A controlled, longitudinal study of dementia in Parkinson's disease.

Serial assessments of cognition, mood, and disability were carried out at nine month intervals over a 54 month period on a cohort of 87 patients with Parkinson's disease (PD) and a matched cohort of 50 control subjects. Dementia was diagnosed from data by rigorously applying DSM-III-R criteria. Initially, 6% (5/87) PD patients were demented, compared with none of the 50 control subjects. A further 10 PD patients met the dementia criteria during the follow up period; this was equivalent, with survival analysis, to a cumulative incidence of 19%. With the number of person years of observation as the denominator, the incidence was 47.6/1000 person years of observation. None of the control subjects fulfilled dementia criteria during the follow up period. The patients with PD who became demented during follow up were older at onset of Parkinson's disease than patients who did not become demented, had a longer duration of Parkinson's disease, and were older at inclusion to the study.

Highly potent inhibitory effects of 5-HT3 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-HT3 anxiolytic, GR38032F, on this form of adaptive inhibition of pain have been examined. The results showed that defeat analgesia was totally inhibited by 1 microgram/kg-1 mg/kg of GR38032F, with partial inhibition evident over the dose range of 0.0001-0.1 microgram/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-HT3 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.

Adaptive pain inhibition in murine resident-intruder interactions.

In dyadic encounters with aggressive resident conspecifics, male intruder mice display an initial acute nonopioid analgesia followed by a more enduring opioid analgesia. The former reaction occurs in association with active defense (flight or fight) and can be seen in response to the scent of an aggressive conspecific or defeat experience per se. In contrast, the latter (opioid) reaction is associated with passive defense (immobility) and occurs in response to extended conspecific attack. The mechanisms underlying these two ecologically-relevant forms of pain inhibition are contrasted and the phenomena are discussed in relation to the question of adaptive significance.

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.

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.

Social conflict analgesia: inhibition of early non-opioid component by diazepam or flumazepil fails to affect appearance of late opioid component.

Two forms of analgesia (opioid and non-opioid) are associated with social conflict in mice. The non-opioid form is seen in response to the scent of an aggressive conspecific or defeat experience, whilst the opioid form occurs in response to extended conspecific attack. Recently, it has been reported that the non-opioid reaction is dose-dependently blocked by diazepam and by Flumazepil (Ro15-1788; a benzodiazepine receptor antagonist). In view of the temporal relationship between these two reactions, the present study was conducted to determine whether activation of non-opioid substrates is a necessary precursor to the development of opioid analgesia. Results indicate that inhibition of non-opioid analgesia by diazepam (2-4 mg/kg), or by Flumazepil (20-40 mg/kg), does not alter the opioid analgesic reaction to conspecific attack. Findings are discussed in relation to the presumed adaptive significance of these biologically-meaningful forms 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.

Benzodiazepine ligands, nociception and 'defeat' analgesia in male mice.

Recent studies have indicated that defeat experience induces acute non-opioid analgesia in intruder mice. To investigate the potential involvement of benzodiazepine receptors in this biologically-relevant form of environmentally-induced antinociception, we initially assessed the effects of some benzodiazepine ligands on basal nociception (tail-flick assay). Chlordiazepoxide (5-30 mg/kg), midazolam (0.625-5 mg/kg), diazepam (0.5-4 mg/kg), Ro15-1788 (5-80 mg/kg) and CGS8216 (5 mg/kg) were found to be ineffective in altering basal nociception. However, higher doses of CGS8216 (10-20 mg/kg) induced significant analgesia, an effect also observed with the beta-carboline derivatives FG7142 (5-20 mg/kg) and DMCM (1-2 mg/kg). Time-course analyses revealed that the onset of CGS8216 analgesia was slower than for FG7142 and DMCM, but that all three drugs produced long-lasting elevations in tail-flick latencies. The analgesic effects of FG7142 and DMCM were completely reversed by Ro15-1788 (20 mg/kg) and by chlordiazepoxide (20 mg/kg), suggesting mediation by benzodiazepine receptor mechanisms. Although CGS8216 analgesia was also reversed by Ro15-1788, it was unaffected by chlordiazepoxide; however, diazepam (5 mg/kg) did significantly attenuate the reaction. Further studies indicated that the antinociceptive consequences of defeat experience were dose-dependently blocked by Ro15-1788 (10-40 mg/kg) and by diazepam (0.5-2 mg/kg). Surprisingly, however, neither chlordiazepoxide (5-20 mg/kg) nor midazolam (1.25-2.5 mg/kg) blocked "defeat" analgesia under present test conditions. Although several issues remain unresolved, present findings would not be inconsistent with the proposal that stimuli associated with the acute stress of defeat experience release an endogenous ligand which acts in an "inverse agonist-like" manner at benzodiazepine sites.

Resident's scent: a critical factor in acute analgesic reaction to defeat experience in male mice.

Although it has recently been reported that defeated male mice evidence an acute non-opioid analgesia, little is currently known about the specific features of the defeat experience with which the analgesic reaction is associated. The present experiments not only confirm that defeat experience reliably induces acute antinociception in intruder mice, but show that a similar reaction also occurs as a consequence of exposure to an aggressive resident which does not attack during the brief test period, a well-characterized non-aggressive resident and the 'unoccupied' soiled home cage of an aggressive resident. Results also indicated that, with appropriate exposure duration, scent alone can give rise to a quantitatively similar analgesia to that observed in defeated mice. Furthermore, time-course comparisons and the absence of naloxone antagonism suggest that 'scent' and 'defeat' analgesias are mediated via a common non-opioid mechanism. Data are discussed in relation to the ecological significance of urinary odours in social communication in mice.

Acute non-opioid analgesia in defeated male mice.

Exposure to repeated attack induces a long-lasting analgesia in male mice. Although this reaction has been linked to the special biological significance of defeat, earlier research has confounded defeat and exposure to further attack. In the present studies, DBA/2 intruder mice were individually placed into the home cages of aggressive conspecifics and removed immediately upon display of the species-characteristic upright submissive posture. Under these test conditions, intruders did indeed show a profound analgesia. However, in marked contrast to the antinociceptive effects of repeated attack, this reaction was of short duration (less than 10 min), was not blocked by naloxone (1-10 mg/kg, IP) and did not show cross-tolerance either to or from morphine (5 mg/kg, IP). These findings are discussed in relation to multiple endogenous pain inhibitory systems and their possible adaptive significance in murine social behaviour.

Extended attack from a resident conspecific is critical to the development of long-lasting analgesia in male intruder mice.

Recent studies have shown that intruder mice display qualitatively different forms of analgesia in response to social encounters with resident conspecifics. An acute (non-opioid) reaction is evident when display of defeat is used as test criterion whereas a much longer-lasting (opioid) response is observed when this criterion is exceeded. Neither reaction can be readily attributed to the effects of physical stimulation per se. Two studies were conducted to determine the critical stimulus leading to a 'switchover' from non-opioid to opioid analgesia in intruder mice. The pattern of results indicates that temporal factors per se are unimportant but that extended exposure to attack is essential to the development of an enduring (opioid-typical) analgesia. It is argued that this finding is consistent with the uncontrollability hypothesis which asserts that opioid analgesia is a consequence of a failure in behavioural coping strategies.

Social conflict analgesia: studies on naloxone antagonism and morphine cross-tolerance in male DBA/2 mice.

It has recently been reported that male mice exhibit pronounced analgesia in response to attack from aggressive conspecifics. Although several studies indicate that this reaction can be blocked by opiate antagonist pretreatment, unequivocal evidence of opioid involvement is very much more limited. In the present study, the phenomenon of conflict analgesia has been studied in male DBA/2 intruder mice following exposure to a criterion level of attack from aggressive BKW residents. Our findings indicate that this analgesia is blocked and reversed by naloxone unaltered by methyl naloxone, except at high doses (75 mg/kg) and fully cross-tolerant with morphine. This profile confirms and extends earlier findings with B6AF1 mice, indicating that the opioid mediation of this biologically-relevant form of environmental analgesia is not strain specific.