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Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis

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Abstract

Purpose

Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague–Dawley rat model of surgically induced osteoarthritis (OA).

Methods

Female rats were ovariectomized and pre-emptive 17β-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17β-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC–MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A).

Results

Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (− 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17β-estradiol. Interestingly, the 17β-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018).

Conclusion

These results clearly indicate that 17β-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

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Funding

This work was sponsored, in part, by Discovery grants (#441651–2013, Eric Troncy; #386637–2010, Francis Beaudry) supporting salaries, and a Collaborative Research and Development grant (#RDCPJ 491953–2016, Eric Troncy, in partnership with ArthroLab Inc.) supporting operations and salaries, from the Natural Sciences and Engineering Research Council of Canada, as well as by an ongoing New Opportunities Fund grant (#9483, Eric Troncy), a Leader Opportunity Fund grant (#24601, Eric Troncy), and supporting pain/function equipment as well as mass spectrometry infrastructure (#36706, Francis Beaudry) from the Canada Foundation for Innovation and the Fonds de recherche du Québec. This study was also supported, in part, by a Pilot Study grant (Serge Marchand, Eric Troncy, Roger Lecomte) from the Quebec Pain Research Network of the Fonds de recherche du Québec – Santé (FRQS), and the Chair in Osteoarthritis (Jean-Pierre Pelletier, Johanne Martel-Pelletier) of the Université de Montréal.

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Authors and Affiliations

  1. Research Group in Animal Pharmacology of Quebec (GREPAQ), Department of Veterinary Biomedicine, Faculty of Veterinary Medicine, Université de Montréal, Saint Hyacinthe, QC, Canada

    Sokhna Keita-Alassane, Colombe Otis, Emilie Bouet, Martin Guillot, Marilyn Frezier, Aliénor Delsart, Maxim Moreau, Francis Beaudry, Bertrand Lussier & Eric Troncy

  2. Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada

    Colombe Otis, Maxim Moreau, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Francis Beaudry, Bertrand Lussier & Eric Troncy

  3. Charles River Laboratories Montreal ULC, Senneville, QC, Canada

    Martin Guillot & Agathe Bédard

  4. Département de Chirurgie, Département d’anesthésie, Faculté de Médecine Et Des Sciences de La Santé, Université de Sherbrooke, Sherbrooke, QC, Canada

    Isabelle Gaumond & Serge Marchand

  5. Sherbrooke Molecular Imaging Center, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada

    Roger Lecomte

  6. Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS), Sherbrooke, QC, Canada

    Roger Lecomte & Serge Marchand

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  1. Sokhna Keita-Alassane
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  2. Colombe Otis
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Contributions

J. P. P., J. M. P., B. L., R. L., S. M., and E. T. conceived and designed the research. S. K. A., C. O., E. B., M. G., M. F., A. D., M. M., A. B., I. G., and B. L. conducted the experiments. C. O., E. B., M. G., F. B., and E. T. performed the data analysis. S. K. A., C. O., E. B., and E. T. wrote the manuscript. All authors read and approved the manuscript. All authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Eric Troncy.

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The study was conducted in accordance with principles outlined in the current Guide to the Care and Use of Experimental Animals published by the Canadian Council on Animal Care and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health, complying with the ARRIVE guidelines.

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Keita-Alassane, S., Otis, C., Bouet, E. et al. Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis. Naunyn-Schmiedeberg's Arch Pharmacol 395, 703–715 (2022). https://doi.org/10.1007/s00210-022-02231-5

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