Nasal Oxytocin for the Treatment of Post-TBI Chronic Headache: Influence of Estrogen
Abstract
Topic Area: Chronic Migraine and Post-Traumatic Headache. The CDMRP recognizes that post-traumatic brain injury (TBI) headache has a tremendous impact on society, affecting many Warfighters and other Americans and so has solicited grant applications that have the potential to address this problem. This impact of TBI is not limited to the actual pain-induced suffering, depression, and debilitation, however, but also by way of the negative effects of its treatment with many patients ending up on opioids, with all of the consequences of this. Because of these issues, there is a tremendous need for novel, non-opioid therapies for chronic headache pain secondary to TBI. We have shown that oxytocin, the hormone better known for inducing labor in pregnant women, may provide such a new approach. We have shown that oxytocin can inhibit the nerve cells carrying pain information to the brain. We have also shown that nasally applied oxytocin goes directly to these nerve cells, bypassing the blood. As a consequence, nasal oxytocin produces strong analgesia in rats, including rats that have undergone TBI and in people with chronic migraine. However, the scientific literature suggests that the amount of estrogen in the blood at any given time may significantly influence the effectiveness of nasally applied oxytocin. We know that women make much more estrogen than men but, critically, the amount they make varies greatly over the menstrual cycle. If estrogen levels do impact the analgesic effect of oxytocin, then this information is critical in determining the optimal dosing and dosing schedule, particularly for women that have undergone TBI. The planned studies will be innovative in that they will be the first studies to the address the question of how estrogen levels can impact the analgesic effect of oxytocin. We plan two studies to address the issue of how changing estrogen levels in the blood will impact the analgesic effect of oxytocin. For the first study, we will administer estrogen benzoate (one of the estrogens) daily, to male and female rats for 4 days – which is the normal menstrual cycle of rats. We will then record the excitability of pain-sensing nerve cells from the rats and look at the effect of the estradiol treatment on the decrease in excitability caused by oxytocin. We expect that the estrogen pretreatment will enhance the inhibitory effect of oxytocin on these cells. However, we expect to see more variability in this effect in female rats as the effect may depend on the day in their cycle in which we test their cells. For the second study, we will pretreat male and female rats with estrogen benzoate as above, but this time, we will test their behavioral response to strong mechanical stimulation of the face – as an indication of pain sensitivity. We will apply oxytocin nasally to the rats and determine whether, and to what extent, pretreatment with estradiol will impact the resultant facial analgesia. We expect that estrogen pretreatment will, in fact, enhance the efficacy of oxytocin. We have previously demonstrated efficacy of nasal oxytocin in patients with chronic migraine headache. However, this treatment has never been tried in patients with chronic headache that followed a TBI. The results of these studies should help us optimize the treatment paradigm such that we will be able to maximize the timing of nasal oxytocin in clinical studies in women and, secondly, suggest that administering estrogen could potentiate the efficacy of this treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110186
Entities
People
- David C Yeomans
Organizations
- Stanford University
- United States Army