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Cited by 18Regulation of Appetite and ObesityNeuropeptides and Animal PhysiologyHypothalamic control of reproductive hormones

Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice

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Adank, Danielle N., Lunzer, Mary M., Lensing, Cody J., Wilber, Stacey L., Gancarz, Amy M., Haskell-Luevano, Carrie·2018·ACS Chemical Neuroscience
DOI 10.1021/acschemneuro.7b00330PMC PMC5821609
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Abstract

Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 ) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm. To our knowledge, this is the first study to test how central administration of these ligands directly to the spinal cord affects energy homeostasis. Results showed, as expected, that MTII IT administration caused a decrease in food and water intake and an overall negative energy balance without affecting activity. As anticipated, IT administration of AGRP caused weight gain, increase of food/water intake, and increase respiratory exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP was notably shorter (2 days) compared to mice given ICV injections of the same concentrations in previous studies (7 days or more).1−4 It appears that IT administration results in a more sensitive response that may be a good approach for testing synthetic compound potency values ranging in nanomolar to high micromolar in vitro EC 50 values. Indeed, our investigation reveals that the spine influences a different melanocortin response compared to the brain for the AGRP ligand. This study indicates that IT administration can be a useful technique for future metabolic studies using melanocortin ligands and highlights the importance of exploring the role of melanocortin receptors in the spinal cord.

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  • Compared to intracerebroventricular and intracisternal magna administration, intrathecal injection can generate a broader and more homogeneous distribution of therapeutics throughout the entire brain via CSF circulation.

    “Compared to other CNS injection routes, such as intracerebroventricular (ICV) and intracisternal magna (ICM) administration, IT injection can generate a broader and more homogeneous distribution of therapeutics throughout the entire bran via CSF circulation.[22]”

    From Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection (2025) · cites this paper as [22]

    The Results and Discussion section says that compounds injected intrathecally can reach the brain, citing small amounts detected there after 20 minutes (page unavailable). It does not establish broader or more homogeneous distribution throughout the entire brain than ICV injection, does not compare IT with intracisternal magna injection, and does not attribute the movement to CSF circulation. (LLM, conf=0.85)

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Research works printed but not linked: 34

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Authors
Adank, D. N., Lunzer, M. M., Lensing, C. J., Wilber, S. L., Gancarz, A. M., & Haskell-Luevano, C.
Affiliations
  • University of Minnesota (US)
  • California State University, Bakersfield (US)
  • Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
ORCID
Venue
ACS Chemical Neuroscience
Publisher
American Chemical Society (ACS)
Published
2017-10-19
Volume
9
Issue
2
Pages
320-327
ISSN
1948-7193 (ISSN-L)
DOI
10.1021/acschemneuro.7b00330
PMC
PMC5821609
OpenAlex
W2762426178
Cited by
18
References
0
Citations by year
2025: 1 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 3
FWCI
1.17
Type
journal article
Language
en
Open access
Locations
  • ACS Chemical Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK091906, R01DK108893)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
intrathecal administration, intracerebroventricular administration, melanin-concentrating hormone, agouti-related protein, melanocortin-4 receptor, energy homeostasis, spinal cord, dietary intake, energy balance, respiratory exchange ratio, ligand potency
MeSH terms
alpha-MSH, Animals, Body Weight, Catheters, Indwelling, Eating, Homeostasis, Injections, Intraventricular, Injections, Spinal, Male, Mice, Inbred C57BL, Peptide Fragments, Time Factors, Cross-Over Studies, Receptor, Melanocortin, Type 4, Agouti-Related Protein, Mice, 129 Strain

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