Strain differences in mice antinociception: relationship between alprazolam and opioid receptor subtypes

This study was designed to investigate the antinociceptive effects of one of the most prescribed benzodiazepines (BZ) -i.e., alprazolam. Groups of CD-1, SWISS, BALB/c and C57BL mice were treated with alprazolam. Analgesia was assayed, using the radiant heat tailflick assay. Alprazolam given i.p. elicited analgesia in a dose-dependent manner only in the BALB/c mice (ED50 1.1 mg/kg). No analgesia was observed in CD-1 or C57BL mice. The sensitivity of SWISS mice was intermediate, but still very low. Intrathecally administered alprazolam elicited analgesia in BALB/c, Swiss and CD-1 mice with ED50 values of 10, 22.8 and 34.6 micrograms, respectively. No analgesia was observed in C57BL mice. Intracerebroventricular injections did not induce analgesia in any of the strains. In other sets of experiments with BALB/c mice, we found a supra-additivity increase in analgesia when a subthreshold dose of alprazolam was given with morphine (mu-subtype agonist). This interaction was antagonized by naloxone and less so by flumazenil. No effect was found when alprazolam was co-administered with other specific opioid agonists (delta and kappa). Our results demonstrate that injections of alprazolam can produce analgesia in different genetic subjects and can modify morphine-induced antinociception. The fact that the interaction between morphine and alprazolam analgesia was sensitive to naloxone but less to flumazenil indicates that the analgesic effects of alprazolam are mediated primarily by an opioid mechanism of action but less by benzodiazepines.