Preserved Thermal Pain in 3xTg-AD Mice With Increased Sensory-Discriminative Pain Sensitivity in Females but Affective-Emotional Dimension in Males as Early Sex-Specific AD-Phenotype Biomarkers.

Toni Cañete,Lydia Giménez-Llort

doi:10.3389/fnagi.2021.683412

Toni Cañete, Lydia Giménez-Llort

Open Access

https://doi.org/10.3389/fnagi.2021.683412

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Abstract

The increase of the aging population, where quite chronic comorbid conditions are associated with pain, draws growing interest across its investigation and the underlying nociceptive mechanisms. Burn injuries associated problems might be of relevance in the older adult’s daily life, but in people with dementia, exposure to high temperatures and heat sources poses a significantly increased risk of burns. In this brief report, the hind paws and tail pain withdrawal reflexes and the emotional responses to thermal nociception in 3xTg-AD mice were characterized for the first time in the plantar test and compared to their non-transgenic (NTg) counterparts. We studied a cohort of male and female 3xTg-AD mice at asymptomatic (2 months), early (6 months), middle (9 months), and advanced (12 and 15 months) stages of the disease and as compared to sex- and age-matched NTg control mice with normal aging. At 20 and 40W intensities, the sensorial-discriminative thresholds eliciting the withdrawal responses were preserved from asymptomatic to advanced stages of the disease compared to NTg counterparts. Moreover, 3xTg-AD females consistently showed a greater sensory-discriminative sensitivity already at premorbid ages, whereas increased emotionality was shown in males. False-negative results were found in “blind to sex and age” analysis, warning about the need to study sexes independently. The current results and previous report in cold thermal stimulation provide two paradigms unveiling sex-specific early AD-phenotype nociceptive biomarkers to study the mechanistic underpinnings of sex-, age- and AD-disease-dependent thermal pain sensitivity.

Highlights

Chronic pain is one of the most frequent causes of suffering and disability, affecting the individual’s quality of life
In a cohort of a total of 216 animals of our 3xTg-Alzheimer’s disease (AD) and NTg mice colonies established at the Behavioral Facility Core, Universitat Autònoma de Barcelona were used (Oddo et al, 2003b)
To avoid errors in the measurement and confounding factors that may elicit a higher sensitivity and response to thermal nociception (Barrot, 2012), it is important to bear in mind that different arousal and attention states, such as alert, resting, and light sleep, could be important modulators of pain sensitivity

Summary

Introduction

Chronic pain is one of the most frequent causes of suffering and disability, affecting the individual’s quality of life. The neural processes of perceiving, encoding, and processing noxious stimuli (nociception) as well as the unpleasant sensory and emotional experience associated with actual or potential tissue damage (pain) define the two inseparable levels of study of one of the most relevant phenomena preserved until the very last seconds of life, becoming an important field of both neuroscience and medical research (Loeser and Treede, 2008). During the progress of Alzheimer’s disease (AD) and other dementias, a difficulty of verbal expression ending in aphasia is added to the increasing severity of cognitive problems, with the consequent worsening or impossibility of trustful self-report. All these factors contribute to pain being under-detected and under-treated, a critical scenario still demanding important research efforts (Giménez-Llort et al, 2020)

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