OnabotulinumtoxinA inhibits dysregulation of descending pain modulation following mild traumatic brain injury in mice

Background: Diminished conditioned pain modulation, a measure of endogenous analgesia, has been reported in patients with persistent post-traumatic headache (PTH), suggesting that inefficient endogenous analgesic mechanisms may contribute to the pain. Injections of onabotulinumtoxinA into the specific regions of the head and neck have shown some benefits in treating post-traumatic headache. We investigated the potential effect of onabotulinumtoxinA on restoring the loss of descending control of nociception (DCN), a preclinical correlate of conditioned pain modulation in humans, induced by mild traumatic brain injury (mTBI) in male and female mice. Methods: We assessed DCN in a mouse weight drop model of mTBI by measuring the difference in responses to a test stimulus (i.e., latency to thermally evoked tail flick) in the absence and presence of a conditioning stimulus (i.e., injection of capsaicin in the forepaw). DCN was assessed on days 2, 4 and 14 after mTBI and on day 14 following a stress challenge elicited by exposure to bright lights, a time reflecting the persistent post-traumatic headache. OnabotulinumtoxinA (0.25 U) was injected over the cranial sutures either 2 h (early administration) or 13 days (delayed administration) post-injury. Results: mTBI transiently decreased DCN with resolution by day 14 post-injury. However, exposure to bright-light stress reinstated the loss of DCN. Sham procedures had no effects on DCN. Early administration of onabotulinumtoxinA prevented mTBI-induced loss of DCN during the transient acute period and the loss of DCN induced by bright-light stress in the persistent phase. Delayed onabotulinumtoxinA prevented bright-light stress-induced loss of DCN in the persistent phase. No sex differences were observed. Conclusions: Decreased DCN has been interpreted as a loss of endogenous analgesia that may result in pain chronification. It likely contributes to the persistent post-traumatic headache. Early or delayed administration of onabotulinumtoxinA was effective in inhibiting mTBI-induced dysregulation of DCN, indicating its potential in preventing the persistence of mTBI-induced post-traumatic headache, as well as reversing established persistent post-traumatic headache. Sexual dimorphism was not observed in these effects. Collectively, the data suggest that onabotulinumtoxinA may be beneficial in treating acute and persistent post-traumatic headache in male and female patients.