Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers

Abstract

Migraine is a common neurological disorder often treated with triptans. Triptan overuse can lead to increased frequency of headache in some patients, a phenomenon termed medication overuse headache. Previous preclinical studies have demonstrated that repeated or sustained triptan administration for several days can elicit persistent neural adaptations in trigeminal ganglion cells innervating the dura, prominently characterized by increased labelling of neuronal profiles for calcitonin gene related peptide. Additionally, triptan administration elicited a behavioural syndrome of enhanced sensitivity to surrogate triggers of migraine that was maintained for weeks following discontinuation of drug, a phenomenon termed 'triptan-induced latent sensitization'. Here, we demonstrate that triptan administration elicits a long-lasting increase in identified rat trigeminal dural afferents labelled for neuronal nitric oxide synthase in the trigeminal ganglion. Cutaneous allodynia observed during the period of triptan administration was reversed by NXN-323, a selective inhibitor of neuronal nitric oxide synthase. Additionally, neuronal nitric oxide synthase inhibition prevented environmental stress-induced hypersensitivity in the post-triptan administration period. Co-administration of NXN-323 with sumatriptan over several days prevented the expression of allodynia and enhanced sensitivity to stress observed following latent sensitization, but not the triptan-induced increased labelling of neuronal nitric oxide synthase in dural afferents. Triptan administration thus promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress. These data provide a biological basis for increased frequency of headache following triptans and highlight the potential clinical utility of neuronal nitric oxide synthase inhibition in preventing or treating medication overuse headache.

Cortical Excitability in Chronic Migraine

“…The biological explanation for this difference is not known, but it is likely related to the different pharmacological actions and targets of these drugs. The clinical differences between NSAID-and triptan-overuse headaches are well known [43] and they were shown to have different effects on the trigeminal system after repeated administration in experimental animals [44]. It remains to be shown if there is a relation between experimental findings and clinical features.…”

Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache

“…Additionally, after termination of triptan exposure and normalization of baseline sensory thresholds, triptan-pretreated rats remained sensitive to putative migraine triggers (e.g. nitric oxide (NO) donor or environmental stress), suggesting a state of “latent sensitization” (18). The reasons for enhanced sensitivity to putative migraine triggers are not understood but one possibility is that these triptan pre-exposed rats may have enhanced susceptibility to generation of CSD events with subsequent activation of trigeminal dural afferents.…”

Headache of Analgesic Abuse as a Cause of New Pain Pathways Development

“…Furthermore, primary therapies such as triptans are also involved in MOH development after chronic use and there is even weaker evidence to explain the underlying pathways that cause this occurrence. At the moment the most probable mechanism of triptaninduced MOH is "induction of neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers" [108], in addition, "triptan administration promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress, which is a biological basis for increased frequency of headache following" [109].…”