Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation

Abstract

Aim: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH.

Methods: [(3)H]diprenorphine binding and [(35)S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions.

Results: In [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to μ- and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H.

Conclusion: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Figure 1

Chemical structures of (−)U50,488H and MB-1C-OH.

Figure 2

Effects of pretreatment with nor-BNI, β-FNA, and naltrindole on MB-1C-OH-induced antinociception in the acetic acid-induced writhing assay. Mice were pretreated with the μ-opioid receptor antagonist, β-FNA (10 mg/kg, sc) 24 h before MB-1C-OH administration; the δ-opioid receptor antagonist, naltrindole (3.0 mg/kg, sc) 30 min before MB-1C-OH administration; or the selective κ-opioid receptor antagonist, nor-BNI (10 mg/kg, sc) 15 min before MB-1C-OH administration and then injected with MB-1C-OH (1.88 mg/kg, sc). Acetic acid solution was intraperitoneally injected 15 min after drug administration. The maximum possible effect (% MPE) was calculated as described in the Materials and methods section, and the number of times the mouse writhed is also shown. Data are presented as the mean±SEM from 10 animals. ^cP<0.01 compared with the control group.

Figure 3

MB-1C-OH-induced antinociceptive effects in the formalin test. The animals were pretreated with MB-1C-OH into subcutaneous. After 15 min, the animals were injected with formalin (20 μL/paw). The amount of time the mice spent licking or flinching during first phase and second phase was recorded. All data are expressed as the mean±SEM (at least five animals in each group). ^cP<0.01 compared with the vehicle group (one-way ANOVA with Dunnett's test).

Figure 4

The depressive effect of MB-1C-OH in the forced swimming test and the sedative effect of MB-1C-OH in the rotarod test. (A) Mice were administered (sc) saline, (−)U50,488H or MB-1C-OH. After 15 min, they were put singly into transparent Plexiglas cylinders containing water at a depth of 10 cm for 6 min. The immobility time was recorded during the final 4 min. Data for each group are presented as the mean±SEM from 5–12 animals. (B) Mice were subcutaneously administered various doses of MB-1C-OH. Then, 15 min later, mice were put singly on a rotarod for 300 s. The duration time before each mouse fell off the rotarod was recorded. Data for each group are presented as the mean±SEM from 10 animals.