Bert Siegfried

Isolation-induced locomotor hyperactivity and hypoalgesia in rats are prevented by handling and reversed by resocialization

Differences in locomotor activity in the open field were found between individually and group-housed rats (isol greater than soc). Daily handling, initiated at postnatal day 1, was without effect in group-housed rats but prevented the isolation-induced hyperactivity. For tail-flick latency, strikingly similar differences (isol greater than soc; prevention by handling) have been observed. The isolation-induced aberrations in both locomotor reactivity in a novel environment and in pain sensitivity could be reversed by subsequent resocialization. This indicates that the altered sensitivities to external stimuli are caused by the environmental manipulation.

Defeat, learned submissiveness, and analgesia in mice: effect of genotype

Defeat-induced unconditioned and conditioned behaviors of C57BL/6 and DBA/2 mice were assessed in a social-learning paradigm. Upon bites, mice of the DBA strain reacted with significantly more escape reactions, while C57 mice showed more immobility, crouch, and defensive sideways and upright postures. Clear genotype-dependent patterns were also evident from the conditioned responses recorded 24 h after defeat. DBA mice displayed more escape and defensive sideways and upright postures upon contact with a nonaggressive partner mouse; in contrast, C57 mice reacted with more immobility and crouch. With an increasing number of bites the sum of learned responses increased in C57 mice while it decreased in mice of the DBA strain. This decrement was paralleled by an increase in the analgesic response measured on the hot plate in defeated DBA mice. The possible role of endogenous opioids in the genotype-dependent interaction of defeat-induced learned submissiveness and analgesia is discussed.

Opioids and behavior: genetic aspects

Three animal models, based on genetic differences in endogenous opioid peptides and opioid receptors, are described. Obese mice and rats, whose pituitary opioid content is elevated, may be used to investigate eating disorders. Recombinant inbred strains of mice, which differ in brain opioid receptors and analgesic responsiveness, can be used for study of opioid-and nonopioid-mediated mechanisms of pain inhibition. Individual reactivity to opioids can be examined in C57BL/6 and DBA/2 inbred strains of mice. A model that combines a variety of opioid effects is offered and suggests the existence of a genetically determined dissociation of opioid effects on locomotor activity and pain inhibition. In addition, stimulatory locomotor responses in the C57BL/6 reaction type are linked to a high risk of drug addiction and facilitatory effects on adaptive processes, while high analgesic potency in the DBA/2 reaction type is accompanied by a low proneness to drug abuse and amnesic properties of opioids.

Exposure to novelty induces naltrexone-reversible analgesia in rats.

The exposure of rats for 2 min to an open field, to a small box, or to inhibitory avoidance training in the small box was followed by a mild analgesia measured by the tail-flick method. The analgesia was observed as soon as 10 s after the exposure and lasted between 10 and 30 min. It was not observed in animals previously made familiar with the test situation, and it was reversed by the administration of naltrexone (0.1 mg/kg). The data suggest that novelty per se is a sufficient stimulus to activate an opioid-mediated analgesic stimulus.

An ethological model for the study of activation and interaction of pain, memory and defensive systems in the attacked mouse. Role of endogenous opioids

The present work reviews neurochemical, physiological and behavioral data recorded from the attacked mouse and integrates them into a model of coping mechanisms during social conflict. More specifically, the possible relationships between systems of pain, memory and defense are presented, with special emphasis on the role of endogenous opioid peptides (EOPs). In recipients of attack, decreased beta-endorphin-like immunoreactivity and changes in opiate and benzodiazepine binding characteristics are found in structures of the brain defensive system. EOPs mediate the social conflict-induced increase of dopamine synthesis in the periaqueductal grey and frontal cortex. Social conflict analgesia in attacked mice is under the control of central opioid and nonopioid (e.g., benzodiazepine, glutamate) mechanisms, and is modified by experience (e.g., long-term analgesic reaction; tolerance). EOPs and pain-inhibitory mechanisms participate in the organization of behavioral defense, recuperative behavior and the memory of attack experience. The data are considered in relation to the perceptual-defensive-recuperative model of fear and pain, forwarded by Bolles and Fanselow.

Effects of isolation on activity, reactivity, excitability and aggressive behavior in two inbred strains of mice

In order to investigate mechanisms of isolation-induced aggressive behaviour, inbred mice of the C57BL/6 and DBA/2 strains were individually housed over a period of 8 weeks. In the DBA/2 strain only, isolation was followed by a clear increase in activity (Animex), reactivity (reactions upon tactile body stimulation), excitability (duration of EEG desynchronization elicited by tactile stimulation of the thorax area under urethane anesthesia) and intermale aggression (biting and fighting responses). The use of inbred strains of mice proved to be a useful tool for the examination of the relationship between various parameters. It is concluded that there are no clear correlations between activity, reactivity and aggressive behavior and that the resulting aggressive responses in the DBA/2 strain are likely due to the increase of excitability.

NMDA receptor blockade in the periaqueductal grey prevents stress-induced analgesia in attacked mice

Microinjections of N-methyl-D-aspartate (NMDA, 0.1 and 1.0 nmol) into the periaqueductal grey (PAG) of the mouse resulted in potential antinociception. In a social conflict situation, attacked mice exhibited a marked analgesia that was prevented by prior injection of the competitive NMDA antagonist, AP-7 (2.0 nmol) or naloxone (6.0 nmol) into the PAG and also by i.p. injection of the non-competitive NMDA antagonist, MK-801 (33 nmol). These results demonstrate that NMDA receptors are involved in endogenous analgesic mechanisms activated by stress.

Learning of submissive behavior in mice: A new model

The experience of winning or loosing fights plays an important role in subsequent aggressive or submissive behaviors. In this study agonistic behavior of male mice was chosen to investigate learning mechanisms in the context of a biologically meaningful situation. An ICR mouse introduced into a group of five C57BL/6 mice was attacked by mice of high social status (Fighter, F), but not by lower ranking animals (Non-Fighter, NF). On this basis the following model was developed to study learning of submissive behavior. Day 1 (baseline trial): An ICR mouse was introduced to a single NF-C57 mouse. Few submissive behaviors (crouch) were observed in naive ICR mice upon contact with NF-C57 mice. Day 2 (learning trial): The same ICR mouse was defeated by an F-C57 mouse until it showed defensive upright posture upon approach. This criterion was reached after a mean latency of 3.5 min and after being exposed to a mean number of 14 bites. Day 3 (retest trial): The same pairs as on day 1 confronted each other. Without being attacked, the ICR mouse showed a significant increase of submissive behavior (crouch, defensive sideways and upright) upon mere contact with the NF-C57 mouse when compared to day 1 and to control mice on day 3. Controls, confronted on all three days with NF-C57 mice, showed no increase in submissive behaviors. The results are discussed in terms of acquisition, memory, retrieval and extinction of learned submissive behavior. It is suggested that the mechanisms underlying learning of submissive behavior include generalization of conditioning and specific extinction processes. The further use of the learning scheme to assess drug effects is illustrated.

Social conflict-induced changes in nociception and β-endorphin-like immunoreactivity in pituitary and discrete brain areas of C57BL/6 and DBA/2 mice

The present study characterizes the time course of social conflict analgesia and its reversibility by opioid antagonist drugs in the C57BL/6 and DBA/2 inbred strains of mice and examines the relationship between alterations in brain and pituitary levels of beta-endorphin-like immunoreactivity (beta-ELIR) and the antinociception elicited by social stress. Data revealed statistically significant strain differences in regard to beta-ELIR in control animals. The pituitary content of beta-ELIR was higher in DBA/2, while the values in the periaqueductal grey (PAG) and in the amygdala were higher in C57BL/6 mice. No interstrain differences were found in the hypothalamus. Exposure to 50 attack bites resulted in a 6-fold higher analgesia in DBA/2 mice and in a strain-independent fall of beta-ELIR in pituitary (approximately 27%) and PAG (23%). PAG but not pituitary beta-ELIR levels in C57BL/6 mice correlated positively with the increase in tail-flick latency after attack. Mere confrontation with a non-aggressive opponent failed to induce analgesia and was associated in C57BL/6 mice with a significant reduction in the beta-ELIR content of both the pituitary and the PAG. The data are discussed in terms of genotype-dependent sensitivity of the beta-endorphin system to stress and its relation to analgesia.

Inhibition of morphine-induced analgesia and locomotor activity in strains of mice: A comparison of long-acting opiate antagonists

The long-acting opiate antagonistic potency of naloxazone (NXZ), beta-chlornaltrexamine (beta-CNA) and beta-funaltrexamine (beta-FNA) was compared using three inbred strains of mice, in which morphine induces either analgesia (DBA/2), locomotion (C57BL/6), or both responses (C3H/He). The antagonists were applied SC 24-120 hr before morphine (10 or 20 mg/kg, IP), followed by the tests after 30 min. The minimal dose which completely antagonized morphine-induced analgesia in DBA and locomotion in C57 mice during 24 hr were: for NXZ 50 and 100 mg/kg, for beta-CNA 0.8 and 6.2 mg/kg, for beta-FNA 1.6 and 12.5 mg/kg, respectively. beta-FNA and beta-CNA more potently blocked morphine-induced analgesia in DBA mice than the activity response in the C57 strain. In contrast, beta-FNA prevented morphine-induced locomotion at a lower dose (6.2 mg/kg) than analgesia (greater than 50 mg/kg) in C3H mice, while beta-CNA was equipotent (1.6 mg/kg). In general, beta-CNA turned out to be the most reactive compound, antagonizing morphine effects in low doses up to 120 hr. beta-FNA selectively antagonized either morphine-induced analgesia or locomotion, depending on the strain used. This suggests that a given morphine response might be caused by a genetically determined multiplicity of opiate receptor types and their mutual interactions.