Behavioral Effects Of Morphine Research Articles

Effects of Acetic Acid and Morphine in Shore Crabs, Carcinus maenas: Implications for the Possibility of Pain in Decapods.

Noxious chemicals, coupled with morphine treatment, are often used in studies on pain in vertebrates. Here we show that injection of morphine caused several behavioural changes in the crab, Carcinus maenas, including reduced pressing against the sides of the enclosure and more rubbing and picking at the mouth parts and, at least for a short time, more defensive displays. Subsequent injection of acetic acid into one rear leg caused rubbing of the injected leg and the injected leg was held vertically off the ground. These activities directed at or involving the specific leg are consistent with previous observations of directed behaviour following noxious stimuli and are consistent with the idea that decapods experience pain. Further, acetic acid but not injection of water induced autotomy of the injected leg in these animals. Because autotomy is temporally associated with directed behaviour, it is possible that the autotomy is a pain-related response. Acetic acid is clearly a noxious substance when applied to decapods. However, morphine had no effect on the activities associated with acetic acid injection and thus there is no evidence for an analgesic effect. Further, the injection of acetic acid did not interfere with behavioural effects of morphine. The activities directed towards the site of injection are like those observed with injection, or with external application, of various noxious substances and the present study adds to a growing body of knowledge about possible pain in decapods.

Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0–10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6–56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.

P.2.27 Influence of a novel G protein-biased opioid, PZM21, on behavioural effects of morphine in mice

Describe a unique case of achiasma in a patient with Kapur-Toriello syndrome.We provide a brief review of achiasma with common findings on examination and imaging studies, and a published classification system. In addition, consistent with the rare Kapur-Toriello syndrome, he had a right unilateral cleft lip and palate, neurologic abnormality in his achiasma, anal atresia, vesicoureteral reflux, hypospadias, and growth deficiency.and Importance: Achiasma is an incredibly rare neurological deficit and we present the first case of achiasma in Kapur-Toriello syndrome.

Effects of morphine on place conditioning and ERK1/2 phosphorylation in the nucleus accumbens of psychogenetically selected Roman low- and high-avoidance rats

Extracellular signal-regulated kinase (ERK1/2) phosphorylation is critical for neuronal and behavioural functions; in particular, phosphorylated ERK1/2 (pERK1/2) expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK1/2 phosphorylation in the Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (conditioned place preference (CPP)) and ERK1/2 phosphorylation in the Roman lines remain unknown. To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place-conditioning apparatus and ERK1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely administered with morphine or undergoing conditioning. Morphine elicited CPP in both Roman lines and decreased pERK1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning. These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.

Duration of action of naloxone subcutaneous pellets in antagonizing the EEG and operant behavioural effects of morphine in the rat.

Duration of action of naloxone subcutaneous pellets in antagonizing the EEG and operant behavioural effects of morphine in the rat.

Morphine sensitization in the pentylenetetrazole-induced clonic seizure threshold in mice: Role of nitric oxide and μ receptors

Behavioral sensitization occurs after repeated administration of μ-opioid receptor agonists following a drug-free period. It seems that the changes in dopaminergic systems induced by μ-opioid receptor agonists play a crucial role in behavioral sensitization to opioids. Nitric oxide also plays a role in some behavioral effects of morphine, including sensitization to the locomotor-stimulating effect. This study investigated whether morphine sensitization appears in seizure threshold and the possible role of μ-opioid receptor and nitric oxide in this sensitization. Sensitization was produced by daily injections of morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg), followed by a 10-day washout period. Then the challenge test was performed using morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg) in different groups. To assess clonic seizure threshold, pentylenetetrazole (PTZ) was administered intravenously. Subcutaneous administration of morphine (0.1 and 0.5 mg/kg) induced sensitization in PTZ-induced clonic seizures in mice. Intraperitoneal administration of L-NAME (20 mg/kg), a nonselective inhibitor of nitric oxide synthase, or naltrexone (10 mg/kg), an opioid receptor antagonist, along with morphine inhibited morphine-induced sensitization in PTZ-induced seizure threshold. In conclusion, at low doses, morphine induces sensitization in PTZ-induced clonic seizures in mice probably as a result of the interaction with μ-receptors and nitric oxide.

Association of the histidine-triad nucleotide-binding protein-1 (HINT1) gene variants with nicotine dependence

The histidine triad nucleotide-binding protein-1 gene (HINT1) is implicated in schizophrenia and in the behavioral effects of morphine and amphetamine. Because nicotine dependence (ND) is highly comorbid with schizophrenia and other substance abuse, we examined the association of HINT1 with ND. Association analyses from two independent samples show that HINT1 gene variants are associated with ND phenotypes. Furthermore, human postmortem mRNA expression shows that smoking status and genotype influence HINT1 expression in the brain. In animal studies, western blot analyses show an increase of HINT1 protein level in the mouse nucleus accumbens (NAc) after chronic nicotine exposure. This increase was reduced after treatment with the nicotinic-receptor antagonist mecamylamine, and 24 and 72 h after cessation of nicotine treatment. These results indicate a genetic association between HINT1 variants and ND, and indicate that nicotine-induced modulation of HINT1 level may be involved in mechanisms of excess smoking.

Behavioral effects of morphine and cocaine in M1 muscarinic acetylcholine receptor-deficient mice

Muscarinic acetylcholine receptors (M1-M5) modulate the activity of the central nervous system and an array of physiological functions. Recent evidence has also implicated muscarinic receptors in behavioral effects of drugs of abuse such as morphine and cocaine. However, the genetic similarity between muscarinic receptors and the coexpression of multiple subtypes in most cells has impeded the development of selective antagonists and the determination of the role of each muscarinic receptor subtype in morphine's and cocaine's behavioral effects. The present studies employ mice deficient in the M1 receptor subtype (M1 KO) to assess morphine antinociception (2.5, 5.0, 10, or 20 mg/kg) and the conditioned rewarding effects of morphine and cocaine (2.5, 5.0, or 10 mg/kg). M1 KO and their wild-type (WT) littermates were tested using a 56 degrees C hotplate assay and a conditioned place preference procedure. Parallel studies using the M1 receptor antagonist, pirenzepine, were also conducted in the background strain C57BL6 mice. The results demonstrate that M1 KO mice display a greater antinociceptive effect of morphine in the hotplate assay; however, the effects of morphine as well as cocaine were attenuated in the conditioned place preference procedure. Comparable results were obtained with the pharmacological antagonism of the M1 receptor by pirenzepine. These results suggest a modulatory role of the M1 muscarinic receptor in opioid antinociception and conditioned drug reward, and demonstrate the utility of M1 receptor knockout models for the determination of the role of the M1 subtype in the behavioral effects of morphine and cocaine.

Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area

Morphine dependence is associated with long-term adaptive changes in the brain that involve gene expression. Different behavioral effects of morphine are mediated by different brain regions, for example, the locus ceruleus (LC), a noradrenergic nucleus, is implicated in physical dependence and withdrawal, whereas the ventral tegmental area (VTA), a dopaminergic nucleus, contributes to rewarding and locomotor responses to the drug. However, the global changes in gene expression that occur in these brain regions after morphine exposure and during withdrawal remain unknown. Using DNA microarray analysis in both mice and rats, we now characterize gene expression changes that occur in these brain regions with chronic morphine and antagonist-precipitated withdrawal. In the LC, numerous genes display common regulation between mouse and rat, including tyrosine hydroxylase, prodynorphin, and galanin. Furthermore, we identify clusters of genes that are regulated similarly by chronic morphine and by withdrawal, as well as clusters that show opposite regulation under these two conditions. Interestingly, most gene expression changes that occur in the VTA in response to chronic morphine are different from those seen in the LC, but the gene expression patterns in the two brain regions are very similar after withdrawal. In addition, we examined two genes (prodynorphin and FK506 binding protein 5) that are strongly regulated by chronic morphine or morphine withdrawal in the LC for their role in regulating withdrawal-associated behaviors. Inhibition of either protein profoundly affects withdrawal responses, demonstrating that the genes identified in this study have important functional roles in mediating opiate-induced behaviors.

Effects of different doses of glucose and insulin on morphine state-dependent memory of passive avoidance in mice.

Behavioral effects of morphine, including its effect on memory, have been demonstrated to be influenced by glucose pretreatment. The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To investigate the effects of glucose and insulin alone or in combination with morphine, on pre-test day, on memory recall in mice. The effects of different doses of glucose (50, 100, and 200 mg/kg, IP) and insulin (5, 10, and 20 IU/kg, IP) alone or in combination with morphine, have been studied in mice. The blood glucose level and locomotor activity of the animals were also measured. Although the administration of glucose alone showed no effect on morphine-induced memory impairment, its co-administration with morphine resulted in a significant and dose-dependent memory enhancement compared with the effects of morphine administration alone. Like glucose, the administration of different doses of insulin alone produced no change in the memory, but when the drug was co-administered with morphine, it significantly reduced morphine-induced memory retrieval. The effect of insulin was the opposite of glucose. None of the animals subjected to insulin treatment showed convulsions. Glucose is suggested to increase, on the test day, the morphine-induced memory enhancement by three different mechanisms: cholinergic or opioidergic modulations, or regulation of the ATP-dependent potassium channels.

Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse

Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, l-cyclorphan (3a) and the benzomorphan, l-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a–c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments l-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (μ), delta (δ) and kappa (κ) opioid receptors. Both 3a and 3b were more selective for the κ receptor than the μ receptor. However, 3b was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were κ agonists. Correlating with the binding results, compound 3a had some δ agonist properties, while 3b was devoid of any activity at the δ receptor. In addition, compounds 3a and 3b had opposing properties at the μ opioid receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist.

Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine

Previous studies in rats have shown that ibogaine inhibits neurochemical and behavioral effects of morphine yet potentiates similar effects of (+)-amphetamine. To assess whether these different functional interactions have a metabolic basis, brain levels of morphine and (+)-amphetamine were measured by gas chromatography-mass spectrometry after ibogaine pretreatment (19 h before injection of morphine or (+)-amphetamine). Ibogaine pretreatment had no effect on brain morphine levels, either at 30 min or 2 h after morphine injection; however, ibogaine significantly increased brain amphetamine levels at 30 min and, to a greater extent, at 2 h after (+)-amphetamine injection. These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme. The functional interactions between ibogaine and (+)-amphetamine, but not those between ibogaine and morphine, may result from a hepatic drug-drug interaction.

Glucose and physostigmine effects on morphine- and amphetamine-induced increases in locomotor activity in mice

Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (1 mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and neurobiological functions.

Behavioral effects of morphine in mice: Role of experimental housing

Behavioral effects of morphine were assessed in isolated-timid Swiss mice, and were compared with those observed following morphine administration in nonaggressive-grouped subjects. For this purpose saline- and morphine- (0.5, 1.0, 2.5, and 5.0 mg/kg, IP) injected isolated-timid and nonaggressive-grouped mice interacting with a social partner were observed during a 4-min test. Three main points emerged from the results: a) in basal conditions, compared with social mice, in timid mice the offensive ambivalent behaviors were significantly less pronounced, while the defensive ambivalent behaviors (and all flight behaviors) were significantly more evident;b) 2.5 mg/kg of morphine increased offensive and decreased defensive ambivalent behaviors in timid mice;c) in social morphine (2.5 mg/kg) treatment increased defensive ambivalent behaviors and time spent in crouch. The results, which show that the behavioral effects of morphine depend on the state of the individual, are interpreted on the basis of the antiemotional properties of this opiate.

Effects of ethylketazocine and morphine alone and in combination with naloxone on schedule-controlled behavior in pigeons.

The behavioral effects of morphine and ethylketazocine were compared in pigeons responding under multiple fixed-interval, fixed-ratio schedules of food presentation. Both morphine and ethylketazocine produced dose-related decreases in rates of responding maintained under either schedule. Maximal effects of morphine were observed about 15-45 min after injection and typically lasted the entire session (about 60 min). Effects of ethylketazocine had a faster onset (maximal effects were observed within 15 min after injection), and shorter duration (effects diminished within the session). Ethylketazocine and morphine had similar potencies. Dose-effect curves for both drugs were shifted to a similar degree by naloxone.

Morphine-induced analgesia and exposure to low-intensity 60-Hz magnetic fields: inhibition of nocturnal analgesia in mice is a function of magnetic field intensity

In 2 experiments male CF-1 mice were exposed for 60 min, during the mid-dark period of the day-night cycle, to low-intensity (0.5–1.5 gauss, rms) 60-Hz magnetic fields and then tested for levels of analgesia induced by morphine (10 mg/kg) injections. The magnetic field exposures inhibited the degree of morphine-induced analgesia in a field intensity-dependent manner in both experiments (P< 0.01) with the largest inhibitory effect after exposure to the 1.5-gauss field. Analysis of the combined data from the two experiments revealed a significant (P<0.001) linear relationship between level of analgesia and magnetic field intensity. Thus, these data demonstrated a functional relationship between the behavioral effects of morphine in mice and the strength of the 60-Hz magnetic field. Possible mechanisms underlying these effects are discussed.

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior.

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0-8.0 mg/kg) or chlordiazepoxide (CDP; 4.0-32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0-8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0-16.0 mg/kg) produced increases in response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential protracted effects of morphine and ethylketocyclazocine challenges on EEG and behavior in the rat

One group of six adult female Sprague-Dawley rats was given a series of automatically administered i.v. morphine injections over eight days. Similarly, a second group of six rats was given ethylketocyclaxocine (EKC). Control rats received chronic i.v. saline injections. Tolerance to EEG and behavioral effects of morphine and EKC was demonstrated. At 15 days morphine post-withdrawal, morphine challenges produced EEG and behavioral stupor for a mean of 5 min, followed by EEG and behavioral arousal for a mean of 131 min. In contrast, morphine challenges in saline control rats produced a biphasic EEG and behavioral response consisting of a mean of 85 min of stupor, followed by a mean of 88 min of arousal. However, at 15 days EKC post-withdrawal, EKC challenges produced a biphasic EEG and behavioral response consisting of a mean of 57 min of depression followed by a mean of 55 min of arousal; control saline rats demonstrated similar responses to EKC challenges. Similar results were obtained at one month post-withdrawal for all groups. Thus, protracted effects on EEG and behavior were evident in rats chronically treated with morphine, but not in rats chronically treated with EKC.

Effects of morphine in different strains of paradise fish (Macropodus opercularis L.): An ethopharmacological analysis

The behavioural effects of morphine on random bred Macropodus opercularis , five strains of this species of fish, and the closely related subspecies M. opercularis concolor , were assessed by an ethopharmacological analysis based on the study of different active and passive behavioural units. The results showed that morphine 1. 1) exerted qualitatively different effects in the different strains, 2. 2) did not involve a general enhancement of active behavioural units or a general behavioural depression, but a selective increase of some of them, or the outcome of stereotyped behaviour. In general these findings stress out the importance of ethopharmacological studies for assessing qualitative behavioural differences which may be related to genetically-modulated neurobiological differences.

Behavioral effects of morphine and phencyclidine in rats: The influence of repeated testing before and after single treatment

Morphine-induced antinociception was determined in rats by using the hot plate procedure (56°C). Two responses of the animals were analysed, i.e. the lick and the jump response. Repeated pre-exposure to the hot plate procedure shortly before morphine treatment augmented the efficacy of morphine to induce antinociception as measured by the lick response but markedly decreased the efficacy of this drug to lengthen the latency of the jump response in the same rat. The ED50 for intraperitoneally injected morphine increased from 1.7 (0.7–3.9) to 9.8 (6.5–14.7) mg/kg when rats were pre-exposed to the hot plate procedure and the latency of the jump response was measured. The slope of the dose-response curve was steeper after pre-exposure. Intraperitoneal or intravenous treatment with morphine markedly ncreased the latency of the jump response up to 3–4 h after injection, but only when rats were exposed twice or more to the hot plate procedure in the first hour(s) after injection. The effect of morphine was even present 24 h after injection. The maintenance of the morphine-induced effect is likely to have depended on opioids, since the effect disappeared after naloxone treatment. Phencyclidine induced a dose-related increase in locomotor activity (ED 50: 0.97 (0.85–1.10) mg/kg) and in circling behavior (ED 50: 1.02 (0.85–1.17) mg/kg) when the rats were tested 15 min after a subcutaneous injection. The effect of phencyclidine lasted longer when the rats were tested repeatedly after drug treatment, than when the rats were tested only once. This phenomenon was due to a decrease with time of the effects measured in the placebo-treated control rats repeatedly exposed to test procedure. The results demonstrate that repeated exposure to tests of behavior before and after treatment with psychoactive drugs markedly influences the behavioral action of these drugs. This has consequences for the determination of the efficacy and the time course of action of these drugs, especially when animals are exposed repeatedly to the test procedure in the absence or presence of the drug.