Female-Specific Mechanisms of Nociplastic Pain in Murine Model

Normally resolving pain can transition into chronic nociplastic pain, which predominately affects women. To facilitate mechanistic studies on nociplastic pain, we developed a murine model in which postinjury thermal stimulation of injured area triggers the transition to a nociplastic pain state more readily in females. This model manifested mechanical hypersensitivity outside the previously injured area beyond the normal resolution time without persistent local inflammation. Ongoing afferent activity at the previously injured area maintained the nociplastic pain state only in females. The development of this peripherally maintained nociplastic pain state was female gonadal hormone-dependent, in which estrogen acting through G protein-coupled estrogen receptor was a critical mechanistic player. In gonad-intact females, allyl isothiocyanate (AITC)-sensitive afferents at the previously injured area maintained the nociplastic pain state; these afferents spontaneously at a higher frequency and had a decreased mechanical threshold compared to control or acute pain-resolved state, which was not observed in ovariectomized females and males. These results demonstrate that postinjury stimulation of an injured area triggers the transition from transient pain to nociplastic pain, females are more susceptible to this transition, and AITC-sensitive afferents at the previously injured area maintain the nociplastic pain state in a female gonadal hormone-dependent manner.