Cerebrovascular and behavioral changes in the nitroglycerin mouse model of migraine

Abstract Background Nitroglycerin (NTG) is an established human migraine trigger, and administration in rodents is a commonly used migraine model. While the sensory sensitivity that occurs in response to NTG in rodents has been extensively studied, other physiological and behavioral responses have not been well characterized. We investigated the cerebrovascular, sleep, and behavioral effects of repeated NTG exposure in freely behaving mice using a minimally invasive microelectronic system. Methods A minimally invasive micro-electronic recording system was used to measure cerebral blood volume (CBV), head movement, and sleep including rapid eye movement (REM) and non-REM (NREM) sleep in freely behaving male and female C57BL/6J mice. Following a 10-day baseline period, 10 mg/kg NTG or vehicle control were administered by intraperitoneal injection every other day as a model of chronic migraine. Results NTG administration resulted in a biphasic change in CBV with an initial acute increase over 15 minutes, followed by a significant and prolonged reduction below baseline, lasting for 2 hours (mixed ANOVA, saline vs NTG X Injection Time, CBV: F (38,836) =9.767, p < 0.001, N = 22). Concurrent telemetry monitoring of blood pressure and heart rate demonstrated CBV reductions persisted despite normalization of systemic blood BP and heart rate. NTG administration also resulted in an acute reduction in animal movement in the 3 hours following administration (mixed ANOVA, saline vs NTG X Injection Time, MLV: F (38, 760) =4.681, p < 0.001; MAV: F (38,836) =1.896, p = 0.001, N = 20–22). Effects on movement significantly increased with successive injections. On injection days, there was a significant increase in NREM sleep accompanied by a non-significant decrease in awake time, with no significant change in REM sleep (mixed ANOVA, saline vs NTG X Condition, NREM%: F (2,44) = 3.333, p = 0.045; awake%: F (2, 44) =3.093, p = 0.055); REM%: F (2,44) = 0.323, p = 0.725, N = 24). Compared to baseline, NREM sleep demonstrated a delayed offset during the injection period, indicating prolonged sleep during the transition period from rest to activity. Conclusions NTG exposure results in significant CBV changes as well as a reduction in animal movement with corresponding increases in NREM sleep. These results show that NTG administration in mice has acute and chronic effects on brain blood flow, movement, and sleep that may have relevance to migraine.