Morphine-Induced Analgesic Tolerance Effect on Gene Expression of the NMDA Receptor Subunit 1 in Rat Striatum and Prefrontal Cortex

Abstract

Introduction:Morphine is a potent analgesic but its continual use results in analgesic tolerance. Mechanisms of this tolerance remain to be clarified. However, changes in the functions of μ-opioid and N-Methyl-D-aspartate (NMDA) receptors have been proposed in morphine tolerance. We examined changes in gene expression of the NMDA receptor subunit 1 (NR1) at mRNA levels in rat striatum and prefrontal cortex (PFC) after induction of morphine tolerance.Methods:Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method.Results:The results showed that long-term morphine a administration induces tolerance to analgesic effect of the opioid, as revealed by a significant decrease in morphine-induced analgesia on day 8 compared to day 1 of the injections (P<0.001). The results also showed that the NR1 gene expression at mRNA level in rats tolerant to morphine was significantly increased in the striatum (P<0.01) but decreased in the PFC (P<0.001).Conclusion:Therefore, changes in the NR1 gene expression in rat striatum and PFC have a region-specific association with morphine-induced analgesic tolerance.

Effects of Acute and Subchronic Anodal Transcranial Direct Current Stimulation (tDCS) on Morphine-Induced Responses in Hotplate Apparatus

“…According to a previous study that represented in the molerat, opioid systems in the CNS may not be involved in the regulation of analgesia, but it can regulate several activity such as motor activity [23]. As well as, the other results of the hotplate test indicated that morphine (5 and 10 mg/kg) induced significant analgesia in naive rats but its analgesic effects in rats receiving 15 days injections of morphine (10 mg/kg) was reduced, showing tolerance to morphine analgesia [22]. The results of several studies have also indicated that NMDA receptor gene expression at mRNA level in rats tolerant to morphine is significantly increased in the striatum but decreased in the PFC.…”

“…According to the Figure -1B, two-way ANO-VA indicated that there is no significant interaction between tDCS and morphine in pain perception after 24 Although, post hoc analysis represented that the pre-test acute anodal left prefrontal tDCS does not significantly alter the analgesic effect in different doses on the day after the last morphine injection.…”

“…This apparatus contains a rectangular cast-iron plate (20×25) that is provided with a thermostat, power supply, and a holding cylinder (with a diagonal of 20 cm and height of 30 cm). Licking one of the hind paws or first jumping was recorded as an index of pain reaction latency in seconds, while the cut-off time of the test was 60 seconds for rats that did not respond [20][21][22]. The test was applied for each rat in 24 hours after the last session of subchronic tDCS or 20 min after the session of acute tDCS.…”

Effects of Acute and Subchronic Anodal Transcranial Direct Current Stimulation (tDCS) on Morphine-Induced Responses in Hotplate Apparatus

“…Also, this proposes structural dependence by the neuromodulatory process to induce analgesia with potential relevance for patient stratification [ 26 ]. According to results of some studies, those indicated that long-term morphine administration creates tolerance to the antinociceptive effect of the opioid, as disclosed by a significant reduction in morphine-induced antinociceptive on day eight compared to day 1 of the injections [ 24 ]. Based on studies, several factors may describe the lack of objective impact of tDCS on morphine consumption and pain perception: the procedure of brain stimulation (tDCS/rTMS; repetitive Transcranial Magnetic Stimulation), possible interactions with anesthetic drugs, variations in subjects’ population, and the prior experience of pain and long-term utilization of antinociceptive drugs.…”

Noncoding RNAs: Novel Targets for Opioid Tolerance

“…The effects of morphine on the spinal cord and brainstem neurons are mainly analgesic [ 102 ]. Long-term or repeated opioid exposure alters the expression levels of some genes in the spinal cord and brain regions, including the midbrain, striatum, hippocampus, and cortex [ 103 , 104 ]. Previous studies have shown that long-term exposure to opioids alters the expression of ncRNAs, which may be partly responsible for the sustained changes in gene expression after morphine treatment [ 105 ].…”