Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism

Abstract

Mechanical distortion of the human cranial venous sinuses is painful as is cranial venous sinus distension during migraine. Sumatriptan, the serotonin (5HT)IB/D-like receptor agonist, is highly effective in relieving migraine headache and part of its action may be due to constriction of cranial dural blood vessels. Using immunohistochemical detection of the immediate early gene Fos, we have mapped the spatial pattern of neural activation in the caudal medulla and the upper cervical spinal cord (C1, C2 and C3) in cats following either electrical or mechanical stimulation of the superior sagittal sinus. Fourteen cats were anaesthetized with alpha-chloralose and prepared for physiological monitoring of blood pressure, heart rate, rectal temperature and expired CO2. Electrical stimulation evoked significant increases in the (median) numbers of Fos-positive cells in laminae I and IIo of the superficial dorsal horn of C1, C2 and C3 cervical spinal cord (88, 92 and 18 cells, respectively) and of the trigeminal nucleus caudalis (TNC) (81 cells). Mechanical stimulation revealed a similar pattern of neural activation but with reduced intensity in laminae I and IIo of the TNC (38 cells) and of C1 and C2 (32 and 31 cells, respectively). The temporalis muscle was stimulated mechanically in the control group and the numbers and distribution of Fos-positive cells were no different from those in non-stimulated controls. Treatment with sumatriptan reduced the numbers of Fos-positive cells found in laminae I and IIo of the TNC and C2 (6, 13 cells and 9 cells, respectively) after mechanical stimulation. These data suggest that the neural effect of sumatriptan alone is sufficient for significant attenuation of transmission in the trigeminal system. The fact that sumatriptan can inhibit trigeminal activation without its vascular effects suggests that drugs without a significant activity on blood vessels may be effective in the treatment of migraine.

Acute and Chronic Craniofacial Pain: Brainstem Mechanisms of Nociceptive Transmission and Neuroplasticity, and Their Clinical Correlates

“…(From Kwan et al, 1993, with permission) on its possible analgesic effects through its release from descending inputs terminating in the VBSNC and spinal dorsal horn (for review, see Dubner and Bennett, 1983;Sessle, 1987;Fields and Basbaum, 1994;Yaksh and Malmberg, 1994). There have been recent reports of the effects of 5-HT-related chemicals, such as the agonist drug sumatriptan, in suppressing c-fos expression in subnucleus caudalis (Nozaki et al, 1992;Cutrer et al, 1995;Eberberger et al, 1995;Shepheard et al, 1995;Hoskin et al, 1996). These effects may be related to the inhibitory action of 5-HT on caudalis neurons (Travagli and Williams, 1996) and could account, at least in part, for the efficacy of this agonist in the management of pain conditions such as migraine (Moskowitz, 1994).…”

Investigation of the Effects of Naratriptan, Rizatriptan, and Sumatriptan on Jugular Venous Oxygen Saturation in Anesthetized Pigs: Implications for Their Mechanism of Acute Antimigraine Action

“…The current mechanisms of action of 5-HT 1B/1D receptor agonists (triptans) in the acute relief of migraine headache are considered to comprise cranial vasoconstriction (Humphrey and Feniuk, 1991), peripheral neuronal inhibition (Moskowitz, 1992) and inhibition of transmission through second-order neurons of the trigeminocervical complex (Hoskin et al, 1996), leading to inhibition of the effects of activated nociceptive terminal afferents (Goadsby, 2000). The observation that donitriptan promotes cerebral oxygen utilization and tissue metabolism (Létienne et al, 2003) implies that this additional mechanism of action may be relevant to the acute headache-relieving effects of donitriptan, and possibly other triptans.…”

Donitriptan Selectively Decreases Jugular Venous Oxygen Saturation in the Anesthetized Pig: Further Insights into Its Mechanism of Action Relevant to Headache Relief

“…The current understanding of the chief mechanisms of triptan action in relieving migraine headache, based on 5-HT 1B/1D receptor activation, comprises cranial vasoconstriction (De Vries et al, 1999a;Pauwels and John, 1999), peripheral (Moskowitz, 1992), and central (Hoskin et al, 1996) inhibition of trigeminal afferents thus preventing neurogenic plasma protein extravasation and sensory neuropeptide release (Goadsby and Knight, 1997;Limmroth et al, 2001). However, the present data suggest that donitriptanevoked enhancement of cerebral oxygen utilization and augmented tissue metabolism provides a further, important, and complementary mechanism to cephalic AVA closure.…”