Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain

Abstract

Introduction Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405. Methods Cutaneous sensitivity to hind paw, and periorbital mechanical stimulation were used as surrogate markers of activation of relevant pain pathways in each respective model. Separate experiments were performed to identify the time-course of treatment response to olcegepant (1 mg/kg i.p.) and ALD405 (10 mg/kg i.p.). Results Olcegepant and ALD405 significantly alleviated cutaneous mechanical hypersensitivity in both models compared with corresponding control treatments (saline and IgG control antibody respectively). As expected, the duration of anti-nociceptive action obtained with ALD405 was considerably longer than that associated with olcegepant. Surprisingly, in the spontaneous rat model the onset of action of ALD405 occurred within just 4 hours after administration. Discussion The current data clearly show that calcitonin gene-related peptide-mediated signaling is critically involved in the manifestation of cutaneous hypersensitivity in distinct rodent models of migraine-like pain and emphasise their translational relevance. Moreover, the unexpected rapidity of onset observed for ALD405 supports i) a probable site of action outside the blood-brain barrier, and ii) a potential clinical utility of specific monoclonal calcitonin gene-related peptide antibodies in the abortive treatment of migraine.

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

“…On day 10, 24 hours after the final NTG injection, baseline mechanical responses were assessed and mice were treated with olcegepant or vehicle. Olcegepant significantly inhibited NTG-induced cephalic allodynia ( Figure 6B), similar to previously published reports [32]. Subsequent golgi analysis of TNC revealed cytoarchitectural alterations in this cohort of animals ( Figure 6C).…”

“…Similar to humans, NTG produces a delayed allodynia in mice [35], as well as photophobia and altered meningeal blood flow [36,37]. Chronic intermittent administration of NTG is used to model chronic migraine [32,[38][39][40][41]. Although, compared to humans, much higher doses of NTG are required in rodents, the allodynia induced in mice is inhibited by migraine-specific medications, such as sumatriptan [35,38,42] and CGRP targeting drugs [32], as well as the migraine preventives propranolol and topiramate [43,44].…”

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

“…These concentrations were chosen based on preclinical migraines models [58,59,60] and using established protocols to convert compound concentrations from rats to mice [61]. However, to account for different routes of administration, intravenous in the reference experiments [58,59,60] versus i.p. in our model, the mouse-adapted concentration was over-titrated 2–4 fold.…”

ATP sensitive potassium (KATP) channel inhibition: A promising new drug target for migraine

“…One model is a genetically inbred strain, the spontaneous trigeminal allodynic (STA) rat, which exhibits tactile hypersensitivity in the head but not in the hindpaws (25,26). The other model uses repeated injection of glyceryl trinitrate (GTN) to provoke a general state of hyperalgesia in mice (27,28). Both animal models respond to migraine-specific drugs including the 5-HT 1B/D receptor agonist sumatriptan, the CGRP receptor antagonist olcegepant and a CGRP antibody (25–28).…”