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HS-599 is a didehydroderivative of buprenorphine that displays high affinity and good selectivity for μ-opioid receptors. We studied its antinociceptive properties after s.c. injection in mice with the tail-flick and hot-plate tests. In the tail-flick test HS-599 (AD50=0.2801 μmol/kg s.c.) behaved as a full agonist and was twice as potent as buprenorphine (AD50=0.4569 μmol/kg s.c.) and 50 times more potent than morphine (AD50=13.3012 μmol/kg s.c.). Whereas the μ-opioid receptor antagonists naloxone (1–10 mg/kg s.c.) and naltrexone (5–15 mg/kg s.c.) antagonized HS-599 induced analgesia, the δ-opioid receptor antagonist naltrindole (20 mg/kg s.c.) and the κ-opioid receptor antagonist nor-binaltorphimine (20 mg/kg s.c.) did not. With the hot-plate test at 50 °C, HS-599 (AD50=0.0359 μmol/kg s.c.) was a full agonist about 130 times more potent than morphine (AD50=4.8553 μmol/kg s.c.). With a high intensity nociceptive stimulus (55 °C) HS-599 (AD50=1.0382 μmol/kg s.c.) remained 7 times more potent than morphine (AD50=7.0210 μmol/kg s.c.) but never exceeded the 55% of the maximum possible effect, behaving as a partial agonist able to antagonize morphine antinociception in a dose-dependent manner. HS-599 promises to be a potent and safe new analgesic, preferentially acting at spinal level. [Copyright &y& Elsevier]

We have studied the possible interaction between three selective opioid-receptor antagonists, nor-binaltorphimine (NB: κ) (5 mg/kg), cyprodime (CY: μ) (10 mg/kg) and naltrindole (NTI: δ) (1 mg/kg), and the cannabinoid receptor agonist CP 55,940, in the modulation of anxiety (plus-maze) and adrenocortical activity (serum corticosterone levels by radioimmunoassay) in male rats. The holeboard was used to evaluate motor activity and directed exploration. CP 55,940 (75 μg/kg, but not 10 μg/kg) induced an anxiogenic-like effect, which was antagonised by NB. The other effects of CP 55,940 (75 μg/kg), a decreased holeboard activity and stimulation of adrenocortical activity, were not antagonised by any of the three opioid receptor antagonists. CY and NTI, when administered alone, induced marked reductions in motor activity, anxiogenic-like effects and stimulation of adrenocortical activity. The selective κ-opioid receptor antagonist NB, on its own, did not modify the level of anxiety but stimulated adrenocortical activity. We provide the first pharmacological evidence about the involvement of the κ-opioid receptor in the anxiogenic-like effect of CP 55,940. [Copyright &y& Elsevier]