Systemic sodium valproate ameliorates impaired short-term memory due to associative morphine analgesic tolerance

Systemic sodium valproate ameliorates impaired short-term memory due to associative morphine analgesic tolerance
Ghazaleh Ghamkharinejad,^1,* Seyed Hossein Marashi,² Yaghoub Fathollahi,³ Forough Foolad,⁴
1. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
3. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
4. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Introduction: Repeated morphine without consistent contextual pairing yields non-associative morphine analgesic tolerance; while prolonged or repeated opioid injections in the presence of specific environmental cues can induce tolerance specific to that setting which named associative morphine analgesic tolerance. Namely, ability to learn and memorize could be ruined by morphine exposure. Effects of a tolerance alleviator sodium valproate on memory impairment were therefore examined in morphine tolerant rats.
Methods: To induce associative tolerance, we used male Wistar rats, weighing 250-300 g at the beginning of experiment. Rats received morphine sulfate (4 mg/kg), s.c. in one of two distinct environments and on alternate days, s.c. saline (2 ml/kg), in the other environment for 13 days. To produce non-associative tolerance, morphine sulfate was injected at their home cages for 8 days. Rats were randomly assigned to saline, morphine (associative and non-associative), sodium valproate (250 mg/kg) and sodium valproate+ morphine groups. Sodium valproate was administrated one hour before morphine sulfate treatment daily to investigate the effects of it on tolerance development. Analgesia was assessed during the tolerance developing period using the Hargreaves apparatus. Following tolerance development, short-term memory was tested using a Y-maze task.
Results: After several administrations, morphine was ineffective when given in the environment in which the rat had previously received morphine o day 13. However, the same dose of morphine was fully effective when administered in the context previously paired with saline on day 14. Thus, using this behavioral protocol and method of drug administration, the analgesic tolerance to morphine could be accounted for by learning factors and therefore was associative. Animals were tolerant to morphine in home cages, indicated that the morphine tolerance observed in these animals was largely independent of context (non-associative). Data showed that sodium valproate alone did not show analgesic effects; nevertheless, administration of valproate along with morphine was acted as an adjuvant analgesic to reverse the development of morphine tolerance. Moreover, chronic morphine impaired short-term spatial memory, while sodium valproate did not impair short-term spatial memory on its own, but sodium valproate treatment an hour before each morphine injections did not prevent this impairment in non-associative morphine analgesic tolerance. Furthermore, no difference was seen in locomotion across the groups.
Conclusion: short-term memory was impaired via both types of morphine tolerance in the Y-maze task. Sodium valproate did not have any analgesic effect and did not impair short term spatial memory on its own, but administering sodium valproate one hour before each morphine injections can improve short-term memory impairment in associative morphine analgesic tolerant rats.
Keywords: Associative morphine tolerance, Opioid, Valproate sodium, Short-term memory