Region Specificity in Endogenous Opioid Peptides and Mu-opioid Receptor Gene Expression in Rat Brain Areas Involved in Addiction After Frequent Morphine Treatment

Abstract

Backgrounds: Molecular mechanisms involved in adverse effects of morphine, including tolerance and dependence, have remained elusive. We examined possible alterations in the gene expression of proenkephalin (Penk), prodynorphin (Pdyn), and mu-opioid receptor (Oprm1) in reward brain areas following frequent morphine treatment. Methods: Two groups of male Wistar rats were used. The groups received either saline (1 mL/kg) or morphine (10 mg/kg) twice daily for eight days. On day 8, rats were decapitated, brain areas involved in addiction were dissected, including the midbrain, striatum, prefrontal cortex (PFC), hippocampus, and hypothalamus, and gene expression was evaluated with real-time PCR. Results: Prolonged morphine treatment decreased Penk, Pdyn, and Oprm1 gene expressions in the midbrain but upregulated them in the striatum compared to the control group treated with saline. Significant increases in Pdyn and Oprm1 gene expressions were detected in the PFC, but there was no significant difference in Penk gene expression between the two groups. Besides, Pdyn gene expression was decreased in the hippocampus and hypothalamus; however, no significant differences in Penk and Oprm1 gene expressions were detected between the groups in these areas. Conclusions: The expression of endogenous opioid peptides and receptors after frequent use of morphine follows a region specificity in brain areas involved in addiction. These alterations may result in new physiological setpoints outside the normal range, which need to be considered when using morphine in medicine.

Increases in Pro-inflammatory Cytokines in the Ventral Striatum Following Frequent Morphine Exposure Impose New Setpoints in the Expression of Biologically-Relevant Genes to Addiction and Neuroinflammation in Rats

“…It has been shown that long-term administration of morphine induces desensitization and/or endocytosis of MORs to attenuate input signaling to the cell (40). However, the increased Oprm1 mRNA due to frequent morphine exposure in the present study may indicate a compensatory mechanism in response to the possible decreases in MORs in the ventral striatum (41). Further, accumulating evidence also shows that morphine, via binding to TLR4, increases pro-inflammatory cytokines, which partly mediate opioid tolerance and dependence (6,42).…”

Alterations in the Expression of Calcium Channels and Neurotrophic Factors in the Cerebellum Are Linked to the Induction of Morphine Dependence and Withdrawal

“…The analgesic effects of morphine were partly restored 30 days post-withdrawal, though not to the levels seen on the first day of administration. Chronic morphine use alters molecular and cellular pathways, especially in brain regions involved in reward and pain processing (23)(24)(25), thus changing the brain's response to the drug (26). Prior research has shown that an eight-day regimen of morphine injections induces tolerance and dependence (26).…”

“…Chronic morphine use alters molecular and cellular pathways, especially in brain regions involved in reward and pain processing (23)(24)(25), thus changing the brain's response to the drug (26). Prior research has shown that an eight-day regimen of morphine injections induces tolerance and dependence (26). Frequent morphine use reduces its therapeutic effects and increases addiction risk (27).…”

“…Frequent morphine use reduces its therapeutic effects and increases addiction risk (27). Extensive studies suggest morphine primarily impacts the reward system, targeting areas like the VTA, striatum, and PFC (26,27). Recent findings highlight a direct link between the cerebellum and VTA, suggesting novel pathways for exploring the cerebellar cortex's role in morphine's effects on the reward system (6).…”

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

“…Both the current study and shown to decrease both sucrose consumption and motivated behavior in opioid-naïve animals 48,49 . Chronic opioid exposure has been associated with decreases in opioid receptor expression and availability as well as decreased endogenous opioid peptide gene expression in the VTA [50][51][52] . And while heroin IVSA in rodents does not seem to change mu opioid receptor expression in either sex 53 , protracted heroin withdrawal in male mice results in increased proopiomelanocortin (precursor to endogenous opioid production) cell reporter signal and mRNA levels in the amygdala and hippocampus, respectively 51 .…”