Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model

Vermeersch, Steve; Benschop, Robert J.; Hecken, Anne Van; Monteith, David K.; Wroblewski, Victor J.; Grayzel, David; Hoon, Jan de; Collins, Emily C.

doi:10.1124/jpet.115.224212

Cited by 52 publications

(71 citation statements)

References 28 publications

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“…168 Oral administration of the CGRP antagonist telcagepant and injection of the humanized monoclonal CGRP antibody galcanezumab (LY2951742) both blocked capsaicin-induced increases in dermal blood flow, as measured by laser Doppler perfusion imaging in healthy human subjects. 168,183 Taken together, these observations all support the contention that CGRP is the major mediator of neurogenic dilator responses arising from the activation of sensory nerves in humans. 81 This situation contrasts with the rat, where these neuropeptides produce not only vasodilation and plasma protein extravasation but also histamine release and mast cell degranulation.…”

Section: Peripheral Sensitization and The Role Of Calcitonin Gene–supporting

confidence: 52%

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

457

364

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Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene–related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene–related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

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Section: Peripheral Sensitization and The Role Of Calcitonin Gene–supporting

confidence: 52%

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

457

364

View full text Add to dashboard Cite

show abstract

“…Sinclair et al [118] demonstrated reduced increase in dermal blood flow after topical capsaicin application in the forearm of healthy volunteers who were pretreated with CGRP antagonist (telcagepant). The degree of inhibition in capsaicin-induced dermal blood flow was shown to be increased with higher LY2951742, CGRP monoclonal antibody, plasma concentrations suggesting dose–response relationship [119]. …”

Section: Discussionmentioning

confidence: 99%

Calcitonin gene-related peptide and pain: a systematic review

et al. 2017

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BackgroundCalcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been clarified.MethodsWe performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials.ResultsThe literature search identified 375 citations of which 50 contained relevant original data. An association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain was found. In 13 out of 20 studies in somatic pain conditions, CGRP levels had a positive correlation with pain. Increased CGRP levels were reported in plasma, synovial and cerebrospinal fluid in subjects with musculoskeletal pain. A randomized clinical trial on monoclonal antibody, which selectively binds to and inhibits the activity of CGRP (galcanezumab) in patients with osteoarthritis knee pain, failed to demonstrate improvement of pain compared with placebo. No studies to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions.ConclusionThe present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act as a neuromodulator in non-headache pain conditions. However, more studies are needed to fully understand the role of CGRP in nociceptive processing and therapy of chronic pain.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-017-0741-2) contains supplementary material, which is available to authorized users.

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“…However, the fact that LY2951742 blocked most of the CGRP-induced peripheral vasodilation [21] suggests that antibodies against CGRP or its receptor would wipe out the entire endogenous CGRP system for at least several weeks. The question we discuss here is, although abolishing the effects of CGRP might be beneficial by preventing migraine attacks, could this also have harmful effects?…”

Section: Trendsmentioning

confidence: 96%