**5. Conclusions**

Migraine is a disorder with a multifactorial etiopathogenesis in which the complicated pharmacological management requires further efforts to develop more efficacious therapies. Research advances strongly contributed in expanding our understanding of the pathways involved in its complex pathophysiology. Animal models have been developed on the base of clinical observations and some of them represent valuable predictive tools for the identification of anti-migraine drugs. Among the animal models developed to date, chemical provocations models based on the use of NTG or inflammatory soup have been the most widely used models to induce hyperalgesia and inflammation. The opioid receptor agonists such as SNC80, ARM390 or JNJ20788560, are revealing to be effective in counteracting hyperalgesia and CSD, respectively induced by chemical provocation using NTG and KCl. Nanoparticulate drug delivery systems might represent novel avenues to improve drug efficacy in brain targeting. In these novel formulations, triptans are encapsulated in nanoparticulates in order to better exert their pharmacological activity in brain by crossing the BBB. Furthermore, new emerging classes of medications, including 5-HT receptor agonists (ditans), CGRP receptor antagonists (gepants) and receptor or ligand antagonists (mAbs) are opening further options in therapeutics for EM and CM. Despite the medications already used in migraine therapeutics, further efforts are required to improve research in the translational pharmacological approach, from animal models to humans, in order to develop new therapeutic strategies.

**Author Contributions:** G.T. wrote the manuscript; P.B. supervised the paper; E.M. conceived the manuscript.

**Funding:** This work was supported by current research funds 2019 of IRCCS "Centro Neurolesi Bonino-Pulejo", Messina, Italy.

**Conflicts of Interest:** The authors declare no conflict of interest.
