Antagonistic effects of naloxone and naloxonazine on sufentanil-induced antinociception and respiratory depression in rats.

Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially binds to the high affinity micro(1) sites, is often used to discriminate between pharmacological effects mediated by micro(1) and micro(2) binding sites. The present series of experiments were undertaken to compare the opioid antagonistic properties of naloxonazine and naloxone (NLX) (a non-selective micro(1)-antagonist) on intravenous (i.v.) and intrathecal (i.t.) sufentanil (SUF)-induced antinociception and respiratory depression. The opioid antagonists were given either intravenously at 5 min after SUF, or subcutaneously (s.c.) 24 h prior to the opioid. Intravenous NLX and NLZ reduced the i.v. and i. t. SUF-induced antinociception, hypercapnia and hypoxia when given directly after the opioid. There were no major differences in activity between both antagonists. Pretreatment with 30 mg/kg NLX did not reverse the i.v. or i.t. SUF-induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg NLX only partially antagonized the i.v. SUF-induced antinociception, while a complete reversal was present of the opioid-induced hypercapnia and hypoxia. With regard to i.t. SUF, doses up to 30 mg/kg NLZ were unable to reduce the antinociception. The respiratory depression was partially affected; with 30 mg/kg NLZ, the i.t. SUF-induced hypercapnia returned to baseline levels, whereas the SUF-induced hypoxia was only minimally affected. These results challenge the classical view of the selectivity of NLZ for the high affinity micro(1) binding sites. They further fail to conform an exclusive role for micro(2) receptor sites in the respiratory depression and spinal analgesia induced by a strong lipophilic opioid such as SUF in rats.