The effects of acute and preventive migraine therapies in a mouse model of chronic migraine

Abstract

Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies.

Keywords: Allodynia; pain; prophylactic; triptan.

Figure 1

Chronic treatment with propranolol inhibited NTG-induced basal and post-treatment hyperalgesia. Male and female C57bl/6 J mice were treated with vehicle (VEH) or propranolol (PROP, 20 mg/kg, ip) daily for 11 days. (a) On days 3, 5, 7, 9, and 11, mice were injected with PROP or VEH, baseline responses were determined 15–20 min later, and mice were then injected with either VEH or NTG (10 mg/kg, ip). Two-way RM ANOVA, p < 0.001 drug and time, no significant interaction. (b) Post-treatment responses were assessed two hours following NTG administration. p < 0.01 drug and time, no significant interaction. n = 7–9/group. The development of basal hypersensitivity and acute NTG-evoked hyperalgesia were blocked by treatment with propranolol. NTG: nitroglycerin; RM: repeated-measures; ANOVA: analysis of variance; ip: intraperitoneally.

Figure 2

Chronic treatment with low or high doses of valproate (VA) did not inhibit basal or post-treatment NTG-induced hyperalgesia. Male and female C57bl/6 J mice were treated with vehicle (VEH) or valproate (VA) daily for 11 days. On days 3, 5, 7, 9, and 11, mice were injected with VA or VEH, baseline responses were determined 15–20 min later, and mice were then injected with either VEH or NTG (10 mg/kg, ip) and tested two hours later. (a) Basal responses for mice were treated with 25 mg/kg VA. Two-way RM ANOVA, p < 0.001 drug, time and interaction. (b) Post-treatment responses for mice treated with 25 mg/kg VA. Two-way RM ANOVA, p < 0.001 for drug, no significant effect of time or interaction. n = 8/group. (c) Basal responses for mice treated with 200 mg/kg VA. Two-way RM ANOVA, p < 0.01 drug, time and interaction. (d) Post-treatment responses to 200 mg/kg VA. Two-way RM ANOVA. p < 0.01 drug, no significant effect of time or interaction. n = 6/group, **p < 0.01, ***p < 0.001. VA did not block migraine-associated pain in the chronic NTG model. NTG: nitroglycerin; RM: repeated-measures; ANOVA: analysis of variance; ip: intraperitoneally.

Figure 3

Chronic treatment with amiloride (AMIL) attenuated NTG-induced basal and post-treatment hyperalgesia. Male and female C57bl/6 J mice were treated with vehicle (VEH) or AMIL (10 mg/kg, ip) daily for 11 days. (a) On days 3, 5, 7, 9, and 11, mice were injected with AMIL or VEH, baseline responses were determined 15–20 min later, and mice were then injected with either VEH or NTG (10 mg/kg, ip). Two-way RM ANOVA, p < 0.01 drug, time and interaction. (b) Post-treatment responses were assessed two hours following NTG administration. p < 0.05 drug and time, no significant interaction. n = 12/group, **p < 0.01, ***p < 0.001. The development of basal hypersensitivity and acute NTG-evoked hyperalgesia were blocked by the novel migraine preventive AMIL. NTG: nitroglycerin; RM: repeated-measures; ANOVA: analysis of variance; ip: intraperitoneally.

Figure 4

Chronic treatment with memantine (MEM) did not significantly alter basal or acute NTG-induced hyperalgesia. Male and female C57bl/6 J mice were treated with VEH or MEM (3 mg/kg, ip) daily for 11 days. (a) On days 3, 5, 7, 9, and 11, mice were injected with MEM or VEH, baseline responses were determined 15–20 min later, and mice were then injected with either VEH or NTG (10 mg/kg, ip). Two-way RM ANOVA, p < 0.01 drug and time, no significant interaction. (b) Post-treatment responses were assessed two hours following NTG administration. p < 0.01 drug, time and interaction. n = 12/group, *p < 0.05, ***p < 0.001. Long-term, MEM did not block migraine-associated pain in the chronic NTG model. NTG: nitroglycerin; RM: repeated-measures; ANOVA: analysis of variance; ip: intraperitoneally.

Figure 5

Chronic treatment with sumatriptan (SUMA) produced basal hypersensitivity and evoked hyperalgesia. Male and female C57bl/6 J mice were treated with vehicle (VEH) or SUMA (0.6 mg/kg, ip) daily for 11 days. (a) On days 3, 5, 7, 9, and 11, mice were injected with SUMA or VEH, baseline responses were determined 15–20 min later, and mice were then injected with either VEH or NTG (10 mg/kg, ip). Two-way RM ANOVA, p < 0.01 drug, time, and interaction. (b) Post-treatment responses were assessed two hours following NTG administration. p < 0.01 drug and time only. n = 8/group, ***p < 0.001. SUMA did not inhibit basal or acute NTG-induced pain, and chronic treatment with sumatriptan alone produced mechanical hypersensitivity. NTG: nitroglycerin; RM: repeated-measures; ANOVA: analysis of variance; ip: intraperitoneally.