Abstract

ɣ-aminobutyric acid (GABA) facilitator valproic acid may be able to curb memory disruption induced by morphine exposure. The effects of the GABA facilitator valproic acid on the behavioral tolerance induced by morphine were investigated. Then hippocampal-dependent tasks named spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Finally, the changes in the expression of hippocampal GABA-A receptors underlying morphine tolerance were also examined. Rats were treated with daily morphine injections, with or without distinct contextual pairing. To examine the effect of valproic acid on morphine tolerance expression, valproic acid was pretreated an hour before morphine. Spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Afterwards the changes in the expression of hippocampal GABAα receptors using the quantitative real-time PCR and western blot techniques to detect GABArα subunits mRNAs and protein level were studied. Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of GABArα mRNAs and protein level. Despite its attenuating effects on the development and expression of both learned and non-associative morphine tolerance, only associative morphine tolerance-induced memory dysfunction was ameliorated by valproic acid pretreatment. We also found that the expression of GABArα1, α2, α5 subunits mRNAs and GABAα protein level were affected heavier in associative morphine tolerant rats. Our data supports the hypothesis that unconditioned and learned morphine tolerance influences short-term memory and the expression of GABArα 1, α2, α5 mRNAs and GABArα protein level differently, and adds to our understanding of the behavioral and molecular aspects of the learned tolerance to morphine effects.

Highlights

  • Opioids, morphine, remain the mainstream prescription for perioperative and chronic pain suppression [1]

  • Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of GABArα mRNAs and protein level

  • associative morphine tolerance (AMT) and non-associative morphine tolerance (NAMT) expression were suppressed by valproic acid pretreatment, as observed in both the behavioral and molecular assays

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Summary

Introduction

Morphine, remain the mainstream prescription for perioperative and chronic pain suppression [1]. The increase in opioid prescriptions has been associated with a higher risk of addiction, opioid-related mortality, and analgesic tolerance [2]. Opioid administration may lead to several complex modifications on the cell level, including receptor phosphorylation, signaling, and trafficking, resulting in the alteration of neuronal MOR (Mu opioid receptors) function in both peripheral and central nervous systems [3,4,5]. Opiate tolerance involves both associative and non-associative changes. Some reports exist on the underlying mechanisms of opiate associative tolerance, the processes that promotes this type of tolerance remains unknown

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