Can prenatal methamphetamine exposure be considered a good animal model for ADHD?

Attention-deficit/hyperactivity disorder (ADHD) is a mental disorder with a heterogeneous origin with a global incidence that continues to grow. Its causes and pathophysiological mechanisms are not fully understood. It includes a combination of persistent symptoms such as difficulty in concentration, hyperactivity and impulsive behavior. Maternal methamphetamine (MA) abuse is a serious problem worldwide, it can lead to behavioral changes in their offspring that have similarities with behavioral changes seen in children with ADHD. There are several types of ADHD animal models, e.g. genetic models, pharmacologically, chemically and exogenously induced models. One of the exogenously induced ADHD models is the hypoxia-induced model. Our studies, as well as those of others, have demonstrated that maternal MA exposure can lead to abnormalities in the placenta and umbilical cord that result in prenatal hypoxia as well as fetal malnutrition that can result in irreversible changes to experimental animals. Therefore, the aim the present study was to compare the cognitive impairments in MA exposure model with those in established model of ADHD - prenatal hypoxia model, to test whether MA exposure is a valid model of ADHD. Pregnant Wistar rats were divided into four groups based on their gestational exposure to MA: (1) daily subcutaneous injections of MA (5 mg/kg), (2) saline injections at the same time and volume, (3) daily 1-hr hypoxia (10 % O2), and (4) no gestational exposure (controls). Male rat offspring were tested for short-term memory in the Novel Object Recognition Test and the Object Location Test between postnatal days 35 and 40. Also their locomotor activity in both tests was measured. Based on the present results, it seems that prenatal MA exposure is not the best animal model for ADHD since it shows corresponding symptoms only in certain measures. Given our previous results supporting our hypothesis, more experiments are needed to further test possible use of prenatal MA exposure as an animal model of the ADHD.

Endogenous antinociceptive system and potential ways to influence It.

The biological significance of pain is to protect the organism from possible injury. However, there exists a situation, where, in the interest of survival, it is more important not to perceive pain. Spontaneous suppression of pain or weakening of nociception is mediated by an endogenous antinociceptive (analgesic) system. Its anatomical substrate ranges from the periaqueductal gray matter of the midbrain, through the noradrenergic and serotonergic nuclei of the brain stem to the spinal neurons, which receive "pain" information from nociceptors. Moreover, the activity of this system is under significant control of emotional and cognitive circuits. Pain can be moderated primarily through stimulation of positive emotions, while negative emotions increase pain. Paradoxically, one pain can also suppress another pain. Analgesia can be induced by stress, physical exercise, orosensory stimulation via a sweet taste, listening to music, and after placebo, i.e. when relief from pain is expected. Since pain has sensory, affective, and cognitive components, it turns out that activation of these entire systems can, in specific ways, contribute to pain suppression.

ADHD symptoms induced by prenatal methamphetamine exposure.

Methamphetamine is commonly used psychostimulant in the Czech Republic and is often abused by pregnant women. Methamphetamine may cause abnormalities in placenta and umbilical cord that results in hypoxia and malnutrition. ADHD is a mental disorder with a heterogeneous origin. The number of patients suffering from ADHD is growing. The pathophysiological mechanisms causing ADHD have not yet been clarified. There are very few rat models for ADHD and include genetic models, chemically induced models (ethanol, nicotine, PCBs, 6-hydroxydopamine lesion) or environmentally induced models (anoxia). The aim of the present study was to test prenatal methamphetamine exposure (5 mg/kg) as a potential novel animal model for ADHD. We found that adult male offspring prenatally exposed to methamphetamine presented hyperactivity while exploring novel environments. Together with cognition changes found in our previous studies, these might represent symptoms similar to those seen in ADHD. More experiments are planned to investigate our hypothesis.

Do multiple body modifications alter pain threshold?

In recent years, epidemiological data has shown an increasing number of young people who deliberately self-injure. There have also been parallel increases in the number of people with tattoos and those who voluntarily undergo painful procedures associated with piercing, scarification, and tattooing. People with self-injury behaviors often say that they do not feel the pain. However, there is no information regarding pain perception in those that visit tattoo parlors and piercing studios compared to those who don't. The aim of this study was to compare nociceptive sensitivity in four groups of subjects (n=105, mean age 26 years, 48 women and 57 men) with different motivations to experience pain (i.e., with and without multiple body modifications) in two different situations; (1) in controlled, emotionally neutral conditions, and (2) at a "Hell Party" (HP), an event organized by a piercing and tattoo parlor, with a main event featuring a public demonstration of painful techniques (burn scars, hanging on hooks, etc.). Pain thresholds of the fingers of the hand were measured using a thermal stimulator and mechanical algometer. In HP participants, information about alcohol intake, self-harming behavior, and psychiatric history were used in the analysis as intervening variables. Individuals with body modifications as well as without body modifications had higher thermal pain thresholds at Hell Party, compared to thresholds measured at control neutral conditions. No such differences were found relative to mechanical pain thresholds. Increased pain threshold in all HP participants, irrespectively of body modification, cannot be simply explained by a decrease in the sensory component of pain; instead, we found that the environment significantly influenced the cognitive and affective component of pain.

The effect of combined treatment of opioids with methylphenidate on nociception in rats and pain in human.

Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin combined therapy with opioid monotherapy in patients with cancer pain. To objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short-term treatment had no significant effect on intensity or frequency of pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient's quality of life.

Prenatal methamphetamine exposure induces long-lasting alterations in memory and development of NMDA receptors in the hippocampus.

Since close relationship was shown between drug addiction and memory formation, the aim of the present study was to investigate the effects of interaction between prenatal methamphetamine (MA) exposure and MA treatment in adulthood on spatial and non-spatial memory and on the structure of the N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Adult male rats prenatally exposed to MA (5 mg/kg) or saline were tested in adulthood. Non-spatial memory was examined in the Object Recognition Test (ORT) and spatial memory in the Object Location Test (OLT) and in the Memory Retention Test (MRT) conducted in the Morris Water Maze (MWM), respectively. Based on the type of the memory test animals were injected either acutely (ORT, OLT) or long-term (MWM) with MA (1 mg/kg). After each testing, animals were sacrificed and brains were removed. The hippocampus was then examined in Western Blot analysis for occurrence of different NMDA receptors' subtypes. Our results demonstrated that prenatal MA exposure affects the development of the NMDA receptors in the hippocampus that might correspond with improvement of spatial memory tested in adulthood in the MWM. On the other hand, the effect of prenatal MA exposure on non-spatial memory examined in the ORT was the opposite. In addition, we showed that the effect of MA administration in adulthood on NMDA receptors is influenced by prenatal MA exposure, which seems to correlate with the spatial memory examined in the OLT.

Behavioral and antinociceptive effects of different psychostimulant drugs in prenatally methamphetamine-exposed rats.

Prenatal exposure to methamphetamine (METH) increases nociceptive sensitivity in adult rats. As the strong analgesics have high abuse potential and drugs of abuse are known to have analgesic properties, the aim was to study analgesic effect of different psychostimulants in control and prenatally METH-exposed rats. Latencies of withdrawal reflexes of hind limbs and the tail on thermal nociceptive stimuli were repeatedly measured in 15-min intervals after the application of 5 mg/kg s.c. of amphetamine (AMPH), methamphetamine (METH), cocaine (COC), 3,4-methylenedioxymethamphetamine (MDMA) or morphine (MOR). In all groups, AMPH induced on hind limbs stronger analgesia than METH and MDMA whereas COC and MOR were practically without any effect. On the tail, effect of AMPH did not differ from that of MOR. All psychostimulants increased defecation in comparison with MOR and in all groups the number of defecation boluses positively correlated with analgesia of the hind limbs. We did not confirm that prenatal exposure to METH makes adult rats more sensitive either to same drug or to other psychostimulants. The different analgesic potencies of psychostimulants and MOR at different body sites indicate the possible existence of a somatotopic organization of pain inhibition, which is controlled by different mechanisms.

Does prenatal methamphetamine exposure induce cross-sensitization to cocaine and morphine in adult male rats?

The aim of the present study was to examine the cross-sensitization induced by prenatal methamphetamine (MA) exposure to challenge dose of cocaine or morphine. Rat mothers received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male offspring (prenatally MA- or saline-exposed) were divided to groups with challenge doses of saline (1 ml/kg), cocaine (5 mg/kg) or morphine (5 mg/kg). Behavior in unknown environment was examined in Laboras, nociception in Plantar test, and active drug-seeking behavior in conditioned place preference (CPP). Our data demonstrate that cocaine increased the exploratory activity in Laboras test in prenatally saline-exposed, but decreased it in prenatally MA-exposed rats. An analgesic effect of cocaine was demonstrated only by the tail withdrawal and it was independent of the prenatal drug exposure. CPP test showed that prenatal MA exposure induced rather tolerance than sensitization to cocaine. In contrast to cocaine effects, morphine decreased rearing activity in both, prenatally MA-exposed and saline-exposed rats, and locomotion only in prenatally MA-exposed rats in the Laboras. In the Plantar test, the results demonstrated that morphine had an analgesic effect in prenatally saline-exposed rats but this effect was suppressed in prenatally MA-exposed rats. In the CPP test morphine induced drug-seeking behavior, which however was not affected by prenatal drug exposure. Thus, our data demonstrate that there is a cross-effect between prenatal MA exposure and the challenge dose of other drug in adulthood, however drug-seeking behavior is not increased by prenatal MA exposure as we expected.

Impact of prenatal methamphetamine exposure on the sensitivity to the same drug in adult male rats.

There are only few studies that examine the effect of prenatal methamphetamine (MA) exposure on the sensitivity to the same drug and the drug-seeking behavior in adulthood. The aim of the present study was to examine the effect of prenatal MA exposure on exploratory behavior and nociception with respect to challenge dose of the same drug. Mothers of the tested offspring received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male offspring (prenatally MA- or saline-exposed) were divided to groups with challenge dose of MA (1 mg/kg) or saline. A modified Open field test (Laboras) was used to examine behavior in unknown environment. Plantar test was used to measure nociception on forelimbs, hind limbs, and the tail. Conditioned place preference (CPP) test was used to examine drug-seeking behavior. Our results in Laboras demonstrated that prenatal MA exposure sensitized the animals to the challenge dose of MA. Specifically prenatally MA-exposed animals that received the challenge MA in adulthood displayed higher locomotion and rearing activity relative to all the other groups. The Plantar test data suggest analgesic effect of MA (1 mg/kg), which however, did not differ based on the prenatal drug exposure. The results of CPP test showed that MA (5 mg/kg) conditioning resulted in increased drug-seeking behavior, but this effect was not affected by prenatal drug exposure. Thus, our data demonstrate that the effects of prenatal MA exposure and the challenge dose of the same drug in adulthood depend on behavioral model used.

Perinatal effect of methamphetamine on nociception in adult Wistar rats.

Methamphetamine is a psychostimulant drug which causes the release of monoamine neurotransmitters. Although drugs of abuse are known to have analgesic effects, there is a lack of evidence regarding the effect of prenatal exposure to methamphetamine on nociception in adulthood. Adult Wistar rats whose mothers had received daily exposure to methamphetamine (5 mg/kg; s.c.) or saline, during gestation or gestation and lactation periods, were examined for: (1) gender differences in nociception; (2) an association between nociception and gross-motor behavior in the plantar test; (3) effects of cross-fostering on nociception; and (4) analgesic effects of an acute injection of methamphetamine (1 mg/kg s.c.). Nociception was tested using the plantar test on postnatal days 85-90. Prenatal methamphetamine increased sensitivity to pain on forelimbs (p<0.0001) and hind limbs (p<0.05) in females only. Prenatal methamphetamine treated male rats fostered by adoptive injection stressed mothers had higher sensitivity to pain than prenatally injection stressed rats fostered by methamphetamine treated mothers (p<0.05). Acute methamphetamine induced analgesia faster in prenatally methamphetamine exposed rats than in controls. In all groups, analgesia increased in the cranio-caudal direction (p<0.0001). From our behavioral data it can be concluded that exposure to methamphetamine during the prenatal period completely dissociates the relationship between nociception and intensity of overall behavior observed in intact animals in adulthood. Thus, our results indicate that perinatal exposure to psychostimulants may have long-term impact on several functions related to dopaminergic system.

Pain perception in neurodevelopmental animal models of schizophrenia.

Animal models are important for the investigation of mechanisms and therapeutic approaches in various human diseases, including schizophrenia. Recently, two neurodevelopmental rat models of this psychosis were developed based upon the use of subunit selective N-methyl-D-aspartate receptor agonists--quinolinic acid (QUIN) and N-acetyl-aspartyl-glutamate (NAAG). The aim of this study was to evaluate pain perception in these models. QUIN or NAAG was infused into lateral cerebral ventricles neonatally. In the adulthood, the pain perception was examined. The rats with neonatal brain lesions did not show any significant differences in acute mechanical nociception and in formalin test compared to controls. However, the neonatally lesioned rats exhibited significantly higher pain thresholds in thermal nociception. Increased levels of mechanical hyperalgesia, accompanying the sciatic nerve constriction (neuropathic pain), were also observed in lesioned rats. Although hyperalgesia was more pronounced in QUIN-treated animals, the number of c-Fos-immunoreactive neurons of the lumbar spinal cord was similar in experimental and control rats. We conclude that neonatal brain lesions attenuated the thermal perception in both nociceptive and neuropathic pain whereas mechanical pain was increased in the model of neuropathic pain only. Thus, nociceptive and neuropathic pain belongs--in addition to behavioral changes--among the parameters which are affected in described animal models of schizophrenia.

Intensity of pain and biochemical changes in blood plasma in spinal cord trauma.

STUDY DESIGN: Cross-sectional, observational and longitudinal. OBJECTIVES: The aim of the study was to analyze the relationship between pain intensity, plasma lipids and severity of spinal cord injuries in patients with paraplegia (n = 11), tetraplegia (n = 16) and polytrauma (n = 15). We concentrated on the hospitalization period immediately following injury. METHODS: Pain intensity was assessed on a visual analog scale immediately after patients were transported to hospital, again 14 days after injury and before discharge from hospital. Blood samples were also obtained at these same times. We measured following biochemical parameters: total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycemia, and C-reactive protein. Data were analyzed with respect to type of injury, state of unconsciousness immediately after injury, hemorrhage, measure of liability (self-inflicted injuries vs casualties), cause of the accident and pre-injury cholesterol levels. RESULTS: On the day of injury, pain intensity correlated positively with HDL cholesterol (r = 0.48, P = 0.04); on the day of discharge from hospital, pain intensity correlated positively with blood glucose levels (r = 0.67, P = 0.0002). Diagnostic subgroups did not differ either in pain intensity or in pain dynamics during hospitalization. Total cholesterol level was lowest in patients with polytrauma. In all patients, the lowest total cholesterol level was observed immediately after injury. HDL cholesterol was highest after injury. CONCLUSION: After spinal cord injury, lower total cholesterol levels reflected more serious trauma intensity and HDL cholesterol predicted more intensive pain. Subjects responsible for their own injuries suffered less intensive pain than those who were not responsible for their injuries.

Prenatal and perinatal factors influencing nociception, addiction and behavior during ontogenetic development.

This review, which summarizes our findings concerning the long-term effects of pre-, peri- and postnatal factors affecting development, nociception and sensorimotor functions, focuses on three areas: 1) perinatal factors influencing nociception in adult rats were examined in rats with hippocampal lesions, after the administration of stress influencing and psychostimulant drugs (dexamethasone, indomethacine and methamphetamine); 2) the effect of pre- and early postnatal methamphetamine administration was shown to impair the development of sensorimotor functions tested in rat pups throughout the preweaning period; 3) the effect of extensive dorsal rhizotomy of the brachial plexus during the early postnatal period was studied with respect to neuropathic pain development and sensorimotor functions. The present study indicates that prenatal or neonatal stress, as well as various drugs, may disturb the development of the nociceptive system and cause long-term behavioral changes persisting to adulthood and that some types of neuropathic pain cannot be induced during the first two postnatal weeks at all. A mature nervous system is required for the development of the described pathological behaviors.

The selective effect of N-feruloylserotonins isolated from Leuzea carthamoides on nociception and anxiety in rats.

The effects of N-feruloylserotonins, substances isolated from the seeds of Leuzea carthamoides (WILLD.) DC., on nociception and anxiety were studied in Wistar rats. Nociceptive responses were measured using the plantar and tail-flick tests which were administered before and after swimming stress (3 min, water temperature 32 degrees C). Anxiety was evaluated using an elevated plus maze. In Experiment I, neither basal nociception nor stress-induced analgesia was influenced significantly. Separating the animals into groups based on their basal nociceptive sensitivity, either high- or low-pain threshold revealed that N-feruloylserotonins have selective effects, especially on rats with high-pain thresholds. In these animals, N-feruloylserotonins reduced the stress-induced analgesia that followed swimming stress. In Experiment II, basal nociceptive sensitivity correlated with indicators of anxiety; high-pain threshold rats were more anxious in the elevated plus maze, with less frequent visits to open arms. The opposite effect was seen in low-pain threshold rats. N-feruloylserotonins did not influence anxiety in low-pain threshold rats, although it reduced anxiety in the high-pain threshold rats as indicated by the increased ratio of open arm visit frequency compared to closed arm visit frequency in the elevated plus maze. From these results we concluded that N-feruloylserotonins have selective stress-reducing effects in stress-sensitive animals.

Tail-flick latency and self-mutilation following unilateral deafferentation in rats.

Unilateral deafferentation induced by transection of the C(4)-C(8) dorsal roots of spinal cord, followed by a complex of abnormal self-mutilating behavior, is interpreted as an animal model of chronic nociception. The objective of our study was to test the differences in tail-flick latency between intact control and unilaterally deafferented animals and to assess the changes in their acute nociceptive sensation. The initial hypothesis was that deafferentation-induced painful sensation might cause stress-induced analgesia that should be manifested as prolonged tail-flick latency. The experiment was carried out on 11 male and 10 female adult Wistar rats. The tail-flick latency was repeatedly measured over a period of 10 consecutive weeks both in the preoperative baseline period and following multiple cervical dorsal rhizotomy. Contrary to our hypothesis, unilateral deafferentation was followed by a significant shortening of the tail-flick latency both in males and females. In deafferented animals, compared to the controls, variations of tail-flick latency were reduced. In individual animals after deafferentation, concurrent dynamic changes were observed in self-mutilating behavior, in a loss and regaining of body weight, and in tail-flick latency. Our data suggest that changes in tail-flick latency may be interpreted in terms of central sensitization and that tail-flick latency might be considered as a useful marker of chronic nociception.

Elevated pain threshold in eating disorders: physiological and psychological factors.

Several studies have found decreased pain sensitivity in patients with eating disorders but it is unclear what physiological and psychological factors are associated with this abnormality. In the present investigation, thermal pain threshold latency, somatoform dissociation, body image disturbance and physiological indices of autonomic neural system activity were measured in 39 female patients with eating disorders (21 with anorexia nervosa and 18 with bulimia nervosa) and 17 healthy women. Pain threshold was elevated in patients with eating disorders, especially those with binge-purging symptomatology. A regression analysis indicated that increased pain threshold is moderately associated with decreased peripheral skin temperature and weakly associated with lack of familiarity with one's own body. However, the between group differences in pain perception remained significant after controlling for peripheral skin temperature. Hence, elevation of pain threshold in eating disorders is a replicable finding, which is not explicable by peripheral indices of autonomic system activity or by somatoform dissociation. In future research it may be evaluated as a potential marker of broader phenotype of decreased interoceptive awareness, which may be associated with vulnerability to the development of eating disorders.

[In Time? Time interval between first symptoms to hospital admission of patients with acute coronary syndromes]. / VCAS? Casový interval od prvních symptomu do prijetí do nemocnice u nemocných s akutními koronárními syndromy.

OBJECTIVE: To assess the pre-hospital delay, i.e. the period which elapses between the onset of pain on the chest and admission to hospital in patients hospitalized on account of acute coronary syndrome. To analyze factors which influence this time interval and obtain thus data for a strategy leading to reduction of the pre-hospital delay. METHOD: Collection of data by means of a questionnaire focused on the time of onset of pain on the chest, time of contact with the health service, time of admission to hospital, type of transport of the patient to hospital, socioeconomic data, manifestations of ischaemic heart disease during the premorbid period and health care provided. Statistical evaluation by the non-paired Mann-Whitney test. RESULTS: Data were assembled from 126 patients admitted to hospital on account of acute coronary syndrome. The median of pre-hospital delay was 5 hours 40 mins., the median of the patient's hesitation 3 hours 44 mins., the median of the transport period was 59 mins. The pre-hospital delay is significantly reduced by transport by the rapid emergency service (p < 0.0001), dispensary care of a cardiologist (p < 0.02) and a previous hospitalization on account of acute myocardial infarction or unstable angina pectoris (p < 0.04). Pre-hospital delay is significantly prolonged in old age pensioners (p < 0.05). On the borderline of signficance is the reduction of pre-hospital delay in patients younger than 80 years (p < 0.06) and patients with higher than elementary education (p = 0.102). CONCLUSION: Prehospital delay in the investigated group is almost three times longer as compared with data from abroad. A most significant part in this delay is played by the long hesitation of patients and transport of the patient to the health institution by other means than the rapid emergency service. In order to provide effective treatment to a larger number of patients with acute coronary syndrome within the shortest time interval it is necessary to inform the population at large on the importance of sudden pain on the chest and the necessity of the quickest possible contact with the rapid emergency service on phone 155. Only then can we expect further improvements of the prognosis of these patients.

Brain maldevelopment and neurobehavioural deviations in adult rats treated neonatally with indomethacin.

The risk of neurodevelopmental toxicity was studied in indomethacin (INDO), an inhibitor of prostaglandin synthesis, which is used in at-risk neonates to prevent the consequences of brain intraventricular haemorrhage or to accelerate the closure of patent ductus arteriosus. Model experiments were carried out in rats of the Wistar strain and Konárovice breed. The drug dose (2 mg/kg, s.c.) was applied to rat pups either once or twice in the following way: (1) on postnatal day 4 (PD:4) or postnatal days 4 and 5 (PD:4-5), i.e. model of brain ontogenic developmental stage in human fetus/preterm neonate of 7-month-gestational age; (2) on postnatal day 9 (PD:9) or postnatal days 9-10 (PD:9-10), i.e. model of brain ontogenic stage in full-term human newborn. The rats were followed up during development (body weight, maturation) until adulthood (age 3-9 months) using tests of behaviour (open field, social memory), nociception (tail flick, plantar test), reproduction and brain neurobiological analysis. The results were evaluated by comparison of litter-mates: treated vs control. No differences between INDO and controls were found in developmental landmarks, adult social memory or reproduction. The pattern of behavioural and neuroendocrine deviations in adult animals was dependent on the ontogenic stage exposed to drug insult. INDO rats of the groups PD:4 and PD:4-5 revealed depression of open field motor activity and emotional reactivity, and higher pituitary weight with lower TSH content. On the other hand, deviations in adult INDO groups PD:9 and PD:9-10 were characterized by pain hypersensitivity, lower pituitary weight with unchanged TSH content and deficit of monoamine transmission in the hypothalamus.

Pain modulation role of melatonin in eating disorders.

The objective of this study was to test the effect of melatonin on thermal pain threshold in female patients with eating disorders. Fourteen patients were included in the study. We found a parabolic relation between pain threshold and the content of urine sulfatoxymelatonin (r = 0.6299, P < 0.05). We can speculate that increase in severity of eating disorder pathology may decrease both the melatonin level and pain sensitivity. In contrast with expected melatonin analgesic effect, our results showed its possible normalizing influence as well on pathologically decreased pain sensitivity.