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.