Comparison of rat models of vascular headache and trigeminal sensitization in male and female rats.

Y. Zhang¹, T. Berkman¹, M. Ciklic¹, A. Doria¹, E. Dugan¹, S.A. Woller², S. Iyengar², T. Hanania¹ M.O. Urban¹

In collaboration with the NIH HEAL Initiative Preclinical Screening Platform for Pain (PSPP), we have characterized rat models of vascular headache and trigeminal sensitization and compared the properties and pharmacology of these models in male and female Sprague Dawley rats. Models of vascular headache and trigeminal sensitization involved administration of the nitric oxide donor isosorbide dinitrate (ISDN; 10 mg/kg, i.p.) or dural infusion of inflammatory soup (IS; 2 mM serotonin, histamine, bradykinin, 0.2 mM PGE2), respectively. Facial allodynia was measured by applying calibrated von Frey filaments to the periorbital region of the face and determining facial sensitivity thresholds. Study groups were randomized, the investigators were blinded to treatment, and groups were sufficiently powered to identify statistically significant effects. For the model of vascular headache, single administration of ISDN in male rats produced facial allodynia which was maximal at 2 hours, while administration of ISDN in female rats produced facial allodynia which was more robust compared to male rats and persisted for 3 hours. Pretreatment with the mu opioid agonist morphine sulfate (6 mg/kg) completely prevented the development of facial allodynia in male and female rats, while administration of the 5-HT1B/1D agonist sumatriptan (1 mg/kg), CGRP receptor antagonist olcegepant (1 mg/kg), or delta opioid agonist SNC80 partially inhibited facial allodynia with generally greater efficacy in male rats compared to female rats. For the model of trigeminal sensitization, a single infusion of IS onto the dura produced transient facial allodynia which persisted for 1- and 3-hours in male and female rats, respectively. Additionally, transient facial allodynia following single infusion of IS in female rats was more robust compared to male rats. Repeated infusion of IS (Days 1-5) in female and male rats produced persistent facial allodynia which was apparent by Day 3 and Day 5, respectively, and continued following cessation of dural infusions on Days 6-7. The data demonstrate that facial allodynia produced in rat models of vascular headache and trigeminal sensitization is generally more robust in female rats compared to male rats. Additionally, certain classes of analgesic compounds, including delta opioid agonists, are more effective in preventing the development of facial allodynia in male rats compared to female rats.