Ineffective Dose Of Morphine Research Articles

Compensatory Role of Insulin in the Extinction but Not Reinstatement of Morphine-Induced Conditioned Place Preference in the Streptozotocin-Induced Diabetic Rats.

Insulin receptors are distributed in the whole brain, including different parts of the reward circuit that modulate dopamine as the primary neurotransmitter implicated in addiction. The goal of the current study was to illuminate the role of insulin in the extinction period and reinstatement of morphine-induced conditioned place preference (CPP) in the naïve and diabetic rats. One hundred and twelve male rats were randomly divided into two naïve and diabetic groups. Diabetes was induced by one dose administration of streptozotocin (STZ; 60mg/kg; IP) ten days before the conditioning procedure. To evaluate the insulin's role in the duration of extinction period of morphine-CPP, naïve and diabetic rats received insulin (10 U/kg; IP) before each morphine injection (5mg/kg; sc) during the 3-day conditioning phase. All rats that passed the conditioning phase and then underwent the extinction period. Morphine priming-induced reinstatement was determined in both naïve and diabetic rats by injection of different ineffective doses of morphine (0.5 and 1mg/kg; sc) in extinguished rats. In the following experiments, three groups of diabetic rats received insulin during the conditioning, expression, or reinstatement phase to illustrate insulin's effect on the morphine-induced reinstatement and the duration of the extinction period (insulin was only treated during the acquisition phase). The results showed that the extinction period and reinstatement of morphine were potentiated in the STZ-induced diabetic rats. The obtained findings also revealed that insulin replacement shortened the extinction period of morphine-induced CPP in STZ-diabetic rats. However, insulin replacements in conditioning, expression, and reinstatement phases did not affect morphine priming-induced reinstatement in diabetic animals.

The involvement of ventral hippocampal microglial cells, but not cannabinoid CB1 receptors, in morphine-induced analgesia in rats.

It is well known that glial cells are involved in pain processing. The purpose of the present study was to investigate the possible involvement of the ventral hippocampal (VH) glial cells in morphine-induced analgesia. A tail-flick apparatus was used to measure pain sensitivity in male Wistar rats that were bilaterally cannulated in the VH by stereotaxic surgery. The results showed that intraperitoneal (i.p.) administration of morphine (2.5-7.5mg/kg) induced analgesia in a time-dependent manner. The blockade of the VH glial cell activation by bilateral microinjection of a glial inhibitor, minocycline (5-15µg/rat) into the VH with an ineffective dose of morphine (2.5mg/kg, i.p) significantly increased morphine analgesia. Considering that the endocannabinoid system via CB1 receptors play a crucial role in pain modulation, we also assessed the possible role of the VH cannabinoid CB1 receptors in the functional interaction between minocycline and morphine in acute pain. Our results indicated that intra-VH injection of the cannabinoid CB1 receptor agonist, arachidonylcyclopropylamide (ACPA; 4-12ng/rat) had no effect on minocycline-induced potentiation of morphine analgesia. It should be considered that intra-VH microinjection of minocycline or ACPA by itself had no effect on tail-flick latency. Our findings suggest that the activation of the VH microglial cells may be involved in mediating pain sensation, because the inhibition of these cells by intra-VH injection of minocycline could potentiate morphine-induced analgesia. Although endocannabinoids have a regulatory role in glia function, the activation of CB1 receptors could not affect the potentiative effect of minocycline on morphine analgesia.

An Assessment between D1 Receptor Agonist and D2 receptor Antagonist into the Ventral Tegmental Area on Conditioned Place Preference and Locomotor Activity.

Background:The release of dopamine (DA) has certain roles in the induction of conditioned place preference (CPP) and motor learning in the ventral tegmental area (VTA). The aim of this study was to investigate the excitatory effects of DA through DA-D1 agonist (SKF38393) and elimination of the inhibitory effects of DA through DA-D2 antagonist (eticlopride) into the VTA and its synergistic effects with an ineffective dose of morphine in the induction of CPP.Materials and Methods:Morphine (2.5 mg/kg; s. c.) did not induce a significant CPP, without any effect on the locomotor activity during the testing phase. SKF38393 (0.125, 0.5, and 1 μg/side) and eticlopride (0.5, 1, and 2 μg/side) individually or simultaneously were microinjected bilaterally into the VTA.Results:The administration of SKF38393 (1 and 2 μg/rat) with ineffective morphine and also without morphine caused CPP on test day, while eticlopride (2 μg/rat) caused CPP with morphine only. Locomotor activity increased in groups receiving D1 agonist and D2 antagonist that presumed to be caused by the reinforcing effect. In addition, the concurrent administration of ineffective doses of D1 agonist and D2 antagonist into the VTA with ineffective morphine caused CPP but not with saline.Conclusions:This study showed that there was a need for morphine to activate the reward circuit through the D2 receptor in the VTA while the administration of the D1 agonist could independently activate the reward circuit. In addition, there was a probable synergistic effect using ineffective doses of D1 and D2 receptors, in the acquisition of morphine-induced CPP.

Role of D1-like and D2-like dopamine receptors within the ventral tegmental area in stress-induced and drug priming-induced reinstatement of morphine seeking in rats.

The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward as well as stress processes. Dopamine is a predominant neurotransmitter in the reward system, which plays an important role in both drug priming-induced and cue-induced reinstatement of cocaine and heroin seeking. It has been shown that this neurotransmitter has a role in stress-induced relapse to drug seeking. Therefore, the present study aims to evaluate the effects of intra-VTA administration of SCH-23390, as a dopamine D1-like receptor antagonist, and sulpiride, as a dopamine D2-like receptor antagonist, on drug priming-induced and food deprivation (FD)-induced reinstatement. The rats were bilaterally implanted by two separate cannulae into the VTA. After the acquisition and extinction of morphine-conditioned place preference, the animals received different doses of SCH-23390 or sulpiride (0.15, 0.4, 1.5 and 4 mg/0.3 µl vehicle per side) into the VTA on the reinstatement day and tested for drug priming-induced reinstatement of morphine (1 mg/kg) or FD-induced reinstatement facilitated by an ineffective dose of morphine (0.5 mg/kg) in separate groups. Our findings indicated that the D1/D2-like receptor antagonists attenuated the drug priming-induced and FD-induced reinstatement. However, these decrements were more significant in groups of animals that received a 24-h FD as a stressor. The data may suggest a role for the VTA dopaminergic system in relapse to drugs of abuse, which may be induced either by re-exposure to morphine or exposure to a stressor.

The Blockade of Glutamate N-methyl-D-aspartate Receptors into the Prelimbic of Prefrontal Cortex Decreases Morphine-induced Conditioned Place Preference in Rat

BACKGROUND: The prelimbic area (PL) of the prefrontal cortex is susceptible to abnormal developmental stimuli that raises the risk of addiction. Glutamate receptors play a key role in opiate reinforcement and reward functions in this area. Therefore, we examined the effect of the DL-2-amino-5-phosphonopentanoic acid (AP5), as N-methyl-D-aspartate (NMDA) receptor antagonist into the PL on the phases of conditioned place preference (CPP) induced by morphine.METHODS: Male Wistar rats were divided into 12 groups (3 surgical groups for each dose of morphine in any phase of CPP) and anaesthetized with chloral hydrate. Cannula was implanted into the PL and the AP5 was injected into this area and morphine-induced CPP was investigated. Data were processed with the commercially available SPSS 22 software using one-way ANOVA and Tukey's test. p<0.05 were considered statistically significant.RESULTS: Our findings indicated, morphine in doses of 2.5 to 10 mg/kg induced CPP. Microinjection of various doses of the AP5 into the PL before the administration of the effective dose of morphine significantly reduced place preference in the acquisition and the expression phases of the CPP test compared to the sham group (p<0.001). In another set of our experiments was seen that, different doses of the AP5 with the ineffective dose of morphine only reduced the expression phase of the CPP (p<0.001) while, produced neither preference nor aversion effect on the acquisition phase (p=0.147).CONCLUSION: It seems that the glutamate NMDA receptors in the PL through memory formation and morphine-related reward signals play a critical role in addiction process during morphine-induced CPP.KEYWORDS: N-methyl-aspartate, morphine, glutamate receptor, prefrontal cortex, reward

Inhibition of microglia in the basolateral amygdala enhanced morphine-induced antinociception: Possible role of GABAA receptors

In clinical medicine, morphine is widely used to relieve many types of pain, but it has several side effects such as the development of tolerance and dependence. In order to decrease the side effects of morphine administration for the treatment of pain, the combination of minocycline as a glial inhibitor and morphine has been suggested in previous studies. It is important to understand which synaptic mechanisms are involved in the potentiative effect of minocycline on morphine antinociception. To this aim, male Wistar rats were bilaterally cannulated in the basolateral amygdala by srereotaxic instrument. A tail-flick apparatus was used to measure the pain threshold. The results revealed that intraperitoneal injection of morphine (2.5–7.5mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of minocycline (5–10µg/rat) by itself had no effect on tail-flick latency, while the microinjection of the same doses of minocycline with an ineffective dose of morphine (5mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of different doses of muscimol (0.001–0.005µg/rat) increased the minocycline-induced potentioation on morphine response in the tail-flick test. Intra-basolateral amygdala microinjection of muscimol by itself had no effect on tail-flick latency. On the other hand, intra-basolateral amygdala microinjection of bicuculline (0.01–0.1µg/rat) inhibited minocycline-induced potentiation of morphine antinociception. It should be noted that intra-basolateral amygdala bicucculine by itself had no effect on tail-flick latency. It can thus be concluded that intra-basolateral amygdala minocycline potentiates morphine response in the tail-flick test. Moreover, basolateral amygdala GABAergic system may be involved in the minocycline-induced potentiation of morphine response via GABAA receptors.

Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation- and drug priming-induced reinstatement of morphine seeking in rats

Dopamine is a predominant neurotransmitter in the nervous system, which plays an important role in both drug priming- and cue-induced reinstatement of cocaine and heroin seeking. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to evaluate the effects of intra-accumbal administration of SCH23390 as a dopamine D1-like receptor antagonist on food deprivation (FD) and drug priming-induced reinstatement. Sixty-eight adult male albino Wistar rats weighing 200–280g were bilaterally implanted by cannulae into the nucleus accumbens (NAc). For induction of the CPP, subcutaneous (sc) administration of morphine (5mg/kg) was used daily during a three-day conditioning phase. The conditioning score and locomotor activity were recorded by using the Ethovision software. Under extinction conditions, rats were given an ‘off’ period and were tested for FD-induced reinstatement following the 24-h or 48-h FD condition, and for drug priming-induced reinstatement under the sated condition following an injection of 0.5 and 1mg/kg (sc) morphine. In the next experiments, animals received different doses of intra-accumbal SCH23390 (0.25, 1 and 4μg/0.5μl saline) bilaterally and were subsequently tested for FD- and morphine priming-induced reinstatement. Our findings indicated that only a dose of 1mg/kg and not 0.5mg/kg of morphine induced the reinstatement of morphine. 24-h FD similar to 48-h FD induced the reinstatement of seeking behaviors facilitated by an ineffective dose of morphine (0.5mg/kg). Furthermore, the D1-like receptor antagonist attenuated FD- and drug priming-induced reinstatement dose-dependently. It is concluded that FD- and drug priming-induced reinstatement may be mediated, at least in some way, by activation of dopamine D1-like receptors in the NAc.

The Possible Role of Medial Prefrontal Cortex Beta-1-Adrenoceptors in Morphine-Induced Amnesia

The prelimbic region of the medial prefrontal cortex (mPFC) in the brain is crucial for memory. Norepinephrine elicits an important influence on mPFC functions. The stimulation of β-adrenoceptors (β-ARs) may play a critical role in the consolidation of long-term memory. The present study examines the possible role of β₁-ARs located in the mPFC on morphine-induced amnesia in rats. The animals were bilaterally implanted with chronic cannulas in the mPFC, trained in a step-through-type passive avoidance task and tested 24 h after training to measure step-through latency. Our present results indicated that posttraining intraperitoneal administration of morphine (2.5, 5 and 7.5 mg/kg) dose-dependently reduced the step-through latency. Different doses of xamoterol (0.01, 0.1 and 1 µg/rat) have shown no significant change in the step-through latency, but posttraining intra-mPFC microinjection of atenolol (0.2 and 0.4 µg/rat) had an amnesic effect. Moreover, atenolol-caused amnesia was reversed by an ineffective dose of xamoterol (0.1 µg/rat). On the other hand, coadministration of an ineffective dose of atenolol (0.1 µg/rat) with an ineffective dose of morphine (2.5 mg/kg) induced an amnesic effect. Meanwhile, xamoterol had no effect on morphine-induced amnesia. These results suggest that β₁-ARs of the prelimbic region in the mPFC may play an important role in morphine-induced amnesia.

Blockade of orexin-1 receptors in the ventral tegmental area could attenuate the lateral hypothalamic stimulation-induced potentiation of rewarding properties of morphine

The orexins (hypocretins) are lateral hypothalamic (LH) neuropeptides that have been implicated in a variety of behaviors ranging from feeding to sleep and arousal. Evidence from animal models suggests a role for orexins in reward processing and drug addiction. In the present study, we investigated the direct effect of an orexin antagonist in the ventral tegmental area (VTA) on acquisition and expression of morphine conditioned place preference (CPP) induced by concurrent stimulation of the LH. Eighty-one adult male Wistar rats weighing 220–280g were unilaterally implanted by two separate cannulae into the LH and VTA. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The animals received SB334867 as a selective orexin-1 receptor antagonist (0.1, 1 and 10nmol/0.3μl DMSO) in the VTA, just 5min prior to intra-LH administration of ineffective dose of carbachol as a cholinergic agonist (62.5nmol/0.5μl saline) that stimulates orexin neurons in the LH and ineffective dose of morphine (1mg/kg, subcutaneously) concurrently during conditioning phase (acquisition experiments) or post-conditioning phase (expression experiments). Data showed that the blockade of orexin-1 receptors in the VTA could inhibit the acquisition (development) but not expression of LH stimulation-induced morphine CPP in the rats. Our findings suggest that the orexinergic projections from the LH to the VTA are involved in the development of the LH stimulation-induced potentiation of morphine rewarding properties and orexin-1 receptors in the VTA have a substantial role in this phenomenon.

Effect of electrical stimulation of nucleus accumbens with low, median and high currents intensities on conditioned place preference induced by morphine in rats.

Background:Some investigators indicated the effect of electrical or chemical stimulation on different parts of the brain and its effect on animal's behaviors. Furthermore, drug addiction is known to be associated with dysfunction of memory and motivational systems. In this study, we aimed to evaluate the effect of electrical stimulation of nucleus accumbens (NAc) with different currents intensities on conditioned place preference (CPP) induced by morphine.Materials and Methods:Male Wistar rats were randomly divided for experimental groups (n = 8). We investigated the influence of electrical stimulation with different current intensities (low: 15 μA, median: 50 μA and high: 100 μA) on NAc with ineffective and effective dose of morphine (0.5 and 5 mg/kg, respectively) on acquisition and expression of morphine-induced place conditioning in male rats.Results:The doses of subcutaneous administration morphine (2.5 and 5 mg/kg, P < 0.05 and P < 0.001; respectively) induced CPP compared with saline group. Furthermore, our findings are showed that electrical stimulation (100 μA) of NAc suppressed morphine-induced CPP. It revealed impairment of learning and memory formation in conditioning process due to morphine administration.Conclusion:It is possible that high current intensity (100 μA) had an accompanied effect by a reversal of the increased tissue contents of dopamine and its metabolites in the NAc of morphine-induced CPP rats. Furthermore, high current intensity in combination with ineffective dose of morphine (0.5 mg/kg) increased morphine-induced CPP probability via the prove reward system.

Role of intra-accumbal cannabinoid CB1 receptors in the potentiation, acquisition and expression of morphine-induced conditioned place preference

Recent studies demonstrate a functional interaction between opioid and endogenous cannabinoid system. These two systems possess similar pharmacological effects on drug addiction and reward. The present study was designed to investigate the role of intra-accumbal cannabinoid CB1 receptors in the acquisition and expression of morphine-induced conditioned place preference (CPP). Two-hundred forty eight adult male albino Wistar rats were used in these experiments. Using a 3-day schedule of conditioning, it was found that subcutaneous administration of morphine (0.2–10mg/kg) induced CPP at the doses of 5 and 10mg/kg. Solely intra-accumbal administration of WIN55,212-2 (1, 2 and 4mmol/0.5μl DMSO) as CB1 receptor agonist could induce CPP. Also, our results showed that ineffective dose of WIN55,212-2 (1mmol) when administered before the ineffective dose of morphine (2mg/kg) could induce the CPP and potentiate the rewarding effect of morphine. On the other hand, intra-accumbal injection of the cannabinoid CB1 receptor antagonist AM251 (90μmol/0.5μl DMSO) alone induced a significant conditioned place aversion. Moreover, intra-NAc injection of AM251 (45 and 90μmol/0.5μl DMSO) inhibited morphine-induced CPP. Interestingly, injection of WIN55,212-2 (1, 2 and 4mmol) or AM251 (15, 45 and 90μmol) into the NAc had no effect on the expression of morphine (5mg/kg)-induced CPP. These observations provide evidence that cannabinoid CB1 receptors in the NAc are involved in development of reward-related behaviors and they can potentiate the rewarding effects of morphine. It seems that these receptors can affect the reward modulatory system at the level of nucleus accumbens in rats.

Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory

Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory.

Different current intensities electrical stimulation of prelimbic cortex of mPFC produces different effects on morphine-induced conditioned place preference in rats

The medial prefrontal cortex (mPFC) is a part of brain reward system involved in higher cognitive functions such as learning and memory. The mPFC receives strong dopaminergic innervations from ventral tegmental area (VTA) that comprises a portion of the mesolimbic dopaminergic system (MLDS), and in turn sends glutamate projection to both the VTA and nucleus accumbens (NAc). In the present study, we investigated the influence of electrical stimulation with different current intensities on prelimbic cortex (PL, subdivision of mPFC) (25, 50, 100, and 150μA) with and without an effective dose of morphine (0.5 and 5mg/kg) on CPP during conditioning and post-conditioning phases. Subcutaneous administration of morphine 5mg/kg produced significant CPP in comparison with saline group. Our findings also showed that electrical stimulation of PL (100μA) suppressed morphine-induced CPP that reveals impaired learning and memory formation in the process of conditioning through the blocking connection from the hippocampus to the prelimbic cortex of mPFC. A lowest current intensity (25μA) in combination with ineffective dose of morphine (0.5mg/kg) increased morphine-induced CPP probability via the prove reward system.

Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.

Nitric oxide in the nucleus accumbens is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible effect of nitric oxide agents injected into the nucleus accumbens (NAc) in the presence or absence of nicotine on morphine state-dependent memory in adult male Wistar rats was investigated. As a model of memory, a step-through type inhibitory avoidance task was used. Post-training injection of morphine (4 and 6mg/kg) dose dependently induced the impairment of memory retention. Administration of morphine (4 and 6mg/kg) before retention induced state-dependent retrieval of the memory acquired under post-training morphine (6mg/kg) influence. Injection of nicotine before retention (0.25 and 0.5mg/kg) alone and nicotine (0.1, 0.25 and 0.5mg/kg) plus an ineffective dose of morphine (2mg/kg) reversed the post-training morphine-induced memory impairment. The amnesia elicited by morphine (6mg/kg) was also prevented by pre-retention intra-NAc administration of a nitric oxide synthase (NOS) inhibitor, l-NAME (0.24μg/rat, intra-NAc). Interestingly, an ineffective dose of nicotine (0.1mg/kg) in combination with low doses of l-NAME (0.06 and 0.12μg/rat, intra-NAc) synergistically improved memory performance impaired by morphine given after training. It is important to note that intra-NAc administration of l-NAME before retention impaired memory retrieval by itself. In contrast, pre-retention administration of l-arginine, a nitric oxide (NO) precursor (0.25 and 0.5μg/rat, intra-NAc), which had no effect alone, prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of nucleus accumbens in the improving effect of nicotine on the morphine-induced amnesia and morphine state-dependent memory.

Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats

Arcaine is a competitive antagonist of the polyamine binding site at the N-methyl-D-aspartic acid receptor which induces state-dependent recall. However, no study has addressed the involvement of other neurotransmitter/neuromodulators in arcaine-induced state dependency. The current study investigates whether the opioid system is involved in arcaine-induced state-dependent memory retrieval of the inhibitory avoidance task (IA) in rats. The systemic administration of arcaine (30 mg/kg, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) 0, 3, 6, or 9 h post-training, reduced step-down latencies at testing. Arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) injection 30 min before testing reversed the performance deficit induced by administration of arcaine or morphine 0, 3 or 6, but not 9 h post-training. The reversal of arcaine-induced impairment of IA performance was completely transferred to morphine and vice versa. The association of low and ineffective doses of morphine and arcaine (10 and 1.5 mg/kg, respectively) were additive and caused state dependency. Naloxone (2 mg/kg, 3 min post-training, or 1 mg/kg, 1 h pre-test, i.p.) reversed the amnesia and the state dependency induced by morphine and arcaine. These results suggest that state dependency induced by arcaine involves the opioid system.

Repeated pretreatment of morphine prevents morphine-induced amnesia: A possible involvement for dorsal hippocampal NMDA receptors.

Learning and memory processes can be affected by morphine administration. It has been previously demonstrated that the effects of morphine depend on the timing of drug administration. In the present study, the effects of microinjections of a NMDA receptor agonist and antagonist into the CA1 regions of the dorsal hippocampi (intra-CA1) on repeated pretreatment of morphine-induced prevention of morphine-induced amnesia have been investigated. Step-through inhibitory avoidance task of memory has been used to examine retrieval of memory formation, 24 h after training in male Wistar rats. The results indicate that post-training administration of morphine (7.5 mg/kg) impaired memory retrieval, but not in the animals, which received previous repeated morphine (7.5 and 10 mg/kg) injections followed by morphine withdrawal. Repeated co-administration of NMDA (7.5 and 10 ng/rat, intra-CA1) with an ineffective dose of morphine (5 mg/kg), once daily for three days reversed morphine-induced amnesia. Repeated bilateral intra-CA1 microinjections of NMDA, once daily for three days followed by a five-day washout had no effect on the expression of amnesia produced by post-training morphine. Three-day administration of the NMDA receptor antagonist, D-AP5 (0.5 - 2 µg/rat, intra-CA1) followed by a five-day washout had no effect on morphine-induced amnesia. On the other hand, intra-CA1 microinjections of the same doses of D-AP5 prior to injection of 7.5 mg/kg of morphine (per day×3 days) decreased the reversal of morphine-induced amnesia. These data imply that the dorsal hippocampal NMDA receptor mechanism(s) may modulate the effect-induced by repeated morphine administration on a challenge dose of morphine-induced amnesia.

Nitric oxide in the ventral tegmental area is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible involvement of nitric oxide systems in the ventral tegmental area (VTA) in nicotine's effect on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats was investigated. Step-through type inhibitory avoidance task was used to test memory retrieval. Post-training administration of morphine (5 and 7.5 mg/kg) induced amnesia. The response induced by post-training morphine was significantly reversed by pre-test administration of the drug. Pre-test injection of nicotine (0.4 and 0.8 mg/kg s.c.) alone and nicotine (0.1, 0.4 and 0.8 mg/kg s.c.) plus an ineffective dose of morphine also significantly reversed the amnesia induced by morphine. Morphine amnesia was also prevented by pre-test administration of l-arginine (1 and 3 μg/rat, intra-VTA), a nitric oxide (NO) precursor. Interestingly, an ineffective dose of nicotine (0.1 mg/kg s.c.) in combination with low dose of l-arginine (0.3 μg/rat, intra-VTA) synergistically improved memory performance impaired by morphine given after training. In contrast, pre-test administration of NG nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor (2 μg/rat, intra-VTA) prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of ventral tegmental area in the improving effect of nicotine on the morphine-induced amnesia.

Involvement of central amygdala NMDA receptor mechanism in morphine state-dependent memory retrieval

In the current study, the effects of intra-central amygdala (CeA) administration of N-methyl- d-aspartate (NMDA) and its competitive antagonist, d-2-amino-5-phosphonopentanoic acid (D-AP5), on morphine state-dependent memory retrieval were investigated. Post-training subcutaneous (s.c.) administration of different doses of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory. The response induced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of this drug (5 and 7.5 mg/kg), indicating morphine state-dependent memory retrieval. Pre-test intra-CeA administration of NMDA (0.01 and 0.05 μg/rat) plus an ineffective dose of morphine (0.5 mg/kg, s.c.) restored memory impairment caused by post-training morphine (7.5 mg/kg). However, pre-test intra-CeA administration of NMDA (0.005–0.05 μg/rat), alone, was ineffective on post-training morphine-induced amnesia. Furthermore, pre-test intra-CeA administration of the same doses of NMDA had no effect on memory retrieval. Pre-test intra-CeA administration of D-AP5 (0.1–1.0 μg/rat) decreased morphine state-dependent memory retrieval. However, pre-test administration of D-AP5 (0.1–1 μg/rat) alone decreased memory retrieval, but restored post-training morphine-induced amnesia. In conclusion, our results suggest which CeA may be potentially critical for morphine state-dependent memory retrieval and that CeA NMDA receptor mechanism(s) interact with the opiodergic system in the modulation of morphine state-dependent memory retrieval.

Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine

The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1μg/mouse) with an ineffective dose of morphine (3mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.