Neurokinins and Their Receptors in the Rat Trigeminal System: Differential Localization and Release with Implications for Migraine Pain

Overview

Journal Mol Pain

Date 2021 Dec 13

PMID 34898306

Citations 15

Authors

Jacob Ca Edvinsson

Philip V Reducha

Majid Sheykhzade

Karin Warfvinge

Kristian A Haanes

Lars Edvinsson

Affiliations

Soon will be listed here.

Abstract

Substance P (SP) and calcitonin gene-related peptide (CGRP) have both been considered potential drug candidates in migraine therapy. In recent years, CGRP receptor inhibition has been established as an effective treatment, in particular as a prophylactic for chronic migraine. Curiously, inhibition of neurokinin receptor 1 (NK1R) failed to alleviate acute migraine attacks in clinical trials, and the neurokinins were consequently abandoned as potential antimigraine candidates. The reason behind this has remained enigmatic.Utilizing immunohistochemistry and semi-quantitative cell counts the expression of neurokinins and their associated receptors was examined in the rat trigeminal ganglion.Immunohistochemistry results revealed SP co-localization in CGRP positive neurons and C-fibres, where it mainly concentrated at boutons. Neurokinin A (NKA) was observed in a population of C-fibres and small neurons where it could co-localize with SP. In contrast, neurokinin B (NKB) did not co-localize with SP and was observed in large/medium sized neurons and Aδ-fibres. All neurokinin receptors (NK1-3R) were found to be expressed in a majority of trigeminal ganglion neurons and A-fibres.The functional release of SP and CGRP in the trigeminovascular system was stimulated with either 60 mM K+ or 100 nM capsaicin and measured with an enzyme-linked immunosorbent assay (ELISA). ELISA results established that SP can be released locally from trigeminovascular system. The released SP was comparatively minor compared to the CGRP release from stimulated dura mater, trigeminal ganglion neurons and fibres. We hypothesize that SP and CGRP signalling pathways may work in tandem to exacerbate painful stimuli in the TGV system.

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References

Harriott A, Strother L, Vila-Pueyo M, Holland P . Animal models of migraine and experimental techniques used to examine trigeminal sensory processing. J Headache Pain. 2019; 20(1):91. PMC: 6734323. DOI: 10.1186/s10194-019-1043-7. View

Nyberg F, Le Greves P, Sundqvist C, Terenius L . Characterization of substance P(1-7) and (1-8) generating enzyme in human cerebrospinal fluid. Biochem Biophys Res Commun. 1984; 125(1):244-50. DOI: 10.1016/s0006-291x(84)80360-5. View

Sherman D, Tait S, Melrose S, Johnson R, Zonta B, Court F . Neurofascins are required to establish axonal domains for saltatory conduction. Neuron. 2005; 48(5):737-42. DOI: 10.1016/j.neuron.2005.10.019. View

Eftekhari S, Salvatore C, Calamari A, Kane S, Tajti J, Edvinsson L . Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010; 169(2):683-96. DOI: 10.1016/j.neuroscience.2010.05.016. View

Ebersberger A, Averbeck B, Messlinger K, Reeh P . Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro. Neuroscience. 1999; 89(3):901-7. DOI: 10.1016/s0306-4522(98)00366-2. View

Pedersen-Bjergaard U, Nielsen L, Jensen K, Edvinsson L, Jansen I, Olesen J . Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle. Peptides. 1991; 12(2):333-7. DOI: 10.1016/0196-9781(91)90022-h. View

. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390(10100):1211-1259. PMC: 5605509. DOI: 10.1016/S0140-6736(17)32154-2. View

Diener H . RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia. 2003; 23(3):183-5. DOI: 10.1046/j.1468-2982.2003.00496.x. View

May A, Burstein R . Hypothalamic regulation of headache and migraine. Cephalalgia. 2019; 39(13):1710-1719. PMC: 7164212. DOI: 10.1177/0333102419867280. View

10.

Moskowitz M, Reinhard Jr J, Romero J, Melamed E, Pettibone D . Neurotransmitters and the fifth cranial nerve: is there a relation to the headache phase of migraine?. Lancet. 1979; 2(8148):883-5. DOI: 10.1016/s0140-6736(79)92692-8. View

11.

Pietrobon D, Moskowitz M . Pathophysiology of migraine. Annu Rev Physiol. 2012; 75:365-91. DOI: 10.1146/annurev-physiol-030212-183717. View

12.

Charles A, Pozo-Rosich P . Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019; 394(10210):1765-1774. DOI: 10.1016/S0140-6736(19)32504-8. View

13.

Pennefather J, Lecci A, Candenas M, Patak E, Pinto F, Maggi C . Tachykinins and tachykinin receptors: a growing family. Life Sci. 2004; 74(12):1445-63. DOI: 10.1016/j.lfs.2003.09.039. View

14.

Edvinsson J, Warfvinge K, Krause D, Blixt F, Sheykhzade M, Edvinsson L . C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain. 2019; 20(1):105. PMC: 6852900. DOI: 10.1186/s10194-019-1055-3. View

15.

Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J . Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985; 62(1):131-6. DOI: 10.1016/0304-3940(85)90296-4. View

16.

. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018; 17(11):954-976. PMC: 6191530. DOI: 10.1016/S1474-4422(18)30322-3. View

17.

Friberg L, Olesen J, Olsen T, Karle A, Ekman R, Fahrenkrug J . Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia. 1994; 14(1):47-54. DOI: 10.1046/j.1468-2982.1994.1401047.x. View

18.

Goadsby P, Edvinsson L, Ekman R . Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990; 28(2):183-7. DOI: 10.1002/ana.410280213. View

19.

Buzzi M, Moskowitz M . The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol. 1990; 99(1):202-6. PMC: 1917483. DOI: 10.1111/j.1476-5381.1990.tb14679.x. View

20.

Cutrer F, Moussaoui S, Garret C, Moskowitz M . The non-peptide neurokinin-1 antagonist, RPR 100893, decreases c-fos expression in trigeminal nucleus caudalis following noxious chemical meningeal stimulation. Neuroscience. 1995; 64(3):741-50. DOI: 10.1016/0306-4522(94)00428-8. View