Three-Day Continuous Oxytocin Infusion Attenuates Thermal and Mechanical Nociception by Rescuing Neuronal Chloride Homeostasis via Upregulation KCC2 Expression and Function

Abstract

Oxytocin (OT) and its receptor are promising targets for the treatment and prevention of the neuropathic pain. In the present study, we compared the effects of a single and continuous intrathecal infusion of OT on nerve injury-induced neuropathic pain behaviours in mice and further explore the mechanisms underlying their analgesic properties. We found that three days of continuous intrathecal OT infusion alleviated subsequent pain behaviours for 14 days, whereas a single OT injection induced a transient analgesia for 30 min, suggesting that only continuous intrathecal OT attenuated the establishment and development of neuropathic pain behaviours. Supporting this behavioural finding, continuous intrathecal infusion, but not short-term incubation of OT, reversed the nerve injury-induced depolarizing shift in Cl− reversal potential via restoring the function and expression of spinal K+-Cl- cotransporter 2 (KCC2), which may be caused by OT-induced enhancement of GABA inhibitory transmission. This result suggests that only continuous use of OT may reverse the pathological changes caused by nerve injury, thereby mechanistically blocking the establishment and development of pain. These findings provide novel evidence relevant for advancing understanding of the effects of continuous OT administration on the pathophysiology of pain.

Oxytocin Disturbs Vestibular Compensation and Modifies Behavioral Strategies in a Rodent Model of Acute Vestibulopathy

“…Oxytocin, on the other hand, plays a crucial role in controlling the GABA developmental polarity shift in pups during labor [ 8 , 9 , 10 ]. Similar to the UVN model, the nerve injury model also induces the downregulation of KCC2, and recently, in this model, Ba et al demonstrated in adult mice that the continuous infusion of oxytocin for three days increased KCC2 expression and function [ 40 ]. Based on our behavioral results, if oxytocin restored KCC2 expression in the ipsilesional vestibular nuclei, then allopregnanolone would enhance the inhibitory action of GABA, leading to a worsening of the syndrome and delayed vestibular compensation.…”