Activation of peripheral NOP receptors reduces periorbital mechanical allodynia evoked by CGRP in mice

Background and Purpose Migraine is a neurovascular disorder largely mediated by calcitonin gene‐related peptide (CGRP). This study explores the role of the nociceptin/orphanin FQ (N/OFQ)–N/OFQ receptor (NOP) system in CGRP‐induced periorbital mechanical allodynia (PMA) in mice. Experimental Approach Male or female wild type (NOP(+/+)) and NOP receptor knockout (NOP(−/−)) mice and CD‐1 mice were used. The brain penetrant, AT‐403, and the peripherally restricted, UFP‐112, NOP agonists were tested for PMA prevention. To identify a potential site of action at the cellular level, the ability of N/OFQ to signal at membrane and endosomal level in NOP‐expressing HEK293 cells, and to inhibit the increase in cyclic adenosine monophosphate (cAMP) induced by CGRP in human Schwann cells (hSCs) was investigated. Key Results CGRP‐induced PMA was comparable in NOP(+/+) and NOP(−/−) mice. AT‐403 and UFP‐112 equally reduced CGRP‐evoked PMA in CD‐1 mice. In NOP‐expressing cells, activation of NOP resulted in the internalisation and movement of NOP away from the plasma membrane marker CAAX and to early endosomes marker Rab5a. N/OFQ stimulated G αi recruitment to NOP at the plasma membrane and from the endosomal compartment. N/OFQ attenuated cAMP increase elicited by CGRP in hSCs. Conclusions and Implications The peripherally restricted NOP agonist showed efficacy similar to the brain‐penetrant compound, indicating that peripheral NOP activation is sufficient to alleviate CGRP‐evoked PMA. Despite NOP ability to halt Gα i recruitment and cAMP increase in cells, further studies are required to confirm that SCs are the cellular site where N/OFQ operates to attenuate the CGRP pro‐migraine action.