Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

Abstract

Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN’s very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ~30 min in male and ~45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggest potential novel risk factors and targets for the treatment of migraine.

Effects of systemic inhibitors of acid‐sensing ion channels 1 (ASIC1) against acute and chronic mechanical allodynia in a rodent model of migraine

“…Similar incomplete effects were reported for amiloride in another rat migraine model with a direct dural acidic stimulation (Yan et al ., ) and in a mice NTG‐induced model of chronic migraine (Tipton et al ., ). The complete reversibility of cephalic allodynia by ASIC1 inhibitors that we observed would suggest that sensitization of the TNC and the upper cervical dorsal horn could depend directly on the activity of TG sensory neurons expressing ASIC1‐containing channels, whereas extra‐cephalic allodynia would be partially independent of them, involving central mechanisms independent of TG fibres activation (Bernstein and Burstein, ) or ASIC‐independent effects of NO on paw sensory fibres (Ferrari et al ., ).…”

Neurovascular contributions to migraine: Moving beyond vasodilation

“…This latter study also showed that blockade of ERK phosphorylation inhibited NTG-mediated afferent sensitization. Further, new data from Levine and colleagues implicate a role for mast cells and endothelial cells in NTG-induced hyperalgesia (Ferrari et al, 2016). The activation of purinergic receptors on endothelial cells also stimulates proflammatory pathways (Erlinge and Burnstock, 2008) including the release of interleukins (Seiffert et al, 2006) known to sensitize meningeal afferents (Zhang et al, 201; Yan et al, 2012).…”

The effect of intravenous administration of liposomal curcumin in addition to sumatriptan treatment in an experimental migraine model in rats

“…2 Consequently, the experimental migraine induced by nitroglycerin (NTG) administration (an NO donor) is one of the most reliable experimental models for migraine inducement in rats. 3 NTG-induced hyperalgesia can be evaluated by assessment of the nociceptive behavior evoked by the formalin test. 2 Common migraine triggers are capable of generating oxidative stress, and oxidative-stress molecules released during migraine attack can contribute to nociceptive mechanism.…”