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Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats

Spinal Cord volume 61, pages 499–504 (2023)Cite this article

Subjects

Abstract

Study design

Preclinical pharmacology.

Objectives

To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats.

Setting

University laboratory in Pennsylvania, U.S.A.

Methods

Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents.

Results

Subcutaneous (SC) administration of 10–30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses.

Conclusions

The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

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Fig. 1: Schematic diagram showing sequence of colorectal distension before and after administration of vehicle or test drug, and representative physiographs showing effects of CRD on blood pressure after administration of vehicle or GR205171.
Fig. 2: Effect of repeated administration of vehicle on CRD-induced hypertension and bradycardia.
Fig. 3: Effect of sequential injection of vehicle or ascending doses of GR205171 or CP-99,994 on CRD-induced MAP and HR changes.

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Data availability

The data generated and analyzed during this study are available upon reasonable request from Dr. Hou at Drexel University.

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Acknowledgements

The authors would like to thank Jason Cook for assistance with statistical analysis.

Funding

Studies were supported by the National Institute of Neurological Disorders and Stroke under award number R41NS117205-01.

Author information

Authors and Affiliations

  1. Dignify Therapeutics LLC, 2 Davis Drive, P.O. Box 13169, Research Triangle Park, Durham, NC, 27709, USA

    Nadia M. J. Rupniak, Karl B. Thor & Lesley Marson

  2. Marion Murray Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Pennsylvania, PA, 19129, USA

    Silvia Fernandes & Shaoping Hou

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  1. Nadia M. J. Rupniak
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Contributions

NMJR and KBT developed the concept and hypotheses underlying the studies. The design of the experiments was developed by NMJR, SH, SF, LM, and KBT. SF conducted the experiments and analyzed the data with LM. NMJR wrote the manuscript with contributions from all coauthors.

Corresponding author

Correspondence to Nadia M. J. Rupniak.

Ethics declarations

Competing interests

NMJR, KBT, and LM are employees and shareholders in Dignify Therapeutics LLC. SF, and SH have no competing interests to declare.

Ethical approval

Institutional Animal Care and Use Committee and National Institutes of Health guidelines on animal care to minimize suffering were followed (IACUC PHS Animal Welfare Assurance #A-3222-01, Protocol No: 20839).

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Rupniak, N.M.J., Fernandes, S., Hou, S. et al. Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats. Spinal Cord 61, 499–504 (2023). https://doi.org/10.1038/s41393-023-00918-x

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