Differential expression of H19, BC1, MIAT1, and MALAT1 long non-coding RNAs within key brain reward regions after repeated morphine treatment

Abstract

Morphine-induced analgesic tolerance and dependence are significant limits of pain control; however, the exact molecular mechanisms underlying morphine tolerance and dependence have remained unclear. The role of long non-coding RNAs (lncRNAs) in morphine tolerance and dependence is yet to be determined. We aimed to explore the association of specific lncRNAs expression in key brain reward regions after repeated injection of morphine. Male Wistar rats received subcutaneous injections of twice-daily morphine (10 mg/kg) or saline (1 mL/kg) for eight days. On day 8 of the repeated injections, induction of morphine analgesic tolerance and dependence was confirmed through a hotplate test and a naloxone-precipitated withdrawal analysis, respectively. Expression of H19, BC1, MIAT1, and MALAT1 lncRNAs was determined from the midbrain, striatum, hypothalamus, prefrontal cortex (PFC), and hippocampus by real-time PCR on day 8 of the repeated injections. The H19 expression was significantly different between morphine-treated and control saline-treated rats in all investigated areas except for the hippocampus. The BC1 expression significantly altered in the midbrain, hypothalamus, and hippocampus, but not in the striatum and PFC after repeated morphine treatment. The MIAT1 and MALAT1 expression site-specifically altered in the midbrain, hypothalamus, and striatum; however, no significant changes were detected in their expression in the PFC and hippocampus after repeated morphine treatment. We conclude that alterations in the expression of these lncRNAs in the brain reward regions especially in the midbrain, striatum and hypothalamus may have critical roles in the development of morphine dependence and tolerance, which need to be considered in future researches.

Keywords: Drug tolerance; Gene expression; Morphine dependence; Pain management; lncRNA.