The effects of 5-HT1A, 5-HT1B and 5-HT1D receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats

doi:10.1016/S0014-2999(98)00764-X

European Journal of Pharmacology

Volume 362, Issue 1, 27 November 1998, Pages 43-46

https://doi.org/10.1016/S0014-2999(98)00764-X Get rights and content

Abstract

Pre-clinical studies have suggested that one mechanism of antimigraine action of the `triptan' 5-HT_1B/1D receptor agonists may be through inhibition of central nociceptive transmission in the trigeminal dorsal horn. In anaesthetized rats, the 5-HT_1B/1D receptor agonist, zolmitriptan (up to 3 mg kg⁻¹, i.v.), inhibited the action potential discharge of single trigeminal neurones to noxious electrical stimulation of the middle meningeal artery. In contrast, the selective 5-HT_1B receptor agonist, CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one), and the 5-HT_1A receptor selective agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) had no effect in this assay at up to 3 mg kg⁻¹, i.v.. Brain penetrant, triptan 5-HT_1B/1D receptor agonists may therefore mediate their central trigeminal anti-nociceptive action in the rat via 5-HT_1D, but not 5-HT_1B or 5-HT_1A, receptors.

Introduction

In recent years, migraine headache has received progressively greater attention following the emergence of the novel and clinically effective anti-migraine 5-HT_1B/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-HT_1B/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-HT_1B/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-HT_1B/1D receptors in anti-migraine therapy, in addition to any peripheral effects.

Although sumatriptan is a selective agonist for 5-HT_1B/1D receptors in humans, binding data suggest that sumatriptan has little selectivity between rat 5-HT_1B and 5-HT_1A receptors (van Wijngaarden et al., 1990). This may also be true for other 5-HT_1B/1D receptor agonists and interpretation of their effects requires caution, since systemic administration in the rat may have non-specific 5-HT_1A-mediated effects. It has also been shown that 5-HT_1D receptors have a more restricted trigeminal distribution than 5-HT_1B receptors (Longmore et al., 1997; Bonaventure et al., 1998), suggesting that 5-HT_1D 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-HT_1A, 5-HT_1B and 5-HT_1D 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-HT_1A, 5-HT_1B and 5-HT_1D 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-HT_1B/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-HT_1B/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-HT_1B and 5-HT_1A 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-HT_1A or 5-HT_1B receptors because

Conclusion

These data show that 5-HT_1A and 5-HT_1B receptors do not appear to be involved in dural nociceptive processing in rats and that the central effects of `triptan' 5-HT_1B/1D receptor agonists in this assay may be mediated by 5-HT_1D 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-HT_1D 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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Short communicationThe effects of 5-HT1A, 5-HT1B and 5-HT1D receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats

Abstract

Introduction

Section snippets

Animal preparation

Cell classification

Effects of zolmitriptan, CP-93,129 and 8-OH-DPAT

Discussion

Conclusion

Acknowledgements

Eur. J. Pharmacol.

Mol. Brain Res.

Neuropharmacology

Eur. J. Pharmacol.

Pain

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Neuropharmacology

Eur. J. Pharmacol.

Short communication
The effects of 5-HT_1A, 5-HT_1B and 5-HT_1D receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats