Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naive rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears to be an innovative approach to treat migraine. The dual enkephalinase inhibitor PL37 has demonstrated analgesic effects in pain models and in early human clinical trials. Using an animal model in which cutaneous hypersensitivity acts as a surrogate for headache, Descheemaeker et al. show that PL37 also has potential for the acute treatment and prophylaxis of migraine.

Automated summary

The dual enkephalinase inhibitor PL37 has shown potential as an acute and prophylactic treatment for migraine, as demonstrated in animal pain models and early human clinical trials. Protecting enkephalins from degradation appears to be an innovative approach for migraine treatment.