Sexual Dimorphism in the Mechanism of Pain Central Sensitization

Abstract

It has long been recognized that men and women have different degrees of susceptibility to chronic pain. Greater recognition of the sexual dimorphism in chronic pain has resulted in increasing numbers of both clinical and preclinical studies that have identified factors and mechanisms underlying sex differences in pain sensitization. Here, we review sexually dimorphic pain phenotypes in various research animal models and factors involved in the sex difference in pain phenotypes. We further discuss putative mechanisms for the sexual dimorphism in pain sensitization, which involves sex hormones, spinal cord microglia, and peripheral immune cells. Elucidating the sexually dimorphic mechanism of pain sensitization may provide important clinical implications and aid the development of sex-specific therapeutic strategies to treat chronic pain.

Keywords: central sensitization; microglia; neuropathic pain; sexual dimorphism.

Figure 1

Sexual dimorphism in the mechanism of pain hypersensitivity induced by GT1b. The schematic illustration demonstrates male and female mice that were injected with GT1b in the spinal cord, with induced microglia activation and mechanical allodynia observed only in male mice (left panel). GT1b-induced pain hypersensitivity in male (upper panel) but not female mice (lower panel) evoked an increase in IL-1β expression through the activation of inflammasomes containing NLRP3 and caspase-1. Meanwhile, female mice showed no pain response and lower expression of IL-1β level, possibly due to indirect inhibition of estrogen to caspase-1.