Sex-specific contrasting role of BECLIN-1 protein in pain hypersensitivity and anxiety-like behaviors

Abstract

Chronic pain is a debilitative disease affecting 1 in 5 adults globally, and is a major risk factor for anxiety (Goldberg and McGee, 2011; Lurie, DI., 2018). Given the current dearth of available treatments for both individuals living with chronic pain and mental illnesses, there is a critical need for research into the molecular mechanisms involved in order to discover novel treatment targets. Cellular homeostasis is crucial for normal bodily functions and investigations of this process may provide better understanding of the mechanisms driving the development of chronic pain. Using the spared nerve injury (SNI) model of neuropathic pain, we found contrasting roles for BECLIN-1 in the development of pain hypersensitivity and anxiety-like behaviors in a sex-dependent manner. Remarkably, we found that male SNI mice with impaired BECLIN-1 function demonstrated heightened mechanical and thermal hypersensitivity compared to male wildtype SNI mice, while female SNI mice with impaired BECLIN-1 function demonstrated similar thresholds to the female wildtype SNI mice. We also found that disruptions of BECLIN-1 prevented SNI induced increases in anxiety-like behaviors in male mice. Our data thus indicate that BECLIN-1 is differentially involved in the nociceptive and emotion components of chronic pain in male but not female mice.

Significance Statement One in five adults suffer from chronic pain, and it is a major risk factor for anxiety. Close to three quarters of the population suffering from chronic pain are women, yet the vast majority of pre-clinical research uses solely male models, and excludes females. In this manuscript, we use female and male mice to discover a novel role for BECLIN-1 in neuropathic pain, and comorbid anxiety-like behaviors in mice. We found that disruptions of Beclin-1 reduces nociceptive hypersensitivity whilst preventing pain-induced increases in anxiety-like behaviors. Notably, these effects were sex-dependent, where only males, but not females, showed BECLIN-1 mediated effects. Our data thus indicates that macroautophagy is differentially involved in nociception and anxiety, in male, but not female mice.