Anxiety-induced antinociception in mice: effects of systemic and intra-amygdala administration of 8-OH-DPAT and midazolam

Rationale: Mice exhibit antinociception after a single experience in the el evated plus maze (EPM), an animal model of anxiety. Objective: This study i nvestigated the mechanisms involved in this form of anxiety-induced antinoc iception. Methods: Nociception was evaluated by means of the writhing test in mice confined either to the open or enclosed arms of the EPM. The effect s of systemic (naloxone, midazolam and 8-OH-DPAT) or intra-amygdala (8-OH-D PAT. NAN-190 and midazolam) drug infusions were investigated in mice previo usly treated i.p. with 0.6% acetic acid, an algic stimulus that induces abd ominal contortions. The effects of these drugs on conventional measures of anxiety (% entries and % time in open arms) in a standard EPM test were als o independently investigated. Results: Open-arm confinement resulted in a h igh-magnitude antinociception (minimum 85%, maximum 450%) compared with enc losed arm confinement. The opiate antagonist naloxone (1 mg/kg and 10 mg/kg ) neither blocked this open arm-induced antinociception (OAIA) nor modified indices of anxiety in EPM. Administration of midazolam (0.5-2 mg/kg, s.c.) increased OAIA and produced antinociception in enclosed confined animals, as well as attenuating anxiety in the EPM. The 5-HT1A receptor agonist 8-OH -DPAT (0.05-1 mg/kg, s.c.) had biphasic effects on OAIA, antagonising the r esponse at the lowest dose and intensifying it at the highest dose. In addi tion, low doses of this agent reduced anxiety in the EPM. Although bilatera l injections of 8-OH-DPAT (5.6 nmol/0.4 mu l) or NAN-190 (5.6 nmol and 10 n mol/0.4 mu l) into the amygdala did not alter OAIA, increased anxiety was o bserved in the EPM. In contrast, intra-amygdala administration of midazolam (10 nmol and 30 nmol/0.4 mu l) blocked both OAIA and anxiety. Conclusions: These results with systemic and intracerebral drug infusion suggest that 5 -HT1A receptors localised in the amygdala are not involved in the pain inhi bitory processes that are "recruited" during aversive situations. However, activation of these receptors does phasically increase anxiety. Although th e intrinsic antinociceptive properties of systemically administered midazol am confounded interpretation of its effects on OAIA, intra-amygdala injecti ons of this compound suggest that benzodiazepine receptors in this brain re gion modulate both the antinociceptive and behavioural (anxiety) responses to the EPM.