Short communicationThe effects of 5-HT1A, 5-HT1B and 5-HT1D receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats
Introduction
In recent years, migraine headache has received progressively greater attention following the emergence of the novel and clinically effective anti-migraine 5-HT1B/1D receptor agonists collectively known as the `triptans'. It has been postulated that the mechanism of action of the `triptans' is within the intracranial extracerebral meningeal vasculature via direct vasoconstriction (Humphrey and Feniuk, 1991) and by inhibition of neurogenic vasodilation and/or extravasation (Moskowitz, 1992).
With the advent of brain penetrant, 5-HT1B/1D receptor agonists (such as rizatriptan, zolmitriptan and naratriptan), an additional central anti-migraine locus of action has been proposed. It has been shown that brain penetrant triptans can inhibit the responses of neurones in the trigeminal nucleus caudalis to electrical stimulation of the meninges (Goadsby and Hoskin, 1996; Cumberbatch et al., 1997; Goadsby and Knight, 1997b). Moreover, anatomical studies show that 5-HT1B/1D receptors are located in the trigeminal ganglia and in the trigeminal nucleus caudalis (Bruinvels et al., 1992, Bruinvels et al., 1994; Longmore et al., 1997; Bonaventure et al., 1998) in the region of termination of dural afferent fibers. These data strongly support a central role of 5-HT1B/1D receptors in anti-migraine therapy, in addition to any peripheral effects.
Although sumatriptan is a selective agonist for 5-HT1B/1D receptors in humans, binding data suggest that sumatriptan has little selectivity between rat 5-HT1B and 5-HT1A receptors (van Wijngaarden et al., 1990). This may also be true for other 5-HT1B/1D receptor agonists and interpretation of their effects requires caution, since systemic administration in the rat may have non-specific 5-HT1A-mediated effects. It has also been shown that 5-HT1D receptors have a more restricted trigeminal distribution than 5-HT1B receptors (Longmore et al., 1997; Bonaventure et al., 1998), suggesting that 5-HT1D receptor selective agonists may have a different activity profile over less selective 5-HT1 receptor agonists. An electrophysiological assay in the anaesthetized rat was used to determine the relative contribution of 5-HT1A, 5-HT1B and 5-HT1D receptors to the central anti-nociceptive actions of the `triptan' anti-migraine compounds in the trigeminal nucleus caudalis. The following compounds were used as agonists for 5-HT1A, 5-HT1B and 5-HT1D receptors (see Table 1); 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one; Macor et al., 1990) and zolmitriptan (Martin, 1997).
Section snippets
Animal preparation
All experiments were conducted and terminated under general anaesthesia. The surgical preparation and experimental protocol have been described in detail previously (Cumberbatch et al., 1997). Briefly, male Sprague–Dawley rats (n=14, 300–450 g) were anaesthetized with halothane, the trachea, the carotid artery and the jugular veins were cannulated and the animal was immobilized in a stereotactic frame. The brainstem was exposed and the skull was thinned over the middle meningeal artery.
Cell classification
A total of 14 neurones from 14 rats were used for pharmacological tests. These neurones were located between 180–910 μm (mean of 564 μm) below the pial surface in the trigeminal nucleus caudalis. All cells received single or multiple single unit action potentials following electrical stimulation of the dura mater, with a mean latency to the first action potential of 4.2 ms (range of 2–13 ms).
Effects of zolmitriptan, CP-93,129 and 8-OH-DPAT
The 5-HT1B/1D receptor agonist, zolmitriptan, at 0.3, 1 and 3 mg kg−1 (i.v.), dose-dependently inhibited
Discussion
The results of this study support the hypothesis that brain penetrant 5-HT1B/1D receptor agonists have central anti-nociceptive effects in the trigeminal nucleus caudalis (Goadsby and Hoskin, 1996; Cumberbatch et al., 1997; Goadsby and Knight, 1997b) and for the first time provide evidence that 5-HT1B and 5-HT1A receptors are not involved in the central processing of dural nociceptive information in the rat.
The effects of zolmitriptan were unlikely to be via 5-HT1A or 5-HT1B receptors because
Conclusion
These data show that 5-HT1A and 5-HT1B receptors do not appear to be involved in dural nociceptive processing in rats and that the central effects of `triptan' 5-HT1B/1D receptor agonists in this assay may be mediated by 5-HT1D receptors. Whilst it is sometimes difficult to predict clinical efficacy, these results suggest that the rat may be a suitable species for the identification of centrally acting 5-HT1D selective agonists that could have therapeutic utility in migraine headache.
Acknowledgements
We would like to thank our colleagues in the Department of Medicinal Chemistry, Terlings Park, for synthesizing the test compounds used in this study. Thanks also go to D. Williamson, S. Shepheard, M. Beer and F.D. Tattersall.
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