The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain...The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.展开更多
This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and f...This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.展开更多
基金funded by the Key Program of the National Natural Science Foundation of China(No.82130122).
文摘The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.
基金supported by the Sichuan Science and Technology Program(No.2022JDZH0029 to JYY)the Special Fund for Clinical Research and Translational Medicine from Chinese Academy of Medical Sciences(No.2022-I2M-C&T-B-117 to JYY)the Sichuan Key Research and Development Project from the Department of Science and Technology of Sichuan Province(No.2022YFS0237 to YMT).
文摘This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
