Suneet Mehrotra

Current and prospective pharmacological targets in relation to antimigraine action.

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1–7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

Female sex hormones and rat dural vasodilatation to CGRP, periarterial electrical stimulation and capsaicin

Background.—The prevalence of migraine is 2 to 3‐fold higher in females than in males, and it is intricately related to the levels of female sex hormones. These hormones may regulate the synthesis and receptor expression of calcitonin gene‐related peptide (CGRP), which mediates neurogenic dural vasodilatation and is implicated in migraine pathogenesis.

The Phe-124-Cys and A-161T Variants of the Human 5-HT1B Receptor Gene Are Not Major Determinants of the Clinical Response to Sumatriptan

Background.—The 5‐HT1B/1D receptor agonist sumatriptan is highly effective in the treatment of migraine. However, some patients do not respond to sumatriptan or experience recurrence of the headache after initial relief. In addition, some patients report chest symptoms after the use of sumatriptan.

Effects of Female Sex Hormones on Responses to CGRP, Acetylcholine, and 5‐HT in Rat Isolated Arteries

Background.—Female sex hormones are implicated in the modulation of reactivity of a wide range of blood vessels under physiological as well as pathological conditions. Migraine, a neurovascular syndrome, is 3 times more prevalent in women during their reproductive period than in men.

Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors.

It has been suggested that during a migraine attack capsaicin‐sensitive trigeminal sensory nerves release calcitonin gene‐related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5‐HT1B/1D water‐soluble), donitriptan (5‐HT1B/1D lipid‐soluble), PNU‐142633 (5‐HT1D water‐soluble) and PNU‐109291 (5‐HT1D lipid‐soluble) on vasodilator responses to capsaicin, α‐CGRP and acetylcholine in dog external carotid artery.

Effects of current and prospective antimigraine drugs on the porcine isolated meningeal artery

Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and α-adrenoceptors, as well as vasodilatation induced by α-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT2A receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by α1-(prazosin), α2-(rauwolscine and yohimbine) and α2C/2B-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, α-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP1 receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A and 5-HT7) and adrenoceptors (α1A, α1B, α1D, α2A, α2B, α2C, β1 and β2), as well as that for the calcitonin receptor like receptor, a component of the CGRP1 receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT1B receptor and β1- and β2-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.

Rat Carotid Artery Responses to α-Adrenergic Receptor Agonists and 5-HT After Ovariectomy and Hormone Replacement

Objective.—To compare the contractile responses to α‐adrenergic receptor agonists and 5‐HT in the rat carotid artery after ovariectomy and subsequent hormone replacement with 17β‐estradiol, progesterone, or the combination of 17β‐estradiol and progesterone.