Ro 64-6198, a selective NOP receptor agonist blocks CGRP-induced migraine-like symptoms and modulates cellular...

The NOP receptor, the fourth member of the opioid receptor family, is found throughout the brain and in the periphery. This receptor is particularly abundant in the trigeminal ganglia and trigeminal nucleus caudalis (TNC), regions intimately involved in cephalic pain, including migraine. Because NOP receptor activation reduces neuronal firing, we have hypothesized that a NOP receptor agonist will block migraine pain and other migraine-associated phenomena such as photophobia. Here we examined the effect of the selective NOP receptor agonist Ro 64-6198 on migraine symptoms induced by systemic administration of both acute and chronic treatment with the migraine-related peptide CGRP. A single injection of CGRP was more effective in inducing periorbital allodynia in male than female mice and this was dose-dependently blocked by Ro 64-6198 (0.3 and 1.0 mg/kg). In female mice chronic treatment (daily for four days) with CGRP induced periorbital sensitivity that lasts at least 24 h after administration and both 0.3 and 1.0 mg/kg Ro 64-6198 blocked both the acute pain and the development of chronic pain. CGRP-induced sensitivity to light (photophobia) was also reversed by 0.3 mg/kg of Ro 64-6198. Ro 64-6198 was not able to block CGRP-induced decrease in locomotion or time spent in the middle of an open field, an indication of anxiety. Finally, Ro 64-6198 also reduced cellular activation in the TNC in CGRP-treated but not vehicle-treated mice suggesting inhibition mostly of CGRP-activated cells. These results suggest that a NOP receptor agonist could be an effective treatment for migraine or other cephalic pain syndromes.