Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2015

Open Access 01-12-2015 | Research article

Nociception-specific blink reflex: pharmacology in healthy volunteers

Authors: JCA Marin, AR Gantenbein, K. Paemeleire, H. Kaube, PJ Goadsby

Published in: The Journal of Headache and Pain | Issue 1/2015

Login to get access

Abstract

Background

The physiology and pharmacology of activation or perception of activation of pain-coding trigeminovascular afferents in humans is fundamental to understanding the biology of headache and developing new treatments.

Methods

The blink reflex was elicited using a concentric electrode and recorded in four separate sessions, at baseline and two minutes after administration of ramped doses of diazepam (final dose 0.07 mg/kg), fentanyl (final dose 1.11 μg/kg), ketamine (final dose 0.084 mg/kg) and 0.9 % saline solution. The AUC (area under the curve, μV*ms) and the latency (ms) of the ipsi- and contralateral R2 component of the blink reflex were calculated by PC-based offline analysis. Immediately after each block of blink reflex recordings certain psychometric parameters were assessed.

Results

There was an effect due to DRUG on the ipsilateral (F 3,60 = 7.3, P < 0.001) AUC as well as on the contralateral (F 3,60 = 6.02, P < 0.001) AUC across the study.
A significant decrement in comparison to placebo was observed only for diazepam, affecting the ipsilateral AUC. The scores of alertness, calmness, contentedness, reaction time and precision were not affected by the DRUG across the sessions.

Conclusion

Previous studies suggest central, rather than peripheral changes in nociceptive trigeminal transmission in migraine. This study demonstrates a robust effect of benzodiazepine receptor modulation of the nociception specific blink reflex (nBR) without any μ-opiate or glutamate NMDA receptor component. The nociception specific blink reflex offers a reproducible, quantifiable method of assessment of trigeminal nociceptive system in humans that can be used to dissect pharmacology relevant to primary headache disorders.
Literature
1.
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M (2001) Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41:646–657CrossRefPubMed
2.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, et al (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2163–2196, PubMedCrossRefPubMed
3.
Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J (2005) Cost of disorders of the brain in Europe. Eur J Neurol 12(Suppl 1):1–27CrossRefPubMed
4.
Goadsby PJ, Lipton RB, Ferrari MD (2002) Migraine- current understanding and treatment. N Engl J Med 346:257–270CrossRefPubMed
5.
Goadsby PJ (2013) Therapeutic prospects for migraine: can paradise be regained? Ann Neurol 74:423–434CrossRefPubMed
6.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J (2014) Randomized, double-blind, placebo-controlled, phase II trial of ALD403, an anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Lancet Neurol 13:1100–1107CrossRefPubMed
7.
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS (2014) CGRP monoclonal antibody LY2951742 for the prevention of migraine: a phase 2, randomized, double-blind, placebo-controlled study. Lancet Neurol 13:885–892CrossRefPubMed
8.
Akerman S, Holland P, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12:570–584CrossRefPubMed
9.
Kaube H, Katsarava Z, Kaufer T, Diener H-C, Ellrich J (2000) A new method to increase the nociception specificity of the human blink reflex. Clin Neurophysiol 111:413–416CrossRefPubMed
10.
Magis D, Ambrosini A, Bendtsen L, Ertas M, Kaube H, Schoenen J (2007) Evaluation and proposal for optimalization of neurophysiological tests in migraine: part 1--electrophysiological tests. Cephalalgia 27:1323–1338CrossRefPubMed
11.
Kimura J (1989) The blink reflex. In: Kimura J (ed) Electrodiagnosis in diseases of nerve and muscle: principles and practice, 2nd edn. Philadelphia, Davis, pp 307–331
12.
Esteban A (1999) A neurophysiological approach to brain stem reflexes. Blink reflex. Neurophysiol Clin 29:7–38CrossRefPubMed
13.
Misulis KE (1997) Essentials of clinical neurophysiology, 2nd edn. Boston, MA, Butterworth-Heineman
14.
Trontelj MA, Trontelj JV (1978) Reflex arc of the first component of the human blink reflex: a single motoneuron study. J Neurol Neurosurg Psychiatry 41:538–547PubMedCentralCrossRefPubMed
15.
Ongerboer de Visser BW (1983) Anatomical and functional organization of reflexes involving the trigeminal system in man: jaw reflex, blink reflex, corneal reflex and exteroceptive suppression. Adv Neurol 39:727–738PubMed
16.
Ellrich J (2000) Brain stem reflexes: probing human trigeminal nociception. News Physiol Sci 15:94–97PubMed
17.
18.
Cruccu G, Ferracuti S, Leardi MG, Fabbri A, Manfredi M (1991) Nociceptive quality of the orbicularis oculi reflexes as evaluated by distinct opiate- and benzodiazepine-induced changes in man. Brain Res 556:209–217CrossRefPubMed
19.
Zsigmond EK, Domino EF (1980) Ketamine: clinical pharmacology, pharmacokinetics and current clinical use. Anaesthesiol Rev 7:13–33
20.
Nicolodi M, Sicutieri F (1995) Exploration of NMDA receptors in migraine: therapeutic and theoretic implications. Int J Pharmacol Res 15:181–189
21.
Afridi S, Giffin NJ, Kaube H, Goadsby PJ (2013) A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology 80:642–647CrossRefPubMed
22.
Holle D, Heber A, Naegel S, Diener HC, Katsarava Z, Obermann M (2014) Influences of smoking and caffeine consumption on trigeminal pain processing. J Headache Pain 15:39, PubMed PMCID: PMC4068369PubMedCentralCrossRefPubMed
23.
Giffin NJ, Katsarava Z, Pfundstein A, Ellrich J, Kaube H (2004) The effect of multiple stimuli on the modulation of the ‘nociceptive’ blink reflex. Pain 108:124–128CrossRefPubMed
24.
Katsarava Z, Ellrich J, Diener H-C, Kaube H (2002) Optimized stimulation and recording parameters of human ‘nociception specific’ blink reflex recordings. Clin Neurophysiol 113:1932–1936CrossRefPubMed
25.
Hommer DW, Matsuo V, Wolkowitz O, Chrousos G, Greenblatt DJ, Waingartner H, Paul SM (1986) Benzodiazepine sensitivity in normal human subjects. Arch Gen Psychiatry 43:542–551CrossRefPubMed
26.
Tucker AP, Kim YI, Nadeson R, Goodchild CS (2005) Investigation of the potentiation effects on fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain. BMC Anesthesiol 5:2PubMedCentralCrossRefPubMed
27.
Peng P, Sandler A (1999) A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology 20:576–599CrossRef
28.
Oda A, Iida H, Dohi S (2000) Patient anxiety scores after low-dose ketamine or fentanyl for epidural catheter placement. Can J Anaesth 47:910–913CrossRefPubMed
29.
Clements JA, Nimmo WS, Grant IS (1982) Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci 71:539–542CrossRefPubMed
30.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Douglas Bremner J, Heninger GR, Bowers MB, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA Antagonist, Ketamine, in humans. Psychotomimentic, perceptual, cognitive and neuroendocrine responses. Arch Gen Psychiatry 51:199–214CrossRefPubMed
31.
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218CrossRef
32.
Kaube H, Katsarava Z, Przywara S, Drepper J, Ellrich J, Diener H-C (2002) Acute migraine headache. Possible sensitization of neurons in the spinal trigeminal nucleus? Neurology 58:1234–1238CrossRefPubMed
33.
Di Clemente L, Coppola G, Magis D, Fumal A, De Pasqua V, Di Piero V, Schoenen J (2007) Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine? Brain 130:765–770CrossRefPubMed
34.
Katsarava Z, Lehnerdt G, Duda B, Ellrich J, Diener H-C, Kaube H (2002) Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis. Neurology 59:1450–1453CrossRefPubMed
35.
Holle D, Gaul C, Krebs S, Naegel S, Diener HC, Kaube H, Katsarava Z, Obermann M (2011) Nociceptive blink reflex and pain-related evoked potentials in hypnic headache. Cephalalgia 31(11):1181–1188. doi:10.​1177/​0333102411412629​
36.
Holle D, Zillessen S, Gaul C, Naegel S, Kaube H, Diener HC, Katsarava Z, Obermann M (2012) Habituation of the nociceptive blink reflex in episodic and chronic cluster headache. Cephalalgia 32:998–1004CrossRefPubMed
37.
Holle D, Gaul C, Zillessen S, Naegel S, Krebs S, Diener HC, Katsarava Z, Obermann M (2012) Lateralized central facilitation of trigeminal nociception in cluster headache. Neurology 78:985–992CrossRefPubMed
38.
39.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ (2002) Triptan medications to treat acute migraine. Lancet 359:1151–1153CrossRef
40.
Katsarava Z, Limmroth V, Baykal O, Akguen D, Diener HC, Kaube H (2004) Differences of anti-nociceptive mechanisms of migraine drugs on the trigeminal pain processing during and outside acute migraine attacks. Cephalalgia 24:657–662CrossRefPubMed
41.
Giffin NJ, Kowacs F, Libri V, Williams P, Goadsby PJ, Kaube H (2003) Effect of adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 23:287–292CrossRefPubMed
42.
Goadsby PJ, Hoskin KL, Storer RJ, Edvinsson L, Connor HE (2002) Adenosine (A1) receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 125:1392–1401CrossRefPubMed
43.
Humphrey PP, Bland-Ward PA, Carruthers AM, Connor HE, Feniuk W, Honey AC, Thomas M (2001) Inhibition of trigeminal nociceptive afferents by adenosine A1 receptor activation: a novel approach towards the design of new anti-migraine compounds. Cephalalgia 21:268–269CrossRef
44.
Dauthier C, Gaudy JH, Bonnet B (1981) Comparative study of the effects of diazepam and fentanyl on the blink reflex threshold in the normal, conscious human. Ann Anesthesiol Fr 22:317–321PubMed
45.
Romaniello A, Valls-Sole J, Iannetti GD, Truini A, Manfredi M, Cruccu G (2002) Nociceptive quality of the laser-evoked blink reflex in humans. J Neurophysiol 87:1386–1394PubMed
46.
de Tommaso M, Guido M, Libro G, Sciruicchio V, Puca F (2000) Zolmitriptan reverses blink reflex changes induced during the migraine attack in humans. Neurosci Lett 289:57–60CrossRefPubMed
47.
Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC (2000) Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 55:139–141CrossRefPubMed
48.
Storer RJ, Akerman S, Goadsby PJ (2001) GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex. Br J Pharmacol 134:896–904PubMedCentralCrossRefPubMed
49.
Storer RJ, Akerman S, Shields KG, Goadsby PJ (2004) GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by midazolam is antagonized by flumazenil. Brain Res 1013:188–193CrossRefPubMed
50.
Lee WK, Limmroth V, Ayata C, Cutrer FM, Waeber C, Yu X-Y, Moskowitz MA (1995) Peripheral GABA-A receptor mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation. Br J Pharmacol 116:1661–1667PubMedCentralCrossRefPubMed
51.
Limmroth V, Lee WS, Cutrer FM, Moskowitz MA (1996) GABAA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges. Br J Pharmacol 117:99–104PubMedCentralCrossRefPubMed
52.
Cutrer FM, Moskowitz MA (1996) The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 36(10):579–585CrossRefPubMed
53.
Storer RJ, Akerman S, Goadsby PJ (2003) Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex. Br J Pharmacol 138:317–324PubMedCentralCrossRefPubMed
54.
Storer RJ, Goadsby PJ (1999) Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. Neuroscience 90:1371–1376CrossRefPubMed
55.
Classey JD, Knight YE, Goadsby PJ (2001) The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res 907:117–124CrossRefPubMed
56.
Goadsby PJ, Classey JD (2000) Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res 875:119–124CrossRefPubMed
57.
Mitsikostas DD, Sanchez del Rio M, Waeber C, Moskowitz MA, Cutrer FM (1998) The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 76:239–248CrossRefPubMed
58.
Mitsikostas DD, Sanchez del Rio M, Waeber C, Huang Z, Cutrer FM, Moskowitz MA (1999) Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br J Pharmacol 127:623–630PubMedCentralCrossRefPubMed
59.
Kimura J (1973) The blink reflex as a test for brain stem and higher central nervous function. In: Desmet JE (ed) New developments in electromyography and clinical neurophysiology 3. Karger, Basel, pp 682–691
Metadata
Title
Nociception-specific blink reflex: pharmacology in healthy volunteers
Authors
JCA Marin
AR Gantenbein
K. Paemeleire
H. Kaube
PJ Goadsby
Publication date
01-12-2015
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2015
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-015-0568-7

Other articles of this Issue 1/2015

The Journal of Headache and Pain 1/2015 Go to the issue

Research article

Patients with migraine are right about their perception of temperature as a trigger: time series analysis of headache diary data

Case report

Ictal epileptic headache revealing non convulsive status epilepticus in a case of eyelid myoclonia with absences

Research article

Positive effects of the progestin desogestrel 75 μg on migraine frequency and use of acute medication are sustained over a treatment period of 180 days

Research article

Thermal and mechanical quantitative sensory testing in chinese patients with burning mouth syndrome – a probable neuropathic pain condition?

Research article

Migraine and restless legs syndrome are associated in adults under age fifty but not in adults over fifty: a population-based study

Short report

Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study