Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice

Abstract

Aim: To investigate the effects of ATPM-ET -N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice. Methods: The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice. Results: The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ-and µ-opioid receptors with K i values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED 50 value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05). Conclusion: ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.

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

“…In the formalin test, MB-1C-OH also significantly inhibited formalininduced flinching behavior in the second phase. These results suggested that MB-1C-OH, a full κ-receptor agonist, produced potent antinociceptive effects and were similar to our previous findings [4,7,16] .…”

“…The hot plate test was performed according to the method we described previously [4,16] . Briefly, the hot plate temperature was set at 55 °C.…”

“…The acetic acid-induced writhing test was performed in mice according to our previously reported procedure [4,16] . Abdominal constriction was induced by the injection of 0.6% acetic acid (10 mL/kg, ip).…”

“…The tail-flick assay was performed according to our previously reported procedure [4,16] . Briefly, a beam of light was focused on the dorsal surface of the tail approximately 1-2 cm from the tip, and the amount of time that it took the mouse to withdraw its tail from the noxious stimulus was recorded.…”

“…Currently, most opioid analgesics, such as morphine, mainly induce analgesia via binding to the μ-opioid receptor, but they are also associated with a spectrum of undesirable side effects, such as physical dependence, respiratory depression, and constipation [2] . Numerous studies have demonstrated that drugs targeting κ-opioid receptor produced potent antinociception with less adverse and fewer addictive side effects than μ-opioid receptor agonists [3][4][5] . Endoh et al reported that TRK-820, a κ-opioid receptor agonist, was 68-to 328-fold more potent than (-)U50,488H, and 41-to 349-fold more potent than morphine in producing antinociception [6] .…”