Fig. 8

The schematic diagram illustrates EE alleviates hyperalgesia by modulating central sensitization in the NTG-induced CM mouse model. A. Mice were reared in SD or EE for 2 months, followed by the establishment of an NTG-induced CM model. B. Mice were examined for mechanical and thermal hyperalgesia in the hind paw and mechanical hyperalgesia in the periorbital region. C. TNC tissues were collected for molecular biological analyses. D. EE reduces activation of microglia and its mediated inflammatory response, as well as the expression of VGLuT1 and CGRP, which are expressed in different neurons of the TNC. VGLuT1 primarily affects the release of glutamate, which acts on excitatory receptors NMDAR or AMPAR to induce central sensitization of neurons. Meanwhile, CGRP regulates cAMP signaling by activating its receptor CGRPR, thereby contributing to central sensitization. Abbreviations: EE, environmental enrichment; NTG, nitroglycerin; VEH, Vehicle; CM, chronic migraine; SD, standard environment; TNC, trigeminal nucleus caudalis; VGluT1, vesicular glutamate transporter 1; CGRP, Calcitonin gene-related peptide; NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor