Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms.

Carbon monoxide (CO) is an endogenous molecule that plays a regulatory role in a number of physiological and pathological processes. It is known that exposure to CO causes headaches. CO is involved in the processes of nociception, neurotransmission and cerebral haemodynamics, and there is also evidence of its anti-nociceptive role. However, the mechanisms through which CO exerts its effects on the meninges and the interaction between CO and ATP, a major inducer of nociceptive activity in trigeminal nerve afferents, remain to be elucidated. The objective of this study was to examine the effect of an exogenous CO on ATP-evoked activity in peripheral afferents using electrophysiological recording of action potentials from the trigeminal nerve in rat half-cranial preparations. The application of a CO donor, specifically CORM-2, like a solution saturated with CO gas, resulted in the activation of afferents and this effect was prevented by the inhibitor of soluble guanylate cyclase (GC)–ODQ. Preliminary CO application suppressed ATP-evoked excitation of trigeminal nerve afferents, and this effect was not mediated by the activation of soluble guanylate cyclase and cyclic nucleotides 8-Br-cGMP and 8-Br-cAMP. We suggest that CO increases the activity of trigeminal afferents through sGC activation and prevents the pro-nociceptive activity of ATP independent of the intracellular levels of cyclic nucleotides.