Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT _1B/1D receptor agonists

Abstract

Triptans are 5HT1B/1D receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and͞or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT 1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization. Migraine is a recurring neurological disorder of unilateral headache affecting 18% of women and 6% of men (1, 2). Migraine pain is thought to be driven by activation and sensitization of peripheral neurons in the trigeminal ganglion that innervate the meninges (i.e., meningeal nociceptors) and central trigeminovascular neurons in the upper cervical and medullary dorsal horn. Several lines of evidence suggest that activation of meningeal nociceptors can be initiated locally by release of inflammatory mediators around meningeal blood vessels (3, 4). Upon such activation, meningeal nociceptors become hyperresponsive (sensitized) to the otherwise innocuous fluctuation in intracranial pressure, resulting in the characteristic throbbing of migraine pain (5-7). The sustained firing of sensitized meningeal nociceptors eventually leads to activation and subsequent sensitization of central trigeminovascular neurons (8), which process sensory signals that originate not only from the dura, but also from the periorbital skin, resulting in increased responsiveness not only to mild changes in intracranial pressure but also to innocuous skin stimulation. This central sensitization, which occurs during migraine in many patients (9), is manifested a...

Migraine and motion sickness: What is the link?

“…Cutaneous allodynia and hyperalgesia develops in the distal extremities during the later stages of migraine headache (Burstein, Cutrer, and Yarnitsky, 2000;Burstein, Collins and Jakubowski, 2004;Levy, Jakubowski and Burstein, 2004;Yarnitsky, Goor-Aryeh, Bajwa, Ransil, Cutre, Sottile and Burstein, 2003). The progression of hyperalgesia from the site of headache to more distal regions implies that sensitization spreads rostally in nociceptive networks as the attack progresses (Burstein et al, 2000).…”

Where do triptans act in the treatment of migraine?

“…Two studies argue for a significant central, presynaptic mechanism. The first used single unit recordings from both presynaptic trigeminal afferents and postsynaptic neurons with dural receptive fields (Levy et al, 2004). As measured by afferent activity at the trigeminal ganglion, sumatriptan was unable to inhibit peripheral sensitization produced by dural application of inflammatory mediators, but recordings from the second order neurons showed that sumatriptan had, in fact, inhibited the transmission of sensitized afferent activity to the central target.…”

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

“…The development of allodynia during migraine appears to be driven by sensitization of trigeminovascular neurons in the dorsal horn which, unfortunately, are not equipped to respond to triptans directly (Potrebic et al, 2003, Levy et al, 2004. Triptans appear to act presynaptically in the dorsal horn, such as to inhibit signal transmission from peripheral (first-order) to central (second-order) trigeminovascular neurons (Levy et al, 2004). Reining-in the central neurons using triptan treatment is possible as long as their excitability remains driven by incoming signals from the meninges, but not after they developed autonomous activity .…”