Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. After intraperitoneal CGRP, motility was decreased in the dark only, similar to motility changes after intracerebroventricular CGRP. In addition, as with intracerebroventricular CGRP, there was no general increase in anxiety as measured in an open-field assay after intraperitoneal CGRP. Importantly, two clinically effective migraine drugs, the 5-HT 1B/D agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after intraperitoneal CGRP injection, but was seen after intracerebroventricular CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves.

CGRP and the Trigeminal System in Migraine

“…173 Photophobia is a distinctive feature of migraine that led to the development of a preclinical model in mice. 174 Intracerebroventricular injection of CGRP induces aversion to bright or dim light in transgenic mice that overexpress the human RAMP1 subunit of the CGRP receptor, but not to wild-type mice, and aversion to bright light in wild-type mice. [174][175][176] Co-administration of olcegepant blocks light aversion.…”

“…174 Intracerebroventricular injection of CGRP induces aversion to bright or dim light in transgenic mice that overexpress the human RAMP1 subunit of the CGRP receptor, but not to wild-type mice, and aversion to bright light in wild-type mice. [174][175][176] Co-administration of olcegepant blocks light aversion. [174][175][176] Moreover, peripherally administered CGRP also produced aversion to bright light that was blocked by a CGRP antibody, in the wild-type and transgenic mice, but failed to induce aversion to low light in the transgenic mice.…”

“…[174][175][176] Co-administration of olcegepant blocks light aversion. [174][175][176] Moreover, peripherally administered CGRP also produced aversion to bright light that was blocked by a CGRP antibody, in the wild-type and transgenic mice, but failed to induce aversion to low light in the transgenic mice. 174 It was concluded that CGRP can elicit photophobia through distinct, and perhaps overlapping, peripheral and central mechanisms.…”

“…174 It was concluded that CGRP can elicit photophobia through distinct, and perhaps overlapping, peripheral and central mechanisms. 174…”

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

“…Furthermore, rats subjected to the 450 g CHI also displayed increased thigmotaxis, another measurement of increased anxiety levels in open field testing (28), a behavior which was not observed previously in the milder CHI paradigm. The prolonged reduction in rearing activity following the more severe head injury could also reflect migraine-like head pain as it was also observed following noxious stimulation of the cranial meninges (19), as well as in response to peripheral and systemic administration of the headache trigger CGRP (29).…”