A Potential Preclinical Migraine Model: CGRP-Sensitized Mice

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine. However, a major challenge for studying CGRP actions is the lack of animal models for migraine. Clinical studies suggested that migraineurs are more sensitive to CGRP than people who do not suffer from migraine. We therefore generated a transgenic mouse that is sensitized to CGRP (nestin/hRAMP1 mice). The mice have elevated expression of a subunit of the CGRP receptor, human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have two symptoms of migraine: photophobia and mechanical allodynia. The light aversion was greatly enhanced by intracerebroventricular administration of CGRP. CGRP had little effect on motility in the light zone, but once in the dark, the mice moved less than controls. The CGRP-induced light aversion was attenuated by co-administration of the CGRP receptor antagonist olcegepant. These findings suggest that CGRP acts as a neuromodulator to increase sensory responses and that regulation of a single gene, hRAMP1, could potentially contribute to migraine susceptibility.

Figure 1. CGRP receptor

Left, schematic of CGRP receptor complex containing RAMP1, CLR, and RCP. Right, Increased sensitivity to CGRP following expression of RAMP1 from an adenoviral vector in cultured trigeminal ganglia neurons. Ad-GFP is a control vector. Figure modified from (24).

Figure 2. CGRP-induced light aversion by nestin/hRAMP1 mice

A. The nestin/hRAMP1 mice spent less time in the light after icv CGRP (0.5 nmol/2 ul) compared to vehicle (PBS) or control mice given CGRP or vehicle. Data are shown from the second 5 min monitoring interval. B. The antagonist olcegepant (0.5 nmol) prevented the CGRP-induced light aversion seen in the nestin/hRAMP1 mice. For both panels, * P<0.05 (Student’s two tailed t test) compared to vehicle. Error bars are standard error of the mean. Figure modified from (45).

Figure 3. Model of CGRP as a neuromodulator of glutamatergic synapses

Co-release of CGRP with glutamate from presynaptic neurons (for example, a peripheral nociceptor) could act presynaptically to further increase neurotransmitter release and/or postsynaptically to increase glutamate receptor activity. In addition, CGRP could act in a paracrine fashion on nearby glia (lower left cell) and/or dural mast cells (not shown) to indirectly act on the neurons.