Fear Extinction-Based Inter-Individual and Sex Differences in Pain-Related Vocalizations and Anxiety-like Behaviors but Not Nocifensive Reflexes.

Peyton Presto,Riley Junell,Guangchen Ji,Zach Griffin,Volker Neugebauer

doi:10.3390/brainsci11101339

Abstract

Inter-individual and sex differences in pain responses are recognized but their mechanisms are not well understood. This study was intended to provide the behavioral framework for analyses of pain mechanisms using fear extinction learning as a predictor of phenotypic and sex differences in sensory (mechanical withdrawal thresholds) and emotional-affective aspects (open field tests for anxiety-like behaviors and audible and ultrasonic components of vocalizations) of acute and chronic pain. In acute arthritis and chronic neuropathic pain models, greater increases in vocalizations were found in females than males and in females with poor fear extinction abilities than females with strong fear extinction, particularly in the neuropathic pain model. Female rats showed higher anxiety-like behavior than males under baseline conditions but no inter-individual or sex differences were seen in the pain models. No inter-individual and sex differences in mechanosensitivity were observed. The data suggest that vocalizations are uniquely suited to detect inter-individual and sex differences in pain models, particularly in chronic neuropathic pain, whereas no such differences were found for mechanosensitivity, and baseline differences in anxiety-like behaviors disappeared in the pain models.

Highlights

Inter-individual and sex differences have been well documented with regard to anxiety- and depression-like conditions [1,2,3] and in pain [4,5,6]
We previously reported that the identification of distinct behavioral phenotypes based on fear extinction (FE) ability in naïve male rats can serve as a predictor for inter-individual differences in pain sensitivity and amygdala neuronal activity in chronic neuropathic pain [42]
Males exhibited a different distribution of phenotypes, where 29 rats (19.8%) showed strong FE learning ability (FE+), 47 rats (30.7%) showed weak FE learning ability (FE−), and the remaining 77 rats (50.3%) showed normal FE learning ability (FE+/−) (Figure 2C)

Summary

Introduction

Inter-individual and sex differences have been well documented with regard to anxiety- and depression-like conditions [1,2,3] and in pain [4,5,6]. The strong negative affective component of pain presents a challenge for effective therapeutic strategies, as patients suffering from chronic pain are at increased risk of developing mood and anxiety disorders, and vice versa [7,8,9,10] This suggests that pain may share neurobiological mechanisms, including emotional network neuroplasticity, with negative emotions such as fear [11,12]. Fear learning and extinction networks have been implicated in neuropsychiatric disorders such as anxiety disorders, post-traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD) [13,14,15] Vulnerability to these disorders has been predicted using fear extinction (FE) learning ability as a biomarker for inter-individual differences in the preclinical [16] and clinical [17] setting

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