Anti-migraine effect of ∆9-tetrahydrocannabinol in the female rat

Abstract

Current anti-migraine treatments have limited efficacy and many side effects. Although anecdotal evidence suggests that marijuana is useful for migraine, this hypothesis has not been tested in a controlled experiment. Thus, the present study tested whether administration of ∆⁹-tetrahydrocannabinol (THC) produces anti-migraine effects in the female rat. Microinjection of the TRPA1 agonist allyl isothiocyanate (AITC) onto the dura mater produced migraine-like pain for 3h as measured by depression of home cage wheel running. Concurrent systemic administration of 0.32 but not 0.1mg/kg of THC prevented AITC-induced depression of wheel running. However, 0.32mg/kg was ineffective when administered 90min after AITC. Administration of a higher dose of THC (1.0mg/kg) depressed wheel running whether rats were injected with AITC or not. Administration of a CB₁, but not a CB₂, receptor antagonist attenuated the anti-migraine effect of THC. These data suggest that: 1) THC reduces migraine-like pain when administered at the right dose (0.32mg/kg) and time (immediately after AITC); 2) THC's anti-migraine effect is mediated by CB₁ receptors; and 3) Wheel running is an effective method to assess migraine treatments because only treatments producing antinociception without disruptive side effects will restore normal activity. These findings support anecdotal evidence for the use of cannabinoids as a treatment for migraine in humans and implicate the CB₁ receptor as a therapeutic target for migraine.

Keywords: Antinociception; Headache; Marijuana; Pain-depressed behavior; Wheel running.

Fig. 1. Baseline levels of running are consistent across trials

Mean levels of running on the recovery days between tests did not differ from baseline running levels. Only rats tested on all three days are included in this analysis (n = 38/group).

Fig. 2. THC dose dependently prevents AITC-induced depression of wheel running

Top: Time course showing that microinjection of AITC onto the dura mater produced migraine-like pain indicated by depression of wheel running that lasted 3 h. Administration of 0.32 mg/kg THC immediately after AITC administration prevented depressed wheel running. Administration of lower and higher doses of THC (0.1 and 1.0 mg/kg) did not prevent AITC-induced depression of wheel running. Bottom: Analysis of mean wheel running activity for the 3-h duration of the migraine shows reversal of migraine-like pain by 0.32 mg/kg THC (n = 10–12/group). * indicates significant difference from vehicle-treated animals (Bonferroni test, P < 0.05).

Fig. 3. The highest dose of THC depresses running in pain-free animals

Top: Time course showing that microinjection of mineral oil onto the dura as a control for AITC had no effect on wheel running. Likewise, low (0.1 mg/kg) and medium (0.32 mg/kg) doses of THC had no significant effect on wheel running in rats treated with mineral oil, whereas 1.0 mg/kg THC depressed running to about 50% of baseline levels for approximately 4 h. Bottom: Analysis of mean wheel running during the 3 h following microinjection of mineral oil onto the dura shows that 1 mg/kg THC significantly decreased wheel running compared to vehicle (n = 6–10/group).* indicates significant difference from vehicle-treated animals (Bonferroni test, P < 0.05).

Fig. 4. Ninety minute THC post-treatment does not restore migraine-depressed running

Top: Administration of THC (0.1 and 0.32 mg/kg) 90 min after microinjection of AITC onto the dura mater did not reverse AITC-induced depression of wheel running. Bottom: Data averaged over the 3-h period following AITC administration revealed no significant differences between groups (n = 7/group).

Fig. 5. Administration of a CB₁ receptor antagonist blocks the anti-migraine effects of THC

Top: Time course showing that administration of a CB₁ (SR141716A) but not CB₂ (SR144528) receptor antagonist 30 min before AITC and THC (0.32 mg/kg) injections blocked the anti-migraine effect of THC. Bottom: A significant decrease in wheel running is evident in rats injected with the CB₁ receptor antagonist compared to vehicle-treated rats when analyzed over the 3-h time course for AITC-induced migraine. All rats were injected with AITC and THC (n = 6–7/group). * indicates significant difference from vehicle-treated animals (Bonferroni test, P < 0.05).

Fig. 6. Administration of cannabinoid receptor antagonists have no effect on wheel running in the absence of AITC and THC administration

Top: Time course for wheel running following administration of vehicle and the CB₁, or CB₂ receptor antagonist 30 min before a control injection of mineral oil onto the dura mater. Bottom: Administration of CB receptor antagonists had no significant effect on wheel running in rats without an AITC-induced migraine. Mean wheel running was analyzed over 3 h following administration of mineral oil onto the dura (n = 6/group).