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Age-dependent and modality-specific changes in the phenotypic markers Nav1.8, ASIC3, P2X3 and TRPM8 in male rat primary sensory neurons during healthy aging

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Abstract

The effects during healthy aging of the tetrodotoxin-resistant voltage-gated sodium channel 1.8 (Nav1.8), the acid-sensing ion channel-3 (ASIC3), the purinergic-receptor 2X3 (P2X3) and transient receptor potential of melastatin-8 (TRPM8) on responses to non-noxious stimuli are poorly understood. These effects will influence the transferability to geriatric subjects of findings obtained using young animals. To evaluate the involvement of these functional markers in mechanical and cold sensitivity to non-noxious stimuli and their underlying mechanisms, we used a combination of immunohistochemistry and quantitation of immunostaining in sub-populations of neurons of the dorsal root ganglia (DRG), behavioral tests, pharmacological interventions and Western-blot in healthy male Wistar rats from 3 to 24 months of age. We found significantly decreased sensitivity to mechanical and cold stimuli in geriatric rats. These behavioural alterations occurred simultaneously with differing changes in the expression of Nav1.8, ASIC3, P2X3 and TRPM8 in the DRG at different ages. Using pharmacological blockade in vivo we demonstrated the involvement of ASIC3 and P2X3 in normal mechanosensation and of Nav1.8 and ASIC3 in cold sensitivity. Geriatric rats also exhibited reductions in the number of A-like large neurons and in the proportion of peptidergic to non-peptidergic neurons. The changes in normal sensory physiology in geriatric rats we report here strongly support the inclusion of aged rodents as an important group in the design of pre-clinical studies evaluating pain treatments.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Prof. Mabel R. Foscolo for technical support and assistance and Dr. Sally N. Lawson, Dr. Patricia Kunda and Dr. Sergio Benitez for helpful comments on the manuscript.

Funding

DNM. and EDP: were supported by doctoral fellowships from the National Research Council of Argentina (CONICET). AMS., SIP. and CGA: are Staff Scientists. This work was funded by Fondo Nacional para la Ciencia y la Tecnología (FONCyT-ANPCyT PICT-2019–02666 to CGA.), Proyecto de Financiamiento de Unidades Ejecutoras (PUE-2017–0025 to CGA., AMS. and SIP.) and by the Proyectos de Investigación Plurianual 2021–2023 (PIP-2230 to CGA) both from CONICET. The sponsors of this research were not involved in experimental design, writing of the manuscript or the decision to submit it.

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Authors and Affiliations

  1. Laboratorio de Estudios Neurobiológicos (LABENE), Facultad de Ciencias Médicas, Instituto de Histología y Embriología de Mendoza (IHEM-CONICET), Universidad Nacional de Cuyo, 5500, Mendoza, Argentina

    Diego N. Messina, Emanuel D. Peralta, Alicia M. Seltzer & Cristian G. Acosta

  2. Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina

    Sean I. Patterson

  3. Instituto de Histología y Embriología - CONICET, Universidad Nacional de Cuyo, 5500, Mendoza, Argentina

    Sean I. Patterson

  4. Histology Laboratory 107, IHEM-Faculty of Medical Sciences, National University of Cuyo, Av. del Libertador 80, 5500, Mendoza, Argentina

    Cristian G. Acosta

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  1. Diego N. Messina
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  2. Emanuel D. Peralta
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  3. Alicia M. Seltzer
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Contributions

DNM: Investigation, Methodology, Formal analysis, Writing—Original draft preparation. EDP: Investigation. AMS: Conceptualization, resources. SIP: Conceptualization, resources, Writing—Review & Editing. CGA: Supervision, Funding acquisition, Writing—Original draft preparation, Conceptualization.

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Correspondence to Cristian G. Acosta.

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Supplementary file1 (TIF 3392 kb)

Schematic representation of the experimental design. A The diagram shows the ages at which each experiment (IHC, behavior assessment and WB) was conducted and the sample size involved (N). B The arrows illustrate the time course for in vivo pharmacological experiments in young (3 months) vs. geriatric (24 months) male Wistar rats. The hours refer to the timing for the last behavioral assessment (3 h prior to i.m. injection of each drug tested), time of injection (0 h) and the three times after where behavior was measured. The drugs administered are listed, albeit each rat received a single dose of a single drug or vehicle. C Illustration of the HCImage generated mask used to measure neuronal area and pixel densities. The arrow indicates a strongly-stained neuron (subjective score of 5) and the asterisks indicate weakly-stained neurons (subjective scores of 0-1). The XY plot shows that objective measurements of pixel intensity and subjective scores fit a linear regression. Values for positive and negative staining are indicated.

Supplementary file2 (2 1081 kb)

Scatter bar-dot plot showing the mean ± SEM cytoplasmic % of maximum intensity for trkA staining at all ages examined. Date tested with Kuskal-Wallis test.

Supplementary file3 (3 4855 kb)

Age-induced changes in DRG neuronal sizes. A Representative images of cresyl-violet stained full sections of L5 DRGs from male rats of 3 and 24 months. B Bar plots showing the average size of small, medium and large neurons at each age examined. Data tested with Kruskal-Wallis test. C Bar plot shows the overall proportions of small, medium and size neurons in L5 DRGs from 3 and 24-month old male rats. Data tested with Chi-square test. D Histograms of size distribution of DRG neurons at all ages examined.

Supplementary file4 (DOCX 13 kb)

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Messina, D.N., Peralta, E.D., Seltzer, A.M. et al. Age-dependent and modality-specific changes in the phenotypic markers Nav1.8, ASIC3, P2X3 and TRPM8 in male rat primary sensory neurons during healthy aging. Biogerontology 24, 111–136 (2023). https://doi.org/10.1007/s10522-022-10000-3

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