ArticlePublisher preview available

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

December 2022
Biogerontology 24(Suppl 2):1-26

DOI:10.1007/s10522-022-10000-3

Authors:

Diego Nicolás Messina

Juan Agustín Maza University

Emanuel David Peralta

National Scientific and Technical Research Council

Sean Patterson

National University of Cuyo

Show all 5 authorsHide

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.

Behavioral patterns throughout aging. A Scatter bar plot shows the paw withdrawal thresholds of male rats at different ages, as estimated using the algorithm proposed by Chaplan (1994). N = 12 rats per age, data tested with Kruskal–Wallis followed by Dunn’s post-hoc test. B Response to hot plate at two different temperatures. Data evaluated with Mann–Whitney test. C Bar plot showing the response to the acetone and warm water tests in young (3 m) through to aged (24 m) rats. N = 12 rats per groups, data tested with Kruskal–Wallis followed by Dunn’s post-hoc test. Statistically significant differences are indicated by asterisks

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Expression pattern of Nav1.8. A Representative images (at × 40) of ABC/DAB staining of L5 DRG sections against Nav1.8 in male Wistar rats of 3, 6, 12, 18 and 24 months of age. B Scatter bar plots showing the % of maximum intensity for Nav1.8 in small (left), medium (middle) and large (right) DRG neurons. Each data point represents the average measurement for a single rat. The asterisks indicate the statistically significant differences between the mean ± SEM for each age. N = 5 rats per age, data tested with Kruskal–Wallis followed by Dunn´s post-hoc test. C Representative Western blot of Nav1.8 protein expression at 3 and 24 months of age with the corresponding β-tubulin III staining as loading control. The right panel shows the result of the quantitative analysis of the bands intensity (N = 3 rats per age). Data evaluated with Mann–Whitney test. D and E Representative confocal images of L5 DRG sections of young (3 m) vs. old (24 m) rats immunolabeled against Nav1.8 vs. a known marker of small, non-peptidergic neurons (IB4) (D) or trkA (a marker of peptidergic neurons) (E). Arrows in D mark Nav1.8 + ve, IB4-ve, medium to large size neurons. In E, open circles indicate Nav1.8-ve/trkA + ve large neurons, and the asterisks indicate large, presumably Aβ, Nav1.8 + ve/trkA + ve neurons. A proportion graph (parts of a whole) located next to each row of images represents the % of Nav1.8 + ve neurons which are either IB4 + ve or trkA + ve

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Expression pattern of ASIC3. A Representative images (at × 40) of ABC/DAB staining of L5 DRG sections against ASIC3 in male Wistar rats of 3, 6, 12, 18 and 24 months of age. B Scatter bar plots showing the % of maximum intensity for ASIC3 in small (left), medium (middle) and large (right) DRG neurons. Each data point represents the average measurement in a single rat. The asterisks refer to statistically significant differences between the mean ± SEM for each age. N = 5 rats per age, data tested with Kruskal–Wallis followed by Dunn’s post-hoc test. C Representative Western blot of ASIC3 protein expression at 3 and 24 months of age with β-tubulin III staining as loading control. The right panel shows the result of the quantitative analysis of the ratios (N = 3 rats per age). Data evaluated with Mann–Whitney test. D and E Representative confocal images of L5 DRG sections of young (3 m) vs. old (24 m) rats immunostained against ASIC3 vs. IB4 (D) or trkA (E). Arrows in D indicate ASIC3 + ve, IB4 weakly positive medium size neurons. The proportion graphs (parts of a whole) next to each row of images represent the % of ASIC3 + ve neurons which are either IB4 + ve or trkA + ve

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Expression pattern of P2X3. A Representative images (at × 40) of ABC/DAB staining of L5 DRG sections against P2X3 in male Wistar rats of 3, 6, 12, 18 and 24 months of age. B Scatter bar plots showing the % of maximum intensity for P2X3 in small (left), medium (middle) and large (right) DRG neurons. Each data point represents the average measurement in a single rat. The asterisks refer to statistically significant differences between the mean ± SEM for each age. N = 5 rats per age, data tested with Kruskal–Wallis followed by Dunn´s post-hoc test. C Representative Western blot images of P2X3 protein expression at 3 and 24 months of age with β-tubulin III staining as loading. The right panel depicts the result of the quantitative analysis of the bands intensity (N = 3 rats per age). Data evaluated with Mann–Whitney test. D and E Representative confocal images of L5 DRG sections of young (3 m) vs. old (24 m) rats immunolabeled against P2X3 vs. IB4 (D) or trkA (E). The proportion graphs (parts of a whole) next to each row of images represent the % of P2X3 + ve neurons which are either IB4 + ve or trkA + ve

…

Expression pattern of TRPM8. A Representative images (at × 40) of ABC/DAB staining of L5 DRG sections against TRPM8 in male Wistar rats of 3 and 24 months of age. B Scatter bar plots showing the mean % of maximum intensity (± SEM) for TRPM8 in small (left), medium (middle) and large (right) DRG neurons. Each data point corresponds to the average measurement in a single rat. N = 5 rats per age, data tested with Student’s t-test with Welsch correction. C Representative Western blot images of TRPM8 expression at 3 and 24 months of age with β-tubulin III staining as loading. The right panel shows the result of the quantitative analysis of the bands intensity ratios (N = 3 rats per age). Data evaluated with Mann–Whitney test. D and E Representative confocal images of L5 DRG sections of young (3 m) vs. old (24 m) rats immunolabeled against TRPM8 vs. IB4 (D) or trkA (E). The proportion graphs next to each row of images represent the % of TRPM8 + ve neurons which are either positive for IB4 or trkA

…

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Biogerontology (2023) 24:111–136

https://doi.org/10.1007/s10522-022-10000-3

RESEARCH ARTICLE

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

DiegoN.Messina· EmanuelD.Peralta· AliciaM.Seltzer·

SeanI.Patterson· CristianG.Acosta

Received: 26 July 2022 / Accepted: 8 November 2022 / Published online: 8 December 2022

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 reduc-

tions 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.

Keywords Aging· Mechanosensation· Cold

sensitivity· Dorsal root ganglion· Sensory neurons

B.V. 2022

Abstract The eﬀects during healthy aging of the tet-

rodotoxin-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 mechani-

cal and cold sensitivity to non-noxious stimuli and

their underlying mechanisms, we used a combination

of immunohistochemistry and quantitation of immu-

nostaining in sub-populations of neurons of the dorsal

root ganglia (DRG), behavioral tests, pharmacological

interventions and Western-blot in healthy male Wistar

Supplementary Information The online version

contains supplementary material available at https:// doi.

org/ 10. 1007/ s10522- 022- 10000-3.

D.N.Messina· E.D.Peralta· A.M.Seltzer· C.G.Acosta

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

e-mail: dmessina@mendoza-conicet.gob.ar

E. D. Peralta

e-mail: peraltaemanuel0@gmail.com

A. M. Seltzer

e-mail: seltezalicia@gmail.com

S.I.Patterson

Instituto de Fisiología, Facultad de Ciencias Médicas,

Universidad Nacional de Cuyo, Mendoza, Argentina

e-mail: seanpat@fcm.uncu.edu.ar

S.I.Patterson

Instituto de Histología y Embriología - CONICET,

Universidad Nacional de Cuyo, 5500Mendoza, Argentina

C.G.Acosta(*)

Histology Laboratory 107, IHEM-Faculty ofMedical

Sciences, National University ofCuyo, Av. del Libertador

80, 5500Mendoza, Argentina

e-mail: cacosta@fcm.uncu.edu.ar

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons

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Mar 2024
INFLAMM RES

Objective and design Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. Methods We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. Results Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1β up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1β had this effect only on young and aged neurons, respectively. Conclusion Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons

Preprint

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Oct 2023

Background The therapeutic failure in the management of chronic inflammatory pain in geriatric populations arises from drug-associated toxicity and lack of specific regulation of nociceptor excitability. Methods We compared 6 and 24 months-old female Wistar rats that underwent cutaneous inflammation to examine the role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in long-term inflammatory pain. We carried out this using a combination of behavioral pain assessments, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA, and the in vitroevaluation of cytokine effects. Results Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1β up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1β had this effect only on young and aged neurons, respectively. Conclusion Our findings demonstrate that inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

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Acid-Sensing Ion Channels and Mechanosensation

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Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer's disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

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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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