Migraine is not just a simple headache. Very often it is accompanied by various symptoms such as nausea, sensitivity to light, noise and visual disturbances, it is characterised by a unilateral throbbing pain sensation that can last for up to 72 hours and is accentuated during physical exercise. 1 in 7 people suffers from migraine and although it is not correlated with age or social background, women tend to suffer twice as much than men. In the UK alone, it is estimated that migraine costs £2 billion a year, hence extensive research is being carried out to develop effective treatments.[1]
Headaches in Migraine – The Crucial Role of CGRP
The headache phase in the migraine occurs when the dilated blood vessels mechanically activate the perivascular trigeminal sensory nerve fibres, the principle sensory nerve in the head. This triggers a pain response with several neurotransmitters, such as substance P and CGRP (calcitonin gene–related peptide), being released to transmit the nociceptive signals from the trigeminal sensory afferents to second-order neurons. CGRP, a potent vasodilator, will aggravate the dilation of cranial blood vessels, cause mast-cell degranulation and initiate neurogenic inflammation within the meninges. As a result, prolonged activation of the meningeal trigeminal nerves, vessels and mast cells causes sensitisation of secondary and tertiary-order neurons which could explain symptoms associated with migraine such as allodynia (skin sensitivity) and photosensitivity.[2]
The role played by CGRP in migraine headaches is widely accepted. Indeed, it has been observed that during a migraine attack, the levels of CGRP in blood and saliva were increased.[3] It was also shown that administrating CGRP to patients prone to migraines resulted in inducing migraine-like headaches.[4]
The role played by CGRP in migraine headaches is widely accepted. Indeed, it has been observed that during a migraine attack, the levels of CGRP in blood and saliva were increased.[3] It was also shown that administrating CGRP to patients prone to migraines resulted in inducing migraine-like headaches.[4]
The Controversial Role of TRPV1 in Migraine Pathology
More recently, it has been shown that the cation channel TRPV1, a nonselective cation channel that is activated by stimuli such as high temperature and capsaicin could also be involved in migraine pathophysiology. Colocalised with CGPR in trigeminal ganglion neurons, TRPV1 when activated promotes the release of CGPR.
It is also known that patients suffering from chronic migraine show elevated levels of nerve growth factor (NGF) in the cerebral spinal fluid and it has been suggested that a NGF-dependent mechanism could lead to the insertion of TRPV1 into the plasma membrane hence increasing the number of TRPV1 channels available for activation on the nociceptor surface membrane. In addition, several studies have also demonstrated that through different pathways, prostaglandins, ATP, BK and possibly NGF reduce the TRPV1 activation threshold by phosphorylating TRPV1 on S502 and S800 and hence causing sensitisation.[5]
Based on this, TRPV1 antagonists seemed to be attractive targets for the treatment of migraine and SB-705498, a TRPV1 antagonist showed promising results in cats. However, in the case of humans, the clinical trial was terminated early due to a lack of efficacy in treating acute migraine.[6] More recently, two TRPV1 receptor antagonists have been shown to be effective in two different experimental models of migraine suggesting that further clinical trials using different TRPV1 antagonists should be performed to better understand the role played by TRPV1 in migraine pathology.[6]
It is also known that patients suffering from chronic migraine show elevated levels of nerve growth factor (NGF) in the cerebral spinal fluid and it has been suggested that a NGF-dependent mechanism could lead to the insertion of TRPV1 into the plasma membrane hence increasing the number of TRPV1 channels available for activation on the nociceptor surface membrane. In addition, several studies have also demonstrated that through different pathways, prostaglandins, ATP, BK and possibly NGF reduce the TRPV1 activation threshold by phosphorylating TRPV1 on S502 and S800 and hence causing sensitisation.[5]
Based on this, TRPV1 antagonists seemed to be attractive targets for the treatment of migraine and SB-705498, a TRPV1 antagonist showed promising results in cats. However, in the case of humans, the clinical trial was terminated early due to a lack of efficacy in treating acute migraine.[6] More recently, two TRPV1 receptor antagonists have been shown to be effective in two different experimental models of migraine suggesting that further clinical trials using different TRPV1 antagonists should be performed to better understand the role played by TRPV1 in migraine pathology.[6]
Working with TRPV1? Have a look at our products:
| Biosensis Antibodies to TRPV1 | Cat. No. |
|---|---|
| Rabbit antibody to human capsaicin receptor (531-541): whole serum | R-053-100 |
| Rabbit antibody to human capsaicin receptor (608-621): whole serum | R-076-100 |
| Mouse monoclonal antibody to rat capsaicin receptor (VR1, TRPV1, 819-838), [Clone BS397]: IgG | M-1714-100 |
| StressMarq Small Molecules | Cat. No. |
| Capsaicin (TRPV1 opener) | SIH-322 |
| BCTC (TRPV1 blocker) | SIH-307 |
| SB-366791 (TRPV1 blocker) | SIH-321 |
Current and Emerging Treatments
Current migraine treatments include the use of nonsteroidal anti-inflammatory drugs (NSAID) such as aspirin, ibuprofen, naproxen and didofenac potassium. When the pain is moderate to severe, triptans (highly selective serotonin 5-HT1B and 5-HT1D receptor agonists) are considered to be the first line of treatment. Indeed, serotonin vasoconstricts the nerve endings and blood vessels and consequently affects nociceptive pain. [7]
However, because of the presence of the 5-HT1B receptors on blood vessels and the vascular risks associated with the use of these drugs, ditans, a novel class of chemicals selectively targeting the 5-HT1F receptors expressed in the trigeminal nerve pathway but lacking the vasoconstrictive properties, are being developed. Currently, lasmiditan is in phase III clinical trials in the US. [8]
However, because of the presence of the 5-HT1B receptors on blood vessels and the vascular risks associated with the use of these drugs, ditans, a novel class of chemicals selectively targeting the 5-HT1F receptors expressed in the trigeminal nerve pathway but lacking the vasoconstrictive properties, are being developed. Currently, lasmiditan is in phase III clinical trials in the US. [8]
As seen previously, CGRP plays an important role in the pathogenesis of migraine and as a result, several small molecules, CGRP receptor antagonists called gepants have been developed. In particular, telcagepant and MK-3207 were shown to be effective treatments for acute migraine, but were terminated due to their liver toxicity.[2] Other drugs based on monoclonal antibodies are currently being developed. These new treatments target either CGRP or the CGRP receptors and currently show promising results in human clinical trials. Aimovig (erenumab) developeed by Amgen and Novartis has recently been FDA-approved as a preventive migraine treatment by blocking the activity of CGRP receptors.[9]
Migraine Research: ImmunoStar Antibodies can help
ImmunoStar has developed an excellent range of antibodies for neuroscience research. These antibodies are put through extensive testing before release to ensure they are both high quality and high titer. This provides excellent reliability and lot-to-lot consistency. They have also been specifically tested for use in immunohistochemistry. They are currently available to purchase through Newmarket Scientific.
Migraine related articles using antibodies from the ImmunoStar range can be found below:
| References | ImmunoStar antibodies |
|---|---|
| Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine, Noseda R et al, PNAS, 2017, 114 (28): E5683-E5692 |
Tyrosine hydroxylase, oxytocin, vasopressin 1 |
| Hypothalamic and basal ganglia projections to the posterior thalamus: Possible role in modulation of migraine headache and photophobia; Kagan R et al, Neuroscience 2013, 248, 359-368 |
Tyrosine hydroxylase, cholecystokinin octapeptide (CCK8) |
| Neurochemical Pathways That Converge on Thalamic Trigeminovascular Neurons: Potential Substrate for Modulation of Migraine by Sleep, Food Intake, Stress and Anxiety, Noesda R et al, Plos one 2014, 9 (8): e103929 |
Tyrosine hydroxylase |
| Dopamine β-Hydroxylase Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons, Bucelli RC et al, J. Pharmacol Exp Ther, 2008, 324 (3): 1172-1180 |
Substance P |
References:
[1] https://www.telegraph.co.uk/news/2018/04/17/new-migraine-treatment-could-help-drugs-fail/ Accessed on 21/05/2018
[2] Migraine, Dodick DW, The Lancet, 2018, 391 (10127), 1315-1330
[3] Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Goadsby PJ et al, Ann Neurol. 1990;28:183–7.
[4] Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Cady RK et al. Headache. 2009;49:1258–66.
[5] TRPV1 in migraine pathophysiology, Meents JE et al, Trends in Molecular Medicine, 2010, 16 (4):153-159
[6] Two TRPV1 receptor antagonists are effective in two different experimental models of migraine, Meents JE et al, The Journal of Headache and Pain, 2015, 16:57
[7] CGRP and serotonin in migraine, Aggarwal M et al, Annal od Neurosciences, 2012 19 (2): 88-94 https://www.researchgate.net/publication/265558756_Serotonin_and_CGRP_in_migraine
[8] Migraine Therapy: Current Approaches and New Horizons, Goadsby PJ et al, Neurotherapeutics, 2018, 15 (2) :271-273
[9] https://www.genengnews.com/gen-news-highlights/amgen-novartis-set-to-launch-migraine-drug-aimovig-next-week-after-fda-approval/81255834 Accessed on 21/05/2018
[9] https://www.genengnews.com/gen-news-highlights/amgen-novartis-set-to-launch-migraine-drug-aimovig-next-week-after-fda-approval/81255834 Accessed on 21/05/2018
Written by Magalie Dale
If you like my post why not connect to me on LinkedIn. 
No comments:
Post a Comment