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 [(-)-3-N-Ethylaminothiazolo [5,4-b]-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.

Figure 1

Chemical structure of ATPM-ET.

Figure 2

Effects of ATPM-ET and (−)U50,488H on naloxone-precipitated jumping and body weight loss in mice treated chronically with morphine. Mice were treated with progressively increasing doses of either ATPM-ET or morphine alone or treated with progressively increasing doses of morphine concomitantly with ATPM-ET (0.1–2 mg/kg, subcutaneously) or (-)U50,488H (2 mg/kg, subcutaneously) for 5 days. Morphine withdrawal jumping and body weight loss were precipitated by naloxone (3 mg/kg, subcutaneously). (A) The number of jumping events was measured for 30 min after naloxone injection. (B) Body weight loss was measured initially and 30 and 60 min after the naloxone injection. Data were presented as the mean±SEM from 10 animals. ^bP<0.05, ^cP<0.01 vs morphine alone.

Figure 3

The induction of morphine sensitization in mice. Two groups were given morphine (10 mg/kg, subcutaneously) or saline (10 mL/kg, subcutaneously) for 7 consecutive days and their activity was measured for 1 h after each administration of drug (or saline) on days 1, 4, and 7. Data are shown as means±SEM. (n=10 per group). ^bP<0.05, ^cP<0.01 vs the corresponding saline group. ^eP<0.05, ^fP<0.01 vs the first administration group.

Figure 4

Effect of ATPM-ET on morphine-induced behavioral sensitization. Mice in the control group were given saline, and the other mice received morphine (10 mg/kg, subcutaneously) for 7 consecutive days. After a 7-d washout period, the mice were challenged with morphine (10 mg/kg, subcutaneously) 15 min after an injection of ATPM-ET (0.75, 1.5, 3 mg/kg, subcutaneously). The mice were then put into test chambers to measure their locomotor activity for 1 h. Data are presented as means±SEM (n=10 per group). ^cP<0.01 vs saline group. ^eP<0.05 vs morphine sensitized/saline group.