Genetic Enhancement of Calcitonin Gene-Related Peptide-Induced Central Sensitization to Mechanical Stimuli in Mice

Abstract

Calcitonin gene-related peptide (CGRP) is a key player in migraine. To address the role of CGRP in mechanical allodynia, which is a common feature of migraine, we used CGRP-sensitized transgenic mice. These mice have elevated nervous system expression of the human receptor activity-modifying protein-1 (hRAMP1) subunit of the CGRP receptor. Under baseline conditions, the nestin/hRAMP1 mice and control littermates had similar hindpaw withdrawal thresholds to von Frey filaments. The effect of CGRP was tested using a filament that elicited a withdrawal response on 20% of its presentations. Following intrathecal injection of 1 nmol CGRP in the nestin/hRAMP1 mice, the response frequency was 80% within 30 min. The antagonist CGRP(8-37) blocked the increased response. In control littermates, a five-fold higher dose of CGRP was required to elicit a similar response. In contrast to intrathecal injection, peripheral CGRP did not increase the mechanical responses. Intraplantar injection of capsaicin was used to test the efficacy of endogenous CGRP. Capsaicin increased mechanical responses in the nestin/hRAMP1 and control mice, although a higher dose was required in controls. In contrast to control mice, there was also a contralateral paw response in nestin/hRAMP1 mice, which is consistent with central sensitization. PERSPECTIVE: In this study we show central CGRP-induced mechanical allodynia that is enhanced by overexpression of RAMP1 in nervous system. These data suggest that hypersensitivity to CGRP could be a potential mechanism underlying central sensitization in migraine and point to CGRP receptor antagonists as a possible therapy for other pain disorders.

Fat location defines sensation

“…Intriguingly, many peptide mediators associated with small-diameter sensory neurons [calcitonin gene-related peptide (CGRP), substance P, brain-derived neurotrophic factor (BDNF)] have been shown to evoke allodynia when applied intrathecally (15)(16)(17). Thus a major afferent barrage from peptidergic nociceptive neurons is likely to sensitize dorsal horn neurons that are normally wired for mechanosensitive input through the (extrasynaptic?)…”

Evidence for anti-inflammatory and putative analgesic effects of a monoclonal antibody to calcitonin gene-related peptide

“…For example; CGRP has been shown to be upregulated in the dorsal root ganglion in models of neuropathic and inflammatory pain (Chao et al, 2008;Iwakura et al, 2010), and has been shown to have a significant role in neurogenic (Lin et al, 2007), dermal, intradermal and subcutaneous inflammation Seybold et al, 1995;Malcangio and Bowery, 1996;Lofgren et al, 1997). A recent study has also demonstrated a role for CGRP in central sensitisation (Marquez de Prado et al, 2009). In addition, there is evidence that the CGRP antagonist CGRP 8-37 has antinociceptive effects in models of central neuropathic pain (Bennett et al, 2000), and spinal nerve-mediated inflammatory (Yu et al, 1996a(Yu et al, , 1998 and neuropathic pain (Yu et al, 1996b).…”

Classification, Mechanism, Biochemistry, and Genetics of Headache

“…32 However, because CGRP is also intimately associated with the signaling of pain by peripheral sensory afferents, nociceptive reflexes were also enhanced in this mouse. 33 Thus, the mutant mice in this experimental paradigm do not present the opportunity to clearly distinguish between the somatosensory and visual sensory aspects of these light-avoidant behaviors. However, these experiments clearly indicate the eloquent role that CGRP plays in the full range of sensory and behavior changes associated with migraine, and provide a valuable animal model of the pathophysiology of migraine.…”