AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence

Abstract

Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4-6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence.

Keywords: AMPA; Morphine; Opioid dependence; Opioid tolerance; Positive allosteric modulator.

Copyright © 2018. Published by Elsevier Ltd.

Figures

Figure 1.. Effects of aniracetam in preventing acute opioid tolerance (A) and dependence (B).

Groups of eight mice were treated with aniracetam (5, 16, 50 mg/kg, i.p.) or saline (equal volume, i.p.) 30 minutes before administration of morphine (100 mg/kg, s.c.). Control mice received equal amount of saline (s.c.) instead of morphine. Opioid tolerance was monitored by significantly reduced antinociception induced by a test dose morphine (10 mg/kg, s.c.) 4.5 h later using the tail-flick test. Opioid dependence was tested by recording the number of naloxone-precipitated withdrawal jumps in 15 min. (A) Aniracetam at higher doses (16, 50 mg/kg, i.p.) significantly prevented the loss of morphine antinociception and reduced the development of acute opioid tolerance. EC50 was estimated from the dose response curve. (B) Aniracetam at all doses only displays partial effects in preventing opioid dependence. Data are expressed as the mean ± S.E.M. *P<0.05; ***P<0.001 compared with saline group; ###P<0.001 compared with morphine alone group.

Figure 2.. Effects of aniracetam on basal nociception (A), morphine antinociception (B) and locomotor activity (C).

(A) Groups of mice received (i.p.) aniracetam (50 mg/kg) or equal volume of saline. The tail-flick test was carried out 0.5, 1, 2 and 4 h after the drug treatment. Aniracetam (50 mg/kg, i.p.) has no effect on basal nociception in mice. (B) Mice received aniracetam (50 mg/kg, i.p.) or saline 30 min before morphine (1, 3, 10 mg/kg, s.c.). Aniracetam did not interfere with the antinociceptive effects produced by morphine. (C) Mice locomotor activity was measured by the rotarod test, in which the latencies to fall from a rotation rod were recorded. Aniracetam (50 mg/kg, i.p.) did not impair the locomotor function of mice. Data are expressed as the mean ± S.E.M.

Figure 3.. Effects of aniracetam in reversing acute opioid (A) tolerance and (B) dependence.

Separate groups of eight mice were treated with morphine (100 mg/kg, s.c.) to develop acute opioid tolerance and dependence. Aniracetam (5, 16, 50 mg/kg, i.p.) was administered 30 min before the test dose of morphine (10 mg/kg, s.c.). (A) Aniracetam (50 mg/kg, i.p.) significantly restored the antinociceptive effect of morphine. Lower doses of aniracetam (5, 16 mg/kg, i.p.) have partial effects on reducing acute opioid tolerance. EC50 was calculated based on the dose response curve. (B) Aniracetam (5, 16, 50 mg/kg, i.p.) partially reduced acute opioid dependence. Data are expressed as the mean ± S.E.M. *P<0.05; **P<0.01; ***P<0.001 compared with saline group; ##P<0.01 compared with morphine alone group.

Figure 4.. Reversal of chronic opioid (A) tolerance and (B) dependence by aniracetam.

Groups of eight mice were treated with morphine (10 mg/kg, s.c.) twice a day for 5 days to produce chronic opioid tolerance and dependence. Control group mice received equal numbers and volume of saline injections. Opioid tolerance and dependence were assessed on day 6 using the method described above. Aniracetam (10, 50, 100 mg/kg, i.p.) were given acutely to mice 30 min before the test dose of morphine on day 6. (A) Aniracetam dose-dependently restored morphine antinociception and reduced opioid tolerance. EC50 was estimated from the dose response curve. (B) Aniracetam at dose of 100 mg/kg significantly reduced naloxone-precipitated withdraw jumps and blocked opioid dependence. Data are expressed as the mean ± S.E.M. **P<0.01; ***P<0.001 compared with saline group; #P<0.05; ##P<0.01; ###P<0.001 compared with morphine alone group.

Figure 5.. Effects of HJC0122 on preventing (A-B) and reversing (C-D) acute opioid tolerance and dependence.

Acute opioid tolerance and dependence were induced in mice by morphine (100mg/kg, s.c.). When mice were treated with HJC0122 (1, 10 mg/kg, i.p.) 30 min before the induction dose of morphine, HJC0122 significantly prevented the development of acute opioid (A) tolerance and (B) dependence. When mice received HJC0122 (1, 10 mg/kg, i.p.) 30 minutes before the test dose of morphine (10 mg/kg, s.c.), HJC0122 significantly reversed the established opioid (C) tolerance and (D) dependence in a dose dependent manner. Data are expressed as the mean ± S.E.M. *P