Morphine Compromises Androgen Biosynthesis by Immature Leydig Cells from Pubertal Rat Testes in Vitro

Overview

Journal Toxicol Res (Camb)

Publisher Oxford University Press

Date 2024 Jan 29

PMID 38283823

Authors

Yao Lv

Yaoyao Dong

Ming Su

Hang Lin

Qiqi Zhu

Huitao Li

Affiliations

Soon will be listed here.

Abstract

Morphine is an analgesic in the opiate family, isolated from many plants. It can inhibit androgen biosynthesis by Leydig cells. Whether morphine directly inhibits androgen biosynthesis and underlying mechanism remains unclear. To investigate the influence of morphine on androgen secretion by rat immature Leydig cells (ILCs) and possible mechanism. Rat ILCs were treated with 0.5-50 μM morphine for 3 h in vitro. Morphine at ≥0.5 μM significantly reduced total androgen secretion. Morphine at 50 μM also compromised luteinizing hormone (LH, 10 mg/kg), 8Br-cAMP (1 mM), and 22R-hydroxycholesterol (20 μM) stimulated total androgen, androstanediol, and testosterone secretion, without affecting pregnenolone, progesterone, androstenedione mediated androgen secretion and testosterone and dihydrotestosterone mediated androstanediol secretion. Further analysis revealed that morphine at ≥0.5 μM downregulated Star expression and at ≥5 μM downregulated expression. Morphine also significantly reduced STAR (≥0.5 μM) and reduced CYP11A1 (≥5 μM) levels. 0.5 μM naloxone significantly antagonized morphine-mediated action. In conclusion, morphine might cause side effects by suppressing androgen biosynthesis via u opioid receptor.

Citing Articles

Guijiajiao-Lujiaojiao Synergistically Promote Spermatogenesis in Tripterygium Wilfordii Polyglycoside-Induced Oligoasthenozoospermia Rats via PI3K/AKT Signaling Pathway.

Huang N, Li H, Sun L, Feng J, Gao Z, Lin Z Am J Mens Health. 2024; 18(6):15579883241293941.

PMID: 39526752 PMC: 11555725. DOI: 10.1177/15579883241293941.

References

Ge R, Hardy M . Variation in the end products of androgen biosynthesis and metabolism during postnatal differentiation of rat Leydig cells. Endocrinology. 1998; 139(9):3787-95. DOI: 10.1210/endo.139.9.6183. View

Connelly M, Williams D . SR-BI and cholesterol uptake into steroidogenic cells. Trends Endocrinol Metab. 2003; 14(10):467-72. DOI: 10.1016/j.tem.2003.10.002. View

Gerendai I, Shaha C, Gunsalus G, Bardin C . The effects of opioid receptor antagonists suggest that testicular opiates regulate Sertoli and Leydig cell function in the neonatal rat. Endocrinology. 1986; 118(5):2039-44. DOI: 10.1210/endo-118-5-2039. View

Mukherjee A, Haldar C . Effect of Naltrexone on photoperiodic regulation of testicular steroidogenesis in adult golden hamster, Mesocricetus auratus. Gen Comp Endocrinol. 2015; 239:89-96. DOI: 10.1016/j.ygcen.2015.10.001. View

Drobnis E, Nangia A . Pain Medications and Male Reproduction. Adv Exp Med Biol. 2017; 1034:39-57. DOI: 10.1007/978-3-319-69535-8_6. View

Balch R, Trescot A . Extended-release morphine sulfate in treatment of severe acute and chronic pain. J Pain Res. 2011; 3:191-200. PMC: 3004644. DOI: 10.2147/JPR.S6529. View

Lv Y, Fang Y, Chen P, Duan Y, Huang T, Ma L . Dicyclohexyl phthalate blocks Leydig cell regeneration in adult rat testis. Toxicology. 2018; 411:60-70. DOI: 10.1016/j.tox.2018.10.020. View

Li X, Tian E, Wang Y, Wen Z, Lei Z, Zhong Y . Stem Leydig cells: Current research and future prospects of regenerative medicine of male reproductive health. Semin Cell Dev Biol. 2021; 121:63-70. DOI: 10.1016/j.semcdb.2021.05.007. View

Aloisi A, Aurilio C, Bachiocco V, Biasi G, Fiorenzani P, Pace M . Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009; 34 Suppl 1:S162-8. DOI: 10.1016/j.psyneuen.2009.05.013. View

10.

Lin H, Ge R, Chen G, Hu G, Dong L, Lian Q . Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero. Proc Natl Acad Sci U S A. 2008; 105(20):7218-22. PMC: 2438230. DOI: 10.1073/pnas.0709260105. View

11.

Ceccarelli I, De Padova A, Fiorenzani P, Massafra C, Aloisi A . Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats. Neuroscience. 2006; 140(3):929-37. DOI: 10.1016/j.neuroscience.2006.02.044. View

12.

Onoyovwe A, Hagel J, Chen X, Khan M, Schriemer D, Facchini P . Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers. Plant Cell. 2013; 25(10):4110-22. PMC: 3877807. DOI: 10.1105/tpc.113.115113. View

13.

Mast N, Annalora A, Lodowski D, Palczewski K, Stout C, Pikuleva I . Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1. J Biol Chem. 2010; 286(7):5607-13. PMC: 3037674. DOI: 10.1074/jbc.M110.188433. View

14.

Fabbri A, Tsai-Morris C, Luna S, Fraioli F, Dufau M . Opiate receptors are present in the rat testis. Identification and localization in Sertoli cells. Endocrinology. 1985; 117(6):2544-6. DOI: 10.1210/endo-117-6-2544. View

15.

Ahmed M, Kurkar A . Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress. Clin Exp Pharmacol Physiol. 2014; 41(4):317-23. DOI: 10.1111/1440-1681.12213. View

16.

Chen P, Zirkin B, Chen H . Stem Leydig Cells in the Adult Testis: Characterization, Regulation and Potential Applications. Endocr Rev. 2019; 41(1). PMC: 7753054. DOI: 10.1210/endrev/bnz013. View

17.

Stocco D, Clark B . Role of the steroidogenic acute regulatory protein (StAR) in steroidogenesis. Biochem Pharmacol. 1996; 51(3):197-205. DOI: 10.1016/0006-2952(95)02093-4. View

18.

Shan L, Hardy M . Developmental changes in levels of luteinizing hormone receptor and androgen receptor in rat Leydig cells. Endocrinology. 1992; 131(3):1107-14. DOI: 10.1210/endo.131.3.1505454. View

19.

Glick S, Maisonneuve I, Raucci J, Archer S . Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res. 1995; 681(1-2):147-52. DOI: 10.1016/0006-8993(95)00306-b. View

20.

Guo J, Zhou H, Su Z, Chen B, Wang G, Wang C . Comparison of cell types in the rat Leydig cell lineage after ethane dimethanesulfonate treatment. Reproduction. 2013; 145(4):371-80. DOI: 10.1530/REP-12-0465. View