Browsing by Author "Prajapati, Jignesh"

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    Prenatal opioid exposure alters pain perception and increases long-term health risks in infants with neonatal opioid withdrawal syndrome
    (Frontiers Media, 2025-04-17) Radhakrishna, Uppala; Radhakrishnan, Rupa; Uppala, Lavanya V.; Trivedi, Tithi S.; Prajapati, Jignesh; Rawal, Rakesh M.; Muvvala, Srinivas B.; Bahado-Singh, Ray O.; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of Medicine
    Background: Opioids are often prescribed for pain relief, yet they pose risks such as addiction, dependence, and overdose. Pregnant women have unique vulnerabilities to opioids and infants born to opioid-exposed mothers could develop neonatal opioid withdrawal syndrome (NOWS). The study of opioid-induced epigenetic changes in chronic pain is in its early stages. This study aimed to identify epigenetic changes in genes associated with chronic pain resulting from maternal opioid exposure during pregnancy. Methods: We analyzed DNA methylation of chronic pain-related genes in 96 placental tissues using Illumina Infinium Methylation EPIC BeadChips. These samples comprised 32 from mothers with infants prenatally exposed to opioids who needed pharmacologic NOWS management (+Opioids/+NOWS), 32 from mothers with prenatally opioid-exposed infants not needing NOWS pharmacologic treatment (+Opioids/-NOWS), and 32 from unexposed control subjects (-Opioids/-NOWS). Results: The study identified significant methylation changes at 111 CpG sites in pain-related genes among opioid-exposed infants, with 54 CpGs hypomethylated and 57 hypermethylated. These genes play a crucial role in various biological processes, including telomere length regulation (NOS3, ESR1, ESR2, MAPK3); inflammation (TNF, MAPK3, IL1B, IL23R); glucose metabolism (EIF2AK3, CACNA1H, NOTCH3, GJA1); ion channel function (CACNA1C, CACNA1H, CLIC4, KCNQ5); autophagy (CTSS, ULK1, ULK4, ATG5); oxidative stress (NGF, NRG1, OPRM1, ATP1A2); aging (GRIA1, NGFR, PRLR, EIF4E); cytokine activity (TRPV4, RUNX1, CXCL8, IL18R1); and the risk of suicide (ADORA2A, ANKK1, GABRG2, IGSF9B). These epigenetic changes may influence 48 signaling pathways-including cAMP, MAPK, GnRH secretion, estrogen signaling, morphine addiction, circadian rhythms, and insulin secretion-profoundly affecting pain and inflammation-related processes. Conclusion: The identified methylation alterations may shed light on pain, neurodevelopmental changes, and other biological mechanisms in opioid-exposed infants and mothers with OUD, offering insights into NOWS and maternal-infant health. These findings may also pave the way for targeted interventions and improved pain management, highlighting the potential for integrated care strategies to address the interconnected health of mothers and infants.
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    Prenatal opioid exposure significantly impacts placental protein kinase C (PKC) and drug transporters, leading to drug resistance and neonatal opioid withdrawal syndrome
    (Frontiers Media, 2024-08-19) Radhakrishna, Uppala; Radhakrishnan, Rupa; Uppala, Lavanya V.; Muvvala, Srinivas B.; Prajapati, Jignesh; Rawal, Rakesh M.; Bahado-Singh, Ray O.; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of Medicine
    Background: Neonatal Opioid Withdrawal Syndrome (NOWS) is a consequence of in-utero exposure to prenatal maternal opioids, resulting in the manifestation of symptoms like irritability, feeding problems, tremors, and withdrawal signs. Opioid use disorder (OUD) during pregnancy can profoundly impact both mother and fetus, disrupting fetal brain neurotransmission and potentially leading to long-term neurological, behavioral, and vision issues, and increased infant mortality. Drug resistance complicates OUD and NOWS treatment, with protein kinase regulation of drug transporters not fully understood. Methods: DNA methylation levels of ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, along with protein kinase C (PKC) genes, were assessed in 96 placental samples using the Illumina Infinium MethylationEPIC array (850K). Samples were collected from three distinct groups: 32 mothers with infants prenatally exposed to opioids who needed pharmacological intervention for NOWS, 32 mothers with prenatally opioid-exposed infants who did not necessitate NOWS treatment, and 32 mothers who were not exposed to opioids during pregnancy. Results: We identified 69 significantly differentially methylated SLCs, with 24 hypermethylated and 34 hypomethylated, and 11 exhibiting both types of methylation changes including SLC13A3, SLC15A2, SLC16A11, SLC16A3, SLC19A2, and SLC26A1. We identified methylation changes in 11 ABC drug transporters (ABCA1, ABCA12, ABCA2, ABCB10, ABCB5, ABCC12, ABCC2, ABCC9, ABCE1, ABCC7, ABCB3): 3 showed hypermethylation, 3 hypomethylation, and 5 exhibited both. Additionally, 7 PKC family genes (PRKCQ, PRKAA1, PRKCA, PRKCB, PRKCH, PRKCI, and PRKCZ) showed methylation changes. These genes are associated with 13 pathways involved in NOWS, including ABC transporters, bile secretion, pancreatic secretion, insulin resistance, glutamatergic synapse, and gastric acid secretion. Conclusion: We report epigenetic changes in PKC-related regulation of drug transporters, which could improve our understanding of clinical outcomes like drug resistance, pharmacokinetics, drug-drug interactions, and drug toxicity, leading to maternal relapse and severe NOWS. Novel drugs targeting PKC pathways and transporters may improve treatment outcomes for OUD in pregnancy and NOWS.