Tyrosine Phosphorylation of NR2B Contributes to Chronic Migraines via Increased Expression of CGRP in Rats

Abstract

Tyrosine phosphorylation of NR2B (NR2B-pTyr), a subunit of the N-methyl-D-aspartate (NMDA) receptor, has been reported to develop central sensitization and persistent pain in the spine, but its effect in chronic migraines has not been examined. We hypothesized that tyrosine phosphorylation of NR2B contributes to chronic migraines (CM) through calcitonin gene-related peptide (CGRP) in rats. Ninety-four male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections. In a subset of animals, the time course and location of NR2B tyrosine phosphorylation were detected by western blot and immunofluorescence double staining. Another set of animals were given either genistein, vehicle, or genistein and recombinant CGRP. The mechanical threshold was measured, the expressions of NR2B-pTyr, NR2B, and CGRP were quantified using western blot, and nitric oxide (NO) was measured with the nitric acid reductase method. NR2B-pTyr expression, in neurons, peaked at 24 hours after CM. Genistein improved the mechanical threshold and reduced migraine attacks 24 and 72 hours after CM. Tyrosine phosphorylation of NR2B decreased the mechanical threshold and increased migraine attacks via upregulated CGRP expression in the rat model of CM. Thus, tyrosine phosphorylation of NR2B may be a potential therapeutic target for treatment of CM.

Association between Body Mass Index and Migraine: A Survey of Adult Population in China

“…Concentrations of calcitonin gene-related peptide (CGRP) levels, which are elevated in obese individuals [ 15 ], are a very important mediator of migraine/chronic migraine, and CGRP inhibitors are effective in the treatment of migraine. Additionally, inflammation has been proposed as a possible contributing mechanism for migraine attacks and obesity itself is proinflammatory by the increase in the concentrations of circulating cytokines [ 16 – 18 ]. Furthermore, migraines, like obesity, have been reported as a risk factor for cardiovascular disorders, as well as for stroke [ 6 , 7 , 19 ].…”

α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

“…The von Frey test was performed on the hind paws ipsilateral to the surgery and at the midline of the forehead where the ophthalmic nerve distributed as described previously. 53 , 54 A positive response for the von Frey test was recorded when the rat retracted its head or hind paw from the rigid tip. Mechanical allodynia was evaluated before IS or PBS infusion and 24 h after I.C.V injection of the vehicle, PNU-282987 or α-bungarotoxin.…”

From transformation to chronification of migraine: pathophysiological and clinical aspects

“…CM animal models have shown increased CGRP gene expression in rodents pain processing areas such as trigeminal nucleus caudalis [116,117]. GTN induced model showed that animal behavioral changes in pain perception correlated with an increased gene expression of CGRP in the medulla-pons region, cervical spinal cord and trigeminal ganglia [118], while it has not been demonstrated after acute GTN administration [119], supporting CGRP contribution in central sensitization.…”