialysates of morphine-tolerant rats. Intrathecal co-infusion of ultra-low dose naloxone (15 pg/h) with morphine attenuated tolerance development, reversed GTs expression, inhibited the NMDAR NR1 subunit expression and phosphorylation, and PKCγ expression, inhibited glial cell activation, and suppressed the morphine-evoked EAAs release. These effects may result in preservation of the antinociceptive effect of acute morphine challenge in chronic morphine-infused rats. Ultra-low dose naloxone infusion alone did not produce an antinociceptive effect. These findings demonstrated that attenuation of glutamatergic transmission and neuroinflammation by ultra-low dose naloxone co-infusion preserves the lasting antinociceptive effect of morphine in rats chronically infused with morphine.     

黄芪总苷和MK-801对宫内窘迫后认知障碍的作用

目的：研究黄芪总苷和地卓西平马来酸（MK-801）对宫内窘迫后的缺氧后新生鼠的Tau蛋白磷酸化程度的影响。方法：采用2×3析因设计：即宫内窘迫（2水平：无处置、施行宫内窘迫即夹闭孕鼠的子宫动脉2/3 持续10 min）和药物（3水平：生理盐水、MK-801、黄芪总苷）的所有组合。新生鼠生长至12周时留取海马,高效液相色谱（HPLC）检测谷氨酸（Glu）含量,IHC-SP检测p-AT8^Ser202与GSK-3β^1H8表达。结果：黄芪总苷可降低宫内窘迫诱发的Glu浓度升高;MK-801对海马中Glu的浓度无明显影响。宫内窘迫可增加海马内磷酸化程度的Tau蛋白p-AT8^Ser202以及促进Tau蛋白磷酸化程度的调控蛋白GSK-3β^1H8的表达;黄芪总苷和MK-801可减缓p-AT8^Ser202磷酸化程度。结论：黄芪总苷可以通过降低海马Glu浓度减缓Tau蛋白的磷酸化;GSK-3β是该信号通路的关键蛋白;黄芪总苷改善由于宫内窘迫诱发导致缺氧后的学习记忆能力低下的效果优于MK-801。