Male-specific mechanisms in a murine model of nociplastic pain
In order to address how acute nociceptive pain can transition to nociplastic pain, we developed a murine model in which acute injury-induced mechanical hypersensitivity was prolonged beyond its normal resolution time following postinjury stimulation at normally innocuous intensity. This model utilized intraplantar capsaicin injection or plantar incision as an acute injury, and vibration or warm water immersion for postinjury stimulation. The prolonged mechanical hypersensitivity in both males and females lasted at least 21 days in the absence of peripheral inflammation, indicating the nociplastic nature of this hypersensitivity. The persistent mechanical hypersensitivity was attenuated by morphine or gabapentin in both sexes but was maintained by sex-specific mechanisms: specifically, by ongoing peripheral afferent activity at the initial injury site in females and by reactive spinal microglia in males. Further investigation into the male-specific mechanisms underlying the nociplastic pain state revealed that activation of spinal microglia drives the postinjury vibration stimulation-triggered transition to a nociplastic pain state, but that microglia activation was not mediated by the BDNF-TrkB pathway, unlike other chronic pain models. After an acute peripheral injury, GABAergic disinhibition was required for postinjury vibration stimulation to trigger the spinal microglia-driven transition to a nociplastic pain state. Even in the absence of an inciting peripheral injury, vibration stimulation could trigger the transition to a spinal microglia-mediated nociplastic pain state in males following direct spinal GABAergic disinhibition by intrathecal injection of the GABAA receptor antagonist bicuculline or the GABAB receptor antagonist CGP 52432. In females, spinal GABAB receptor inhibition, but not GABAA receptor inhibition, followed by vibration stimulation was able to trigger a transition to the nociplastic pain state. However, this pain state in females was not mediated by spinal microglia. Proinflammatory cytokines, but not prostaglandins, at the spinal level contributed to the maintenance of nociplastic pain state in males. Overall, these findings provide key insights for understanding the sex-specific mechanisms underlying the transition to and maintenance of the nociplastic pain state, indicating that spinal microglia are potential therapeutic targets to prevent and treat nociplastic pain in males.