Behavioral change related to Wenchuan devastating earthquake in mice

It has been suggested that some animals are much more capable of perceiving certain kinds of geophysical stimuli which may precede earthquakes than humans, but the anecdotal phenomena or stories about unusual animal behaviors prior to an earthquake should be interpreted with objective data. During the Wenchuan magnitude 8.0 earthquake that happened in Wenchuan county (31.0° north latitude, 103.4° east longitude) of Sichuan province, China, on May 12, 2008, eight mice were monitored for locomotor activity and circadian rhythm in constant darkness with temperature 22–24 °C and humidity 55–65% for 38 days. The ongoing monitoring of locomotor activity of mice in our laboratory made it possible to design a posteriori study investigating whether the earthquake was associated with any change in animal behavior. Based on analyzing the recorded data with single cosinor, we found that the locomotor activity dramatically decreased in six of these eight mice on day 3 before the earthquake, and the circadian rhythm of their locomotor activity was no longer detected. The behavioral change lasted for 6 days before the locomotor activity returned to its original state. Analyses of concurrent geomagnetic data showed a higher total intensity during the span when the circadian rhythm in locomotor activity weakened. These results indicated that the behaviors, including circadian rhythm and activity, in these mice indeed changed prior to the earthquake, and the behavioral change might be associated with a change of geomagnetic intensity. Bioelectromagnetics 30:613–620, 2009. © 2009 Wiley‐Liss, Inc.     

Geomagnetic activity and enhanced mortality in rats with acute (epileptic) limbic lability

Presumably unrelated behaviors (e.g. psychiatric admissions, seizures, heart failures) have been correlated with increased global geomagnetic activity. We have suggested that all of these behaviors share a common source of variance. They are evoked by transient, dopamine-mediated paroxysmal electrical patterns that are generated within the amygdala and the hippocampus of the temporal lobes. Both the probability and the propagation of these discharges to distal brain regions are facilitated when nocturnal melatonin levels are suppressed by increased geomagnetic activity. In support of this hypothesis, the present study demonstrated a significant correlation of Pearsonr=0.60 between mortality during the critical 4-day period that followed induction of libic seizures in rats and the ambient geomagnetic activity during the 3 to 4 days that preceded death; the risk increased when the 24 h geomagnetic indices exceeded 20 nT for more than 1 to 2 days.     

Day time wheel running activity in laboratory rats following geomagnetic event of 5–6 July 1974

Albino laboratory rats that were given free access to running wheels while maintained on a 12:12 h L:D schedule were observed to display marked increases in day cycle activity following an unusually intense geomagnetic storm. The activity changes were not immediate but peaked one day to several days after the storm. Two less intense geomagnetic storm conditions during the 51 day observation period were associated with less marked activity increases. Ambient room temperature fluctuations were not significantly correlated with either geomagnetic activity or day cycle activity measures.     

The effect of hyperthyroidism on opiate receptor binding and pain sensitivity

This study was conducted to determine the effect of thyroid hormone on opiate receptor ligand-binding and pain sensitivity. Specific opiate receptor-binding was performed on brain homogenates of Swiss-Webster mice. There was a significant increase in 3H-naloxone-binding in thyroxine-fed subjects (hyperthyroid). Scatchard analysis revealed that the number of opiate receptors was increased in hyperthyroid mice (Bmax = 0.238 nM for hyperthyroid samples vs. 0.174 nM for controls). Binding affinity was unaffected (Kd = 1.54 nM for hyperthyroid and 1.58 nM for control samples). When mice were subjected to hotplate stimulation, the hyperthyroid mice were noted to be more sensitive as judged by pain aversion response latencies which were half that of control animals. After morphine administration, the hyperthyroid animals demonstrated a shorter duration of analgesia. These findings demonstrate that thyroxine increases opiate receptor number and native pain sensitivity but decreases the duration of analgesia from morphine.     

Daily repeated magnetic field shielding induces analgesia in CD-1 mice

We have recently observed that a single exposure of mice to a magnetically shielded environment can attenuate opioid induced analgesia. Here, we report the effect of repeated exposures to the same magnetically shielded environment. Adult male Swiss CD-1 mice were placed in a Mu-metal lined box or an opaque Plexiglas box (sham condition) for 1 h per day for 10 consecutive days. Nociception was measured as the latency time to a foot lift/lick in response to an aversive thermal stimulus (hotplate analgesiometer, 50 +/- 1 degrees C) before and immediately after exposure. Multiple experiments were conducted in which thermal latency was tested on each of the 10 days or on days 1, 5, and 10, with some utilizing post-exposure testing only. It was shown that mice can detect and will respond to the repeated absence of the ambient magnetic field, with a maximum analgesic response occurring over days 4-6 of exposure and returning to baseline thereafter. The effect was robust, independent of pre-exposure and intermittent testing, and seems to be opioid related, since the results obtained on day 5 were similar to those from a 5 mg/kg dose of morphine and were abolished with the opioid antagonist, naloxone.     

Expression of stress-evoked analgesia, connected with activity of animals in a forced swimming test]

The influence of forced swimming on the development of stress-induced analgesia was studied in 35 SHR mice, 65 NMRI mice, and 23 white outbred male rats. Mice were subjected to swimming conditions (at a temperature of 11 degrees C) for a period of 4 minutes and rats for 6 minutes. Pain thresholds were measured by a footshock. It was shown that behavioral response to acute stress is associated with a change in the pain tolerance threshold: activity of an animal under test conditions positively correlated with stress-induced analgesia. The response to stress and parameters of stress-induced analgesia depend on the genetic factor and age, however, the correlation between the activity during exposure to stress and the extent of stress-induced analgesia conserves in all cases.     

The effect of food and water deprivation on post-stress analgesia in mice and levels of beta-endorphin and dynorphin in blood plasma and hypothalamus

Pain sensitivity of food and/or water-deprived male mice was tested on a hotplate. The most pronounced analgesia ensued in animals given no food and water, and no food but water ad libitum, the least one in water-deprived mice. The magnitude of the rise in pain threshold depended on the duration of deprivation and was correlated with the increase in the blood plasma beta-endorphin level. In the hypothalamus beta-endorphin level increased after 72-h food deprivation only. The level of dynorphin remained unchanged. Naloxone (10 mg/kg) almost completely reversed food or water-deprivation induced analgesia.     

Diurnal variations in tonic pain reactions in mice

Diurnal changes in the behavioural reactions to subcutaneous formalin injection (20 microl, 1%) into the dorsum of an hindpaw were examined in female CBA/J mice aged 70-75 days, maintained in a 12/12 dark/ light cycle (light on at 07.00 h; light off at 19.00 h). Mice showed higher pain scores, as expressed by the amount of time spent licking the injected paw and by the number of flinching episodes, when tested under red light at the beginning of the dark phase (19.00-22.00: Dark group) than when tested either under white or red light at the beginning of the light phase of the diurnal cycle (7.00-10.00). The increases in pain reactions at night were found both during the first (0-10 min) and the second (11-55 min) phase of the behavioural response to formalin injection. They were not due to aspecific increases in motor behaviour, since self-grooming actually decreased in the Dark group during the second phase of the response, and the amount of locomotor activity after the injection was similar to, or lower than, that found in mice tested in the morning under white or red light, respectively. In another group of female CBA/J mice tested in the hotplate apparatus (at a temperature of 52 degrees), paw-lick latencies were significantly higher in mice tested at dark during the night, whereas jump (escape) latencies were higher in the morning. These results demonstrate different diurnal variations in the reactions to brief or prolonged noxious stimulation in mice, with greater responses to tonic pain at the onset of the dark phase.     

Further Evidence of Emotional Allodynia in Unmedicated Young Adults with Major Depressive Disorder

Background

Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness) is heightened in individuals with major depressive disorder(MDD), a phenomenon we termed “emotional allodynia”. The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.

Methods

Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC) received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP). All subjects rated the intensity and affect(pleasantness/unpleasantness) of each stimulus. Sensory(pain intensity) and affective(pain unpleasantness) thresholds were determined by methods of constant stimuli.

Results

The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.

Conclusions

These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should examine whether emotional allodynia is a result of or vulnerability for depression and the role it plays in the increased susceptibility for pain complaints in this disorder.     

Sex differences in nociceptive withdrawal reflex and pain perception

Experimentally induced pain often reveals sex differences, with higher pain sensitivity in females. The degree of differences has been shown to depend on the stimulation and assessment methods. Since sex differences in pain develop anywhere along the physiological and psychological components of the nociceptive system, we intended to compare the nociceptive flexion reflex (NFR) as a more physiological (spinal) aspect of pain procession to the verbal pain report of intensity and unpleasantness as the more psychological (cortical) aspect. Twenty female and twenty male healthy university students were investigated by use of nociceptive flexion reflex threshold (staircase method) after electrical stimulation of the N. suralis. Furthermore, we assessed supra-threshold reflex responses (latency, amplitude and area) by applying 10 stimuli 5 mA above reflex threshold. Following each stimulation, the subjects provided pain ratings of intensity and unpleasantness on a visual analogue scale. Females exhibited marked lower nociceptive flexion reflex thresholds than males, while the supra-threshold reflex response tailored to the individual reflex threshold did not show any significant differences. The verbal pain ratings, corrected for NFR threshold, were not found to differ significantly. The large sex differences in nociception that were present in NFR threshold but not in the pain ratings corroborate the hypothesis that spinal processes contribute substantially to sex differences in pain procession.     

Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels

Background

Formalin injection into rodent hind paws is one of the most commonly employed pain assays. The resulting nocifensive behaviors can be divided into two phases differing in timing, duration and underlying mechanisms. Spinal sensitization has long been felt to participate in the second phase of this response, although this sensitization is incompletely understood. By using correlative analysis between spinal gene expression and mouse strain-dependent intensity of late phase behavior, we hypothesized genes participating in variability of the response could be identified.

Results

Late phase formalin behavior scores among 10 inbred mouse strains were correlated with a spinal cord gene expression database constructed using expression arrays. Messenger RNA levels for several genes were highly correlated with the late phase behavioral responses. Most of these genes had already been implicated in mechanisms regulating pain and analgesia. One of the most strongly correlated genes, Mapk8 coding for c-Jun N-terminal kinase 1 (JNK1), was chosen for further analysis. Studies using additional strains of mice confirmed that spinal cord mRNA expression levels of Mapk8 followed the pattern predicted by strain-specific levels of formalin behavior. Interestingly, spinal cord JNK1 protein levels displayed an inverse relationship with mRNA measurements. Finally, intrathecal injections of the selective JNK inhibitor, SP600125, selectively reduced late phase licking behavior.

Conclusions

Wide differences in pain behaviors, including those resulting from the injection of formalin, can be observed in inbred strains of mice suggesting strong genetic influences. Correlating levels of gene expression in tissues established to be mechanistically implicated in the expression of specific behaviors can identify genes involved in the behaviors of interest. Comparing formalin late phase behavior levels with spinal cord gene expression yielded several plausible gene candidates, including the Mapk8 gene. Additional molecular and pharmacologic evidence confirmed a functional role for this gene in supporting formalin late phase responses.     

Barcoding human physical activity to assess chronic pain conditions

Background

Modern theories define chronic pain as a multidimensional experience – the result of complex interplay between physiological and psychological factors with significant impact on patients'' physical, emotional and social functioning. The development of reliable assessment tools capable of capturing the multidimensional impact of chronic pain has challenged the medical community for decades. A number of validated tools are currently used in clinical practice however they all rely on self-reporting and are therefore inherently subjective. In this study we show that a comprehensive analysis of physical activity (PA) under real life conditions may capture behavioral aspects that may reflect physical and emotional functioning.

Methodology

PA was monitored during five consecutive days in 60 chronic pain patients and 15 pain-free healthy subjects. To analyze the various aspects of pain-related activity behaviors we defined the concept of PA ‘barcoding’. The main idea was to combine different features of PA (type, intensity, duration) to define various PA states. The temporal sequence of different states was visualized as a ‘barcode’ which indicated that significant information about daily activity can be contained in the amount and variety of PA states, and in the temporal structure of sequence. This information was quantified using complementary measures such as structural complexity metrics (information and sample entropy, Lempel-Ziv complexity), time spent in PA states, and two composite scores, which integrate all measures. The reliability of these measures to characterize chronic pain conditions was assessed by comparing groups of subjects with clinically different pain intensity.

Conclusion

The defined measures of PA showed good discriminative features. The results suggest that significant information about pain-related functional limitations is captured by the structural complexity of PA barcodes, which decreases when the intensity of pain increases. We conclude that a comprehensive analysis of daily-life PA can provide an objective appraisal of the intensity of pain.     

Exposure to oscillating magnetic fields influences sensitivity to electrical stimuli. II. experiments on humans

To assess the effect of a magnetic treatment on pain perception, we compared the sensory threshold in 18 healthy volunteers. We determined the threshold by noninvasive electrical stimulation of the tooth pulp and skin before and after exposure to an altered magnetic field of low intensity and to a sham treatment. Five different parameters were recorded: the sensory and pain thresholds for the tooth and the sensory, pain, and tolerance thresholds for the skin. Two hours of exposure to a weak, oscillating magnetic field induced a significant decrease in three parameters (dental sensory and cutaneous pain and tolerance thresholds), whereas the other two parameters showed a similar tendency. When the same subjects were exposed to a sham treatment, only marginal, nonsignificant variations in all parameters were observed. These results represent the first piece of evidence that weak alterations of the magnetic field may induce hyperalgesia in humans. © 1995 Wiley-Liss, Inc.     

Effects of stimulus repetition rate on ABR threshold,amplitude and latency in neonatal and adult Mongolian gerbils

The ABR wave forms of 16-day-old and adult Mongolian gerbils were evoked by click stimuli presented at rates ranging from 1 to 80/sec. Wave I and wave IV thresholds were determined for each of 5 click rates. Amplitudes and latencies of waves I and IV were measured at each of 7 click rates and 3 intensity levels (15, 40 and 65 dB above threshold). Thresholds for waves I and IV in the adult gerbil and wave I in the 16 day gerbil were unaffected by changes in stimulus repetition rate. Neonatal wave IV thresholds were unaffected by click rate for rates below 25/sec but increased approximately 7 dB/decade increase in click rate when rate exceeded 25/sec. Increasing click rate produced greater reductions in ABR amplitude among neonates than adults for both waves I and IV. Decreases in amplitude due to increasing rate were independent of intensity level in both neonatal and adult subjects. Increasing rate produced similar increases in wave I latency among 16 day and adult subjects, but produced much greater increases in wave IV latency among neonates. Stimulus intensity level and click rate acted independently on wave I and wave IV latency in adult subjects and wave I latency in neonates. However, an interaction between rate and intensity was observed with respect to neonatal wave IV latency.     

The Effects of Space and Terrestrial Weather Factors on Arterial Stiffness and Endothelial Function in Humans

A differential evolution algorithm was used to detect the biotropic influence of geomagnetic activity on several parameters of human vascular tone. Studies of the characteristics of vascular tone in healthy volunteers showed that arterial stiffness and endothelial function, as well as blood pressure and heart rate, depend on the geomagnetic and, in most cases, weather conditions. The pulse wave velocity (PWV) was measured to characterize the arterial stiffness and was found to be the most sensitive to the effects of space weather parameters. The strength of the effect of geomagnetic activity was for the first time observed to depend on the configuration of terrestrial weather parameters. A linear correlation between the K index of geomagnetic activity and PWV was estimated at r =–0.44 (p = 0.0003), although the relationship was detectable exclusively in the case of certain terrestrial weather parameters. Endothelial dysfunction and the pulse-rate response to variations in geomagnetic activity implicated nitrogen monoxide in body adaptation to variations in geomagnetic activity.

     

Impaired social contacts with familiar anesthetized conspecific in CA3‐restricted brain‐derived neurotrophic factor knockout mice

Familiarity is conveyed by social cues and determines behaviors toward conspecifics. Here, we characterize a novel assay for social behaviors in mice—contacts with anesthetized conspecific—which eliminates reciprocal interactions, including intermale aggression and shows behaviors that are independent of the demonstrator's activity. During the initial 10 minutes (phase‐1), the wild‐type (WT) subjects contacted the anesthetized conspecifics vigorously regardless of familiarity. During the subsequent 80 minutes (phase‐2), however, they contacted more with familiar than unfamiliar conspecifics. We then applied this test to highly aggressive mice with a hippocampal CA3‐restricted knockout (KO) of brain‐derived neurotrophic factor (BDNF), in which aggression may mask other social behaviors. The KO mice showed less preference for contacting familiar conspecifics than did WT mice during phase‐2 but no differences during phase‐1. Among nonsocial behaviors, WT mice also spent less time eating in the presence of familiar than with unfamiliar conspecifics, which was not seen in KO mice. In addition, KO mice exhibited reduced pain sensitization. Altogether, these findings suggest that CA3‐specific deletion of BDNF results in deficits in circuits that process social cues from familiar conspecifics as well as pain and may underlie empathy‐like behaviors.     

Behaviors of mice given forced-swimming.

Behaviors of mice in the forced swimming test are motionlessness, climbing and the other stereotypical behaviors. We observed these behaviors in different ages and sex and in repeated forced swimming trials. The findings were 1) quantities of the climbing and the other behaviors were different with the age and sex, 2) repeated per day forced swimming remarkably increased motionlessness and motionlessness is memorized for at least 14 days, and 3) climbing is the typical opposite behavior of motionlessness and was related to adrenergic but not serotonergic neuronal activity. When these behaviors are recognized as adaptation behaviors, we conclude that mice given repeated forced swimming, but not mice given one trial of forced swimming, can be considered as a model of human depression relating to adrenaline neuronal activity.     

Peripheral Nerve Injury Is Associated with Chronic,Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.     

Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice

We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using "four core genotypes" C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3-4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In Experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In Experiment 2 (test of development of tolerance to morphine), mice were injected twice daily with 10 mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP (3-(2-carboxypiperazin-4yl) propyl-1-phosphonic acid) (10 mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10 mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In Experiment 3, mice were injected with morphine (10 mg/kg) or saline, 15 min before intraplantar injection of formalin (5%/25 microl). XX mice licked their hindpaw more than XY mice within 5 min of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.     

Reduced nociceptive responses in mice with alloxan induced hyperglycemia after garlic (Allium sativum Linn.) treatment.

Administration of ethanol (95%) extract (45 mg/kg body wt/day for 28 days) of garlic (A. sativum) to alloxan induced diabetic (ALX-D) mice significantly lowered the serum glucose levels, nociceptive response in tail-flick, hotplate, allodynia, formalin test and relative thickness, weight of hind paw in formalin induced Paw oedema test, over 28 days, thus, showing the reversal trend in hyperglycemia and hyperalgesia compared to ALX-D mice. The reversal of hyperglycemia and hyperalgesia was progressive and more effective as duration of extract administration increased. The results suggest therapeutic potential of ethanol extract of garlic for anti-hyperglycemic and anti-nociceptive effects in diabetes.