Defeat Analgesia Research Articles

Effects of acute social defeat on activity in the forced swim test: Parametric studies in DBA/2 mice using a novel measurement device

In the early stages of an agonistic encounter between mice, the loser of the conflict initially exhibits pronounced flight and escape attempts. When exposure to attack is prolonged, however, defeated mice display a decrease in these active defenses and become increasingly passive. The generality of such defeat-induced passivity was investigated in the present study by examining acutely defeated mice in the forced swim test, a nonsocial but threatening environment that normally engenders high levels of escape behavior. In the present experimental model, highly aggressive male C57BL/6 mice were used to defeat smaller male intruders of the DBA/2 strain in a series of brief (2-min) encounters spaced 2 min apart. In Experiment 1, DBA/2 mice were administered four defeat encounters and were then given a 10-min swim test following a postdefeat delay of 0, 30, or 60 min. Activity in the swim test was determined both by a novel, automated device that detected movement-induced perturbations in the water medium via infrared beam interruptions and by the standard observational measurement of percent time immobile. Both activity measures indicated a significant suppression effect of defeat on swim activity, the magnitude of which declined steadily as the delay between the defeat encounters and the swim test increased. In Experiment 2, DBA/2 mice experienced zero, one, two, three, or four defeat encounters spaced 2 min apart and were administered the swim test 30 min following the last defeat encounter. Activity in the swim test decreased as the number of defeat encounters increased. The present findings suggest that defeat-induced passivity in mice is of a global nature, persisting in other threatening environments in which high levels of escape activity would normally be observed. Similarities between the parameters of the present phenomenon and those of opioid-mediated defeat analgesia are discussed. Aggr. Behav. 24:257–269, 1998. © 1998 Wiley-Liss, Inc.

Effects of acute social defeat on activity in the forced swim test: Parametric studies in DBA/2 mice using a novel measurement device

In the early stages of an agonistic encounter between mice, the loser of the conflict initially exhibits pronounced flight and escape attempts. When exposure to attack is prolonged, however, defeated mice display a decrease in these active defenses and become increasingly passive. The generality of such defeat-induced passivity was investigated in the present study by examining acutely defeated mice in the forced swim test, a nonsocial but threatening environment that normally engenders high levels of escape behavior. In the present experimental model, highly aggressive male C57BL/6 mice were used to defeat smaller male intruders of the DBA/2 strain in a series of brief (2-min) encounters spaced 2 min apart. In Experiment 1, DBA/2 mice were administered four defeat encounters and were then given a 10-min swim test following a postdefeat delay of 0, 30, or 60 min. Activity in the swim test was determined both by a novel, automated device that detected movement-induced perturbations in the water medium via infrared beam interruptions and by the standard observational measurement of percent time immobile. Both activity measures indicated a significant suppression effect of defeat on swim activity, the magnitude of which declined steadily as the delay between the defeat encounters and the swim test increased. In Experiment 2, DBA/2 mice experienced zero, one, two, three, or four defeat encounters spaced 2 min apart and were administered the swim test 30 min following the last defeat encounter. Activity in the swim test decreased as the number of defeat encounters increased. The present findings suggest that defeat-induced passivity in mice is of a global nature, persisting in other threatening environments in which high levels of escape activity would normally be observed. Similarities between the parameters of the present phenomenon and those of opioid-mediated defeat analgesia are discussed. Aggr. Behav. 24:257–269, 1998. © 1998 Wiley-Liss, Inc.

Neuropharmacological aspects of adaptive pain inhibition in murine “victims” of aggression

This review outlines recent research on a subset of physiological responses in murine “victims” or aggression. In a typical resident-intruder paradigm, the detailed study of intruders has revealed that exposure to conspecific attack (and related stimuli) is associated with two forms of analgesia which appear to be integral components of the murine defensive repertoire. In response to intense/enduring attack, intruder mice display a profound, long-lasting and opioid-mediated analgesia. This reaction is highly correlated with defensive immobility and may function to reduce involuntary cues to further attack. In contrast, the inhibition of pain reactivity in mice tested immediately upon the display of defeat is less intense, shorter-lasting, non-opioid in nature and may function to facilitate active defenses such as escape. As this form of pain inhibition is also evident in intruders exposed to the scent of an aggressive male conspecific, a possible anticipatory defensive function linked to mechanisms of anxiety has been proposed. This hypothesis is supported by 1) the prevention of defeat analgesia by a range of antianxiety drugs (benzodiazepines, 5-hydroxytryptamine1A [5-HT1A] receptor agonists, and 5-HT3 receptor antagonists) and 2) the effects of social defeat on behavior in the elevated plusmaze model of anxiety. These findings are discussed in relation to coping mechanisms in murine “victims” of aggression. © 1995 Wiley-Liss, Inc.

Anxiety enhancement in the murine elevated plus maze by immediate prior exposure to social stressors

Anxiety has been implicated in the acute nonopioid analgesic reaction seen in defeated mice. In the present study, behavioural responses to the elevated plus-maze test were examined in male DBA/2 mice immediately following defeat by an experienced aggressive conspecific. Compared to home-cage controls, defeat reduced total arm entries and rearing, although anxiety enhancement was indicated by decreases in percent open-arm entries and percent time spent on the open arms. These effects were accompanied by significant increases in nonexploratory behaviour (movement arrest and grooming) and risk assessment (closed arm returns, protected head dipping, and stretch-attend postures). This anxiogenic effect of social defeat was partially replicated in mice merely exposed to the scent of an aggressive male conspecific. The specificity of present findings to socially relevant stressors was confirmed by the general lack of effect on plus-maze behaviour of prior exposure to a novel cage or to interaction with a nonaggressive male. Present results are not only consistent with the anxiety hypothesis of defeat analgesia but also show that the elevated plus-maze test is sensitive to alterations in anxiety produced by ecologically relevant stimuli. Possible implications for pharmacological studies are discussed.

Antinociceptive effects of elevated plus-maze exposure: influence of opiate receptor manipulations

It has been suggested that anxiety may be a critical factor in certain forms of non-opioid environmental analgesia. In the present study, 5-min exposure to the elevated plus-maze test of anxiety (EPM) induced a mild, though enduring, elevation in tail-flick latencies in male mice. Pretreatment with the opiate antagonist naltrexone (0.1-10.0 mg/kg) failed to block EPM-induced antinociception: indeed, the highest dose actually enhanced the response. This effect could not be attributed to intrinsic analgetic activity of naltrexone. Rather, analysis of EPM behaviours suggested that it may have been secondary to an anxiogenic effect of the compound. The involvement of non-opioid substrates in the form of pain inhibition was further supported by the failure of chronic morphine treatment (7 days; 7.5 mg/kg) to alter either the antinociceptive or behavioural response to EPM exposure. Irrespective of treatment history, mice showed a retest EPM profile of enhanced anxiety, with tail-flick data suggesting a major contribution of anticipatory factors. Several important methodological variables are discussed and findings are contrasted with parallel studies on non-opioid defeat analgesia.

Stereospecific inhibition of non-opioid defeat analgesia in male mice by MDL 72832, a selective 5-HT 1A receptor agonist

The effects of MDL 72832, a potent and stereoselective ligand for 5-HT 1A sites, on basal nociception and non-opioid defeat analgesia in male mice were examined. Neither (+)- nor (−)-MDL 72832 significantly altered basal tail-flick latencies. In contrast, (−)-MDL 72832 potently inhibited defeat analgesia (0.1–0.5 mg/kg i.p.), with similar effects produced by (+)-MDL 72832 only at substantially higher doses (3.0–5.0 mg/kg i.p.). These data clearly demonstrate a stereoselective action of this 5-HT 1A ligand on non-opioid defeat analgesia.

Highly potent inhibitory effects of 5-HT 3 receptor antagonist, GR38032F, on non-opioid defeat analgesia in male mice

Behavioural and pharmacological evidence indicates that non-opioid analgesia in defeated male mice is initiated by anxiety and that serotongergic (5-HT) substrates are implicated. In the present study, the effects of the novel putative 5-HT 3, anxiolytic, GR38032F, on this form of adaptive inhibition of pain have been examined. The results showed that defeat analgesia was totally inhibited by 1 μg/kg-1 mg/kg of GR38032F, with partial inhibition evident over the dose range of 0.0001–0.1 μg/kg and loss of efficacy at smaller doses. These highly potent effects of GR38032F are consistent with its anxiolytic profile in animal models and cannot be accounted for by indirect actions on basal nociception. These findings point to a potentially important modulatory role for 5-HT 3 receptor mechanisms in defeat analgesia and, more generally, provide further evidence for the involvement of 5-HT in the mediation of non-opioid forms of environmentally-induced antinociception.

Prevention of the analgesic consequences of social defeat in male mice by 5-HT1A anxiolytics, buspirone, gepirone and ipsapirone.

Behavioural and pharmacological studies have suggested that anxiety may be an important factor in the initiation of non-opioid analgesia in defeated male mice. In the present study, the effects of three 5-HT1A anxiolytics (buspirone, ipsapirone and gepirone) on basal nociception and defeat analgesia were examined. Results show that the analgesic consequences of social defeat were potently blocked by all three compounds, with a rank-order potency (minimum effective doses) of ipsapirone (0.05 mg/kg) greater than gepirone (0.1 mg/kg) greater than buspirone (0.5 mg/kg). These inhibitory effects on defeat analgesia were observed in the absence of intrinsic activity on basal nociception (tail-flick assay). When administered alone, (-)pindolol produced biphasic effects on defeat analgesia with enhancement at 0.5 mg/kg and inhibition at 5.0 mg/kg. Lower doses of (-)pindolol (0.05 and 0.25 mg/kg) which did not affect defeat analgesia when administered alone, totally blocked the inhibitory effects of ipsapirone (0.5 mg/kg). Data are discussed in relation to the involvement of 5-HT1A receptor mechanisms in this adaptive form of pain inhibition.

5HT1A agonist, 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT), inhibits non-opioid analgesia in defeated mice: influence of route of administration

Recent studies have suggested that anxiety may be an important factor in the non-opioid analgesic response to defeat in muroid rodents. In the present study, we have examined the influence of the 5-HT1A receptor agonist, 8-OH-DPAT, on basal nociception and defeat analgesia in male DBA/2 mice. Our results show that, while devoid of intrinsic activity on the mouse tail-flick assay, 8-OH-DPAT blocks the analgetic consequences of defeat. A ten-fold potency differential was observed as a function of route of injection, with minimum effective doses of 0.1 and 1.0 mg/kg for subcutaneous and intraperitoneal administration, respectively. Although further studies are required, these preliminary data support 5-HT1A receptor involvement in the mediation of this form of adaptive pain inhibition.

Blockade of non-opioid analgesia in intruder mice by selective neuronal and non-neuronal benzodiazepine recognition site ligands.

In male mice, the biologically significant experience of social defeat is associated with an acute non-opioid form of analgesia. Recent studies have shown that this reaction is sensitive to certain benzodiazepine receptor ligands but is unaffected by others. The present experiments were designed to assess the possibility that activity at "non-neuronal" benzodiazepine binding sites might account for this unusual pharmacological profile. Our results show that defeat analgesia was blocked by clonazepam (0.06-3 mg/kg), Ro05-4864 (2.5-20 mg/kg), Ro05-5115 (20 mg/kg), PK11195 (5-20 mg/kg) and PK14067 (10-20 mg/kg). Furthermore, when given in combination, subthreshold doses of PK11195 (2.5 mg/kg) and clonazepam (0.03 mg/kg) totally prevented defeat analgesia. All of these effects were observed in the absence of intrinsic activity on basal nociception. Together with earlier findings, current data imply that inhibition of defeat analgesia by ligands for neuronal and/or non-neuronal benzodiazepine recognition sites is most probably unrelated to their activity at these sites. Alternative explanations for the overall patterns of results are considered.

Effects of an endogenous anxiolytic adrenal steroid, alpha-THDOC, on non-opioid defeat analgesia in male mice: interaction with Ro15-1788

The effects of the putative anxiolytic adrenal steroid, 3α, 5α-tetrahydro deoxycorticosterone (α-THDOC), on non-opioid defeat analgesia in male mice were examined. Although devoid of intrinsic activity on the tail-flick assay, 5 mg/kg α-THDOC was found to significantly attenuate the analgesic consequences of defeat experience; lower (2.5 mg/kg) and higher (10-20 mg/kg) doses were ineffective. The β-isomer of THDOC also significantly reduced defeat analgesia, but only at the highest dose tested (20 mg/kg). Control experiments demonstrated that 5 per cent ethanol, which was employed as a vehicle for the steroids, was without effect per se on basal nociception and, over the limited dose range of 5-10 per cent, did not alter defeat analgesia. Finally, the benzodiazepine receptor antagonist, Ro15-1788 (5 mg/kg) failed to influence the inhibitory effects of either THDOC isomer. Results are discussed in relation to the potential modulation of this form of adaptive pain inhibition by adrenal steroids which influence the GABA receptor-coupled chloride ionophore.

Potent inhibition of non-opioid defeat analgesia in male mice by benzodiazepine antagonist Ro15-3505

In male mice, defeat in social encounters is associated with an acute non-opioid analgesia, a reaction that may also be seen in response to the scent of a territorial conspecific. As this form of pain inhibition is blocked by diazepam and Ro15-1788, benzodiazepine receptor mediation has been proposed. To further test this hypothesis, the effects of a novel benzodiazepine receptor antagonist (Ro15-3505; 0.625–20 mg/kg) on basal nociception and defeat analgesia have been examined. Results show that, although devoid of intrinsic activity on the mouse tail-flick assay, Ro15-3505 totally blocks the analgesic consequences of defeat at doses above 1.25 mg/kg. Despite certain inconsistencies in the literature, present data provide further support for benzodiazepine receptor mediation of this ecologically-relevant form of pain inhibition.

Are the analgesic effects of social defeat mediated by benzodiazepine receptors?

Social conflict in mice is associated with at least two forms of analgesia. A long-lasting opioid reaction is evident in intruder mice exposed to prolonged attack, whilst an acute non-opioid analgesia is seen in response to either defeat experience per se or the territorial scent-marking of an aggressive conspecific. Recent work from this laboratory has suggested that the non-opioid analgesic reaction to defeat experience may be mediated via benzodiazepine receptor mechanisms. The present studies were designed to further test this tentative hypothesis. Results confirmed that defeat analgesia is dose-dependently blocked by Ro15-1788 (20–40 mg/kg) and diazepam (2–4 mg/kg), and also indicated partial antagonism of the reaction by CGS8216 (2.5 mg/kg). The partial agonists CGS9896 (2.5–20 mg/kg) and ZK91296 (2.5–20 mg/kg) were ineffective in blocking the reaction, a finding also obtained with the full agonist ZK93423 (0.05–10 mg/kg). However, the antagonist/weak inverse agonist ZK93426 was found to possess significant intrinsic analgesic activity (10 mg/kg) and to enhance defeat analgesia (5–10 mg/kg). Although several interpretative frameworks for the current pharmacological profile are considered, it is concluded that full clarification of the substrates of defeat analgesia must await further investigations.