Hyperhomocysteinemia Increases Cortical Excitability and Aggravates Mechanical Hyperalgesia and Anxiety in a Nitroglycerine-Induced Migraine Model in Rats

Abstract

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal hyperhomocysteinemia (hHCY) in respect of the development of behavioral correlates of headache and spreading cortical depolarization (CSD) in a migraine model induced by the administration of the nitric oxide (NO) donor nitroglycerin. Animals with hHCY were characterized by migraine-related symptoms such as mechanical hyperalgesia, high-level anxiety, photophobia, as well as an enhanced level of neuronal activity in the somatosensory cortex along with a lower threshold of CSD generation. Likewise, acute or chronic intermittent administration of nitroglycerin also induced the development of mechanical allodynia, photophobia and anxiety in control groups. However, these symptoms were more pronounced in rats with hHCY. Unlike hHCY, nitroglycerin administration did not affect the threshold of CSD generation, but like hHCY, increased the background neuronal activity in layers 2/3 and 4 of the cerebral cortex. The latter was more pronounced in animals with hHCY. Thus, the migraine profile associated with hHCY can be further exaggerated in conditions with enhanced levels of migraine triggering the gaseous transmitter NO. Our data are consistent with the view that high levels of plasma homocysteine can act as a risk factor for the development of migraine.

Effects of Nitric Oxide on the Activity of P2X and TRPV1 Receptors in Rat Meningeal Afferents of the Trigeminal Nerve

“…In addition, NG caused an increase in the nNOS expression in the trigeminal nucleus caudalis (TNC) [53], in the dura and trigeminal ganglia [54][55][56], whereas the nNOS inhibitor 7NI prevented the NGinduced activation of structures involved in trigeminal nociception [44,54,57]. No changes in the thresholds and parameters of CSD in the rats' somatosensory cortex were observed after the administration of NG that confirms the predominantly peripheral and brain stem mechanisms of its action [38]. Despite a significant amount of data related to the mechanisms of NG-induced sensitization of nociceptive pathways, the role of P2X3 and TRPV1 receptors-the key pain transducers expressed in the meningeal nociceptors-in the effects of NO has not been studied.…”

“…The endogenous stimuli of NOS include proinflammatory cytokines, CGRP, and an increase in intracellular calcium concentration due to the activation of NMDA receptors [13], whose functional role was shown in the neurons of the trigeminal ganglion both in the soma and in the endings of the trigeminal nerve-innervated meninges [37]. In addition, cortical spreading depression (CSD), which is considered the electrophysiological correlate of migraine with aura, may contribute to a NO release that causes not only vascular but also neuronal effects [13,38,39].…”

“…Nitroglycerin (NG, Ozon Pharmaceuticals, Zhigulevsk, Russia) was used to create a model of chronic migraine in rats with testing the mechanical sensitivity and photophobia [38,79]. NG (10 mg/kg in 0.9% NaCl solution) was repeatedly administered intraperitoneally (IP) [38,79], five times every second day for nine days (days 1, 3, 5, 7, and 9). Mechanical hypersensitivity was measured 2 h before (pre-injection/basal response) and 2 h after (post-injection response) NG injections [80].…”

“…At 30 min before the test, the rat was placed in an individual transparent box with a mesh floor. The mechanical withdrawal thresholds were determined according to the up-and-down method [38,40,81]. Von-Frey filaments were applied by approaching the plantar surface of the paw from the underside of the mesh stand.…”

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings

“…Concerning CSF, according to one study [ 246 ], patients with aura have higher CSF Hcy levels than patients without aura. The elevated levels of Hcy enhance migraine symptoms such as increased cortical excitability, mechanical allodynia, photophobia, and anxiety in rats [ 234 , 247 ].…”