The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats

Abstract

Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFA-injected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain.

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

“…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.…”

“…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).…”

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

“…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].…”

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

“…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).…”