Effect of dural inflammatory soup application on activation and sensitization markers in the caudal trigeminal nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid

Abstract

Background The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in trigeminal activation. Aim We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the caudal trigeminal nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. Material and methods After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the caudal trigeminal nucleus was removed for immunohistochemistry. Results and conclusion Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the caudal trigeminal nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain

“…Indeed, in our experimental model, the classical algogen capsaicin operating via calcium-permeable TRPV1 receptors, promoted the large release of CGRP. Likewise, inflammatory conditions in the meninges can induce significant CGRP release, which was blocked by kynurenic acid, suggesting involvement NMDA receptors in this effect [54]. However, we did not find here the elevation of CGRP release after glutamate or NMDA treatments.…”

The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors

“…Elevated levels of KYNA have also been implicated in rapid progression among lung cancer patients [ 17 ], HIV-related illnesses [ 18 ], cataracts [ 19 ], tick-borne encephalitis [ 20 ], and partial seizures in epileptic patients [ 19 ]. Most recently, KYNA has also been associated with antidepressant-like and antimigraine-like effects as well [ 21 , 22 ].…”

The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

“…KYNA levels are increased in the blood of patients suffering from multiple sclerosis [53], inflammatory bowel disease [54], and type 2 diabetes [55], while in the blood of patients with chronic schizophrenia [56], Alzheimer dementia [57], cluster headache [58], chronic migraine [59], and Parkinson's disease [57] KYNA levels are decreased. Interestingly, the recent review pointed out that lover levels of KYNA accompany psychiatric disorders affecting cognitive domains, but higher levels of KYNA are observed in patients suffering from schizophrenia [20,[60][61][62]. In people affected by Huntington's disease, a reduction in KYNA in the cerebrospinal fluid and several brain regions was observed [60].…”

“…In patients suffering from rheumatoid arthritis, a positive correlation between serum KYNA and morning stiffness and pain was shown [61]. Additionally, it was observed that kynurenic acid exerts analgesic properties in an animal model of migraine, induced by dural inflammatory soup [62]. Therefore, it seems possible that pharmacological intervention affecting the production of KYNA-and at the same time the processes connected with the activity of excitatory amino acids in the CNS-may contribute to pain modulation.…”