EC Pharmacology And Toxicology

Research Article Volume 13 Issue 2 - 2025

Evaluation of Metoclopramide Hydrochloride-Induced Alterations in Prolactin Receptor Expression, Aquaporin-3, Oxytocin Receptors, and Other Key Biomarkers in the Mammary Glands of Lactating Wistar Rats

Emmanuel Nachamada Solomon1*, Yaduma Wandiahyel Gaiuson2, Umar Hajara Ali1, Olowomeye Oluwakemi Mary3, Abdulrauf Rukayya Adebisi1, Umar Baraka1, Onaadepo Olufunke4, Emmanuel Anami Solomon5 and Bako Ibrahim Gaya1

1Department of Human Physiology, College of Medical Sciences, Faculty of Basic Medical Sciences, Ahmadu Bello University, Zaria, Kaduna, Nigeria
2School of Molecular Bioscience, College of Medical, Veterinary and Life Science, University of Glasgow, Davidson Building, Glasgow G128QQ, UK
3Department of Human Physiology, Faculty of Basic Medical Sciences, College of Medicine, Achievers University, Owo, Ondo State, Nigeria
4Department of Human Physiology, Faculty of Basic Medical Sciences, University of Abuja, Nigeria
5Adamawa State College of Nursing and Midwifery, Yola, Adamawa State, Nigeria
*Corresponding Author: Emmanuel Nachamada Solomon, Department of Human Physiology, College of Medical Sciences, Faculty of Basic Medical Sciences, Ahmadu Bello University, Zaria. Kaduna, Nigeria.
Received: December 26, 2024; Published: February 10, 2025



Galactagogues, which can be either synthetic or derived from plants, are utilized to stimulate, sustain, and enhance milk production. Metoclopramide, a powerful promoter of prolactin secretion, achieves this via dopamine receptors in the hypothalamus. This study focused on exploring the molecular mechanisms underlying metoclopramide's galactagogue effects in lactating Wistar rats. Twelve lactating Wistar rats at the time of parturition were randomly divided into two groups of six animals each. The first group, served as the control. The second group was administered metoclopramide hydrochloride (5 mg/kg) orally for fourteen days. At the conclusion of the experiment, the rats were anesthetized and sacrificed, with blood and tissue samples collected for molecular, biochemical, and histological analysis. Treatment with metoclopramide hydrochloride significantly increased milk production compared to the control group by elevating serum prolactin and oxytocin levels, mammary prolactin and oxytocin receptors, aquaporin-3, mRNA prolactin receptor gene, and pituitary gland SOD, while reducing mammary gland ROS production and pituitary gland MDA levels. These findings suggest that metoclopramide hydrochloride positively modulates hormonal and molecular pathways essential for lactation via upregulation of mammary prolactin and oxytocin receptors, aquaporin-3, and the mRNA prolactin receptor gene.

 Keywords: Metoclopramide; Galactagogues; Lactation; Receptors; Aquaporin-3; Mammary Gland

  1. Hussain NHN., et al. "Metoclopramide for milk production in lactating women: A systematic review and meta-analysis”. Korean Journal of Family Medicine6 (2021): 453-463.
  2. Oberfichtner K., et al. "Breastfeeding in primiparous women - expectations and reality: a prospective questionnaire survey”. BMC Pregnancy and Childbirth1 (2023): 654.
  3. Gianni ML., et al. "Breastfeeding difficulties and risk for early breastfeeding cessation”. Nutrients10 (2019): 2266.
  4. Mortel M and Mehta SD. "Systematic review of the efficacy of herbal galactogogues”. Journal of Human Lactation: Official Journal of International Lactation Consultant Association2 (2013): 154-162.
  5. Penagos Tabares F., et al. "Pharmacological overview of galactogogues”. Veterinary Medicine International (2014): 602894.
  6. Liu M., et al. "Neurokinin-1 receptor antagonists in preventing postoperative nausea and vomiting: a systematic review and meta-analysis”. Medicine19 (2015): e762.
  7. Abdelmonem H., et al. "The efficacy and safety of metoclopramide in relieving acute migraine attacks compared with other anti-migraine drugs: a systematic review and network meta-analysis of randomized controlled trials”. BMC Neurology1 (2023): 221.
  8. Gabay, M. P. "Galactogogues: Medications that induce lactation”. Journal of Human Lactation: Official Journal of International Lactation Consultant Association 3 (2002): 274-279.
  9. Mathews AT., et al. "Metoclopramide induces preparturient, low-level hyperprolactinemia to increase milk production in primiparous sows”. Domestic Animal Endocrinology 74 (2021): 106517.
  10. Keller SR., et al. "Effect of metoclopramide treatment of bitches during the first week of lactation on serum prolactin concentration, milk composition, and milk yield and weight gain of their puppies”. American Journal of Veterinary Research2 (2018): 233-241.
  11. Bronson FH and Whitten WK. "Oestrus-accelerating pheromone of mice: assay, androgen-dependency and presence in bladder urine”. Journal of Reproduction and Fertility1 (1986): 131-134.
  12. Agematsu Y., et al. "Early detection of pregnancy of the rat”. Jikken Dobutsu. Experimental Animals4 (1983): 209-212.
  13. Charan J and Kantharia ND. "How to calculate sample size in animal studies?" Journal of Pharmacology and Pharmacotherapeutics4 (2013): 303-306.
  14. Emmanuel NS., et al. "Body weight changes and serum growth hormone comparative assessment in female lactating wistar rats (Rattus norvegicus) treated with metoclopramide and some atypical antipsychotics”. Journal of Advances in Medical and Pharmaceutical Sciences2 (2018): 1-6.
  15. Abdulghani MAM., et al. "Effect of monosodium glutamate on serum sex hormones and uterine histology in female rats along with its molecular docking and in-silico toxicity”. Heliyon10 (2022): e10967.
  16. Sampson DA and Jansen G R. "Measurement of milk yield in the lactating rat from pup weight and weight gain”. Journal of Pediatric Gastroenterology and Nutrition4 (1984): 613-617.
  17. Tzou SC., et al. "Preparation of mouse pituitary immunogen for the induction of experimental autoimmune hypophysitis”. Journal of Visual Experiment 46 (2010): 2181.
  18. Tolg C., et al. "Mouse mammary gland whole mount preparation and analysis”. Bio-Protocol13 (2018): e2915.
  19. Battagello DS., et al. "The rat mammary gland as a novel site of expression of melanin-concentrating hormone receptor 1 mRNA and its protein immunoreactivity”. Frontiers in Endocrinology 11 (2020): 463.
  20. Livak KJ and Schmittgen TD. "Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method”. Methods4 (2001): 402-408.
  21. Alturkistani HA., et al. "Histological stains: A literature review and case study”. Global Journal of Health Science3 (2015): 72-79.
  22. Olguín HJ., et al. "The role of dopamine and its dysfunction as a consequence of oxidative stress”. Oxidative Medicine and Cellular Longevity (2016): 9730467.
  23. Gürgen SG., et al. "Metoclopramide use to induce lactation can alter DRD2 and BDNF in the prefrontal cortex of offspring”. Journal of Chemical Neuroanatomy 109 (2020): 101844.
  24. Yawata S., et al. "Pathway-specific control of reward learning and its flexibility via selective dopamine receptors in the nucleus accumbens”. Proceedings of the National Academy of Sciences of the United States of America31 (2012): 12764-12769.
  25. Gomes RC., et al. "Effects of metoclopramide on the mouse anterior pituitary during the estrous cycle”. Clinics (Sao Paulo) 6 (2011): 1101-1104.
  26. Vega C., et al. "Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei”. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology6 (2010): R1701-R1708.
  27. Augustine RA., et al. "Prolactin regulation of oxytocin neurone activity in pregnancy and lactation”. The Journal of Physiology11 (2017): 3591-3605.
  28. Baskerville TA and Douglas AJ. "Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders”. CNS Neuroscience and Therapeutics3 (2010): e92-e123.
  29. Melis MR., et al. "Oxytocin induces penile erection when injected into the ventral subiculum: role of nitric oxide and glutamic acid”. Neuropharmacology7 (2010): 1153-1160.
  30. Succu S., et al. "Oxytocin injected into the hippocampal ventral subiculum induces penile erection in male rats by increasing glutamatergic neurotransmission in the ventral tegmental area”. Neuropharmacology 1-2 (2011): 181-188.
  31. Bioletto F., et al. "Central and peripheral regulation of the GH/IGF-1 axis: GHRH and beyond". Reviews in Endocrine and Metabolic Disorders (2024).
  32. Ozgur, R., et al. "Reactive oxygen species regulation and antioxidant defence in halophytes”. Functional Plant Biology: FPB 9 (2013): 832-847.
  33. Tan C., et al. "Effects of dietary supplementation of nucleotides from late gestation to lactation on the performance and oxidative stress status of sows and their offspring”. Animal Nutrition (Zhongguo Xu Mu Shou Yi Xue Hui)1 (2021): 111-118.
  34. Thébault S. "Potential mechanisms behind the antioxidant actions of prolactin in the retina”. Experimental Eye Research 160 (2017): 56-61.
  35. Yang R., et al. "Effect of prolactin on cytotoxicity and oxidative stress in ovine ovarian granulosa cells”. PeerJ 11 (2023): e15629.
  36. Jeding I., et al. "Characterization of the potential antioxidant and pro-oxidant actions of some neuroleptic drugs”. Biochemical Pharmacology3 (1995): 359-365.
  37. Mancini A., et al. "Hormonal regulation of total antioxidant capacity in seminal plasma”. Journal of Andrology 5 (2009): 534-540.
  38. Yen GC and Hsieh CL. "Antioxidant effects of dopamine and related compounds”. Bioscience, Biotechnology, and Biochemistry 10 (1997): 1646-1649.
  39. Uvnäs Moberg K., et al. "Oxytocin is a principal hormone that exerts part of its effects by active fragments”. Medical Hypotheses 133 (2019): 109394.
  40. Erbas O., et al. "Oxytocin provides protection against diabetic polyneuropathy in rats”. Neurological Research1 (2017): 45-53.
  41. Brunton PJ and Russell JA. "Maternal brain adaptations in pregnancy”. Knobil and Neill's Physiology of Reproduction (Fourth Edition) (2014): 1957-2026.
  42. Petraglia F., et al. "Neuroendocrine mechanisms in pregnancy and parturition”. Endocrine Reviews6 (2010): 783-816.
  43. Day RE., et al. "Human aquaporins: regulators of transcellular water flow”. Biochimica et Biophysica Acta 5 (2014): 1492-1506.
  44. Mobasheri A and Barrett-Jolley R. "Aquaporin water channels in the mammary gland: from physiology to pathophysiology and neoplasia”. Journal of Mammary Gland Biology and Neoplasia1 (2014): 91-102.
  45. Matsuzaki T., et al. "Expression and immunolocalization of water-channel aquaporins in the rat and mouse mammary gland”. Histochemistry and Cell Biology4-5 (2005): 501-512.
  46. Breves JP., et al. "Prolactin and cortisol in tilapia gill”. The Journal of Endocrinology3 (2022): 325-337.
  47. Kaihoko Y., et al. "Distinct expression patterns of aquaporin 3 and 5 in ductal and alveolar epithelial cells in mouse mammary glands before and after parturition”. Cell and Tissue Research 3 (2020): 513-526.
  48. Emmanuel NS., et al. "Haematological changes, oxidative stress assessment, and dysregulation of aquaporin-3 channel, prolactin, and oxytocin receptors in kidneys of lactating wistar rats treated with monosodium glutamate”. Naunyn-Schmiedeberg’s Archives of Pharmacology (2024).
  49. Emmanuel NS., et al. "Preliminary monosodium glutamate-induced changes in mammary gland receptors and gene expression, water channel, oxidative stress, and some lactogenic biomarkers in lactating rats”. The Journal of Basic and Applied Zoology1 (2024): 1-15.

Emmanuel Nachamada Solomon., et al. “Evaluation of Metoclopramide Hydrochloride-Induced Alterations in Prolactin Receptor Expression, Aquaporin-3, Oxytocin Receptors, and Other Key Biomarkers in the Mammary Glands of Lactating Wistar Rats” ”. EC Pharmacology and Toxicology  13.2 (2025): 01-11.