The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats

Hirsch, Silke; Corradini, Laura; Just, Stefan; Arndt, Kirsten; Doods, Henri

doi:10.1016/j.pain.2013.01.002

Cited by 64 publications

(60 citation statements)

References 73 publications

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“…This is in agreement with the observation that several parts of the brain involved in pain transmission by the trigeminal nerve appear not to be protected by the BBB and are therefore potential targets of CGRP-R antagonists (Eftekhari et al, 2013). Additionally, should CGRP antibodies prove efficacious for the treatment of other chronic impairments, such as osteoarthritis (Mapp et al, 2012;Hirsch et al, 2013;Benschop et al, 2014) and menopausal flushing (Gupta et al, 2007;Hay and Poyner, 2009), the favorable dosing scheme of antibodies over small molecules could increase their therapeutic value. The first positive results from clinical proof-of-concept studies in migraine prevention with LY2951742 and ALD-403 were presented at the 2014 American Academy of Neurology conference, and additional clinical trials with LY2951742 (Bigal and Walter, 2014) and other antibodies to CGRP (LBR-101) or CGRP-R (AMG334) are underway.…”

Section: Discussionsupporting

confidence: 86%

“…The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator (Brain et al, 1985), but also has well established roles in neurogenic inflammation and nociception (Hirsch et al, 2013). CGRP is widely expressed in the central and peripheral nervous system and is able to facilitate the production and secretion of numerous proinflammatory mediators that lead to hyperemia, edema, and pain in inflamed tissues (Cady et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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

Vermeersch

Benschop

Hecken

et al. 2015

J Pharmacol Exp Ther

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LY2951742, a monoclonal antibody targeting calcitonin generelated peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicininduced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

Vermeersch

Benschop

Hecken

et al. 2015

J Pharmacol Exp Ther

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“…Consistent with this finding, higher expression of IL-1b was observed in synovial macrophages which, when depleted by the treatment of mice with liposomal clodronate, led to decreased IL-1b gene expression in ST. Taken together, these findings indicate that IL-1b is produced mainly by macrophages in synovium. Numerous studies have implicated the involvement of CGRP in the peripheral mechanisms of OA pain [6,[17][18][19][20][21][22]. For example, suppression of the expression of CGRP in the synovium of an adjuvant-induced arthritis rat model has been shown to attenuate the pain [17].…”

Section: Discussionmentioning

confidence: 99%

Synovial macrophage-derived IL-1βregulates the calcitonin receptor in osteoarthritic mice

Takano

Uchida

Miyagi

et al. 2015

Clinical and Experimental Immunology

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SummaryRecent studies have reported that calcitonin gene-related peptide (CGRP) contributes to joint pain. However, regulation of the CGRP/CGRP receptor signalling in osteoarthritis (OA) is not fully understood. To investigate the regulation of CGRP/CGRP receptor signalling by macrophages in the synovial tissue (ST) of OA joints, we characterized the gene expression profiles of CGRP and CGRP receptors in the ST of OA mice (STR/Ort). In addition, we examined whether macrophage depletion by the systemic injection of clodronate-laden liposomes affected the expression of CGRP and CGRP receptors in ST. of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80 1 cell fraction expressed IL-1b highly, whereas the F4/80 2 cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL-1b and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL-1b treatment of cultured synovial cells up-regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL-1b and regulators of CLR in OA mice. Therefore, macrophages and IL-1b may be suitable therapeutic targets for treating OA pain.

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“…CGRP is involved in pain neurotransmission at different levels of the nervous system and acts via potentiation of the excitatory effect induced by diverse noxious stimuli (Biella et al, 1991). The role of CGRP in nociception has been demonstrated in studies of migraine (Benemei et al, 2009), noxious heat (Mogil et al, 2005), mechanical hyperalgesia (Hirsch et al, 2013), and secondary hyperalgesia (Zhang et al, 2001). Moreover, blockade of the TRPV1 receptor reduces the release of both glutamate and CGRP (Puttfarcken et al, 2010), and stimulation by capsaicin, noxious heat, or protons increased CGRP release from TRPV1 neurons (Sauer et al, 2001;Fischer et al, 2003;Bernardini et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

et al. 2013

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammationinduced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.

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The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats

Cited by 64 publications

References 73 publications

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

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

Synovial macrophage-derived IL-1βregulates the calcitonin receptor in osteoarthritic mice

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

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