Abstract Details

Intrinsically photosensitive retinal ganglion cells (ipRGCs), which transmit melanopsin and cone signals, have been implicated in mediating visual discomfort in humans and amplified in those with migraine. Aversion to light after triggers (e.g. calcitonin gene-related peptide, CGRP) has been used as a preclinical model of migraine, but the photoreceptor basis of this behavior has yet to be examined.

To measure avoidance to stimuli targeting melanopsin, L-cones, and/or S-cones in a mouse model of migraine.

Transgenic red cone knock-in (RCKI, B6.129-Opn1mw^{tm1(OPN1LW)Nat}/J) mice were studied. Light avoidance was tested in a two-zone chamber that was illuminated by narrow-band LEDs that targeted photopic opsins: 365 nm (UV; rodent S-cone), 460 nm (blue; melanopsin), and 630 nm (red; human L-cone). The zones were set to differing relative contrast levels (0.50 to 1.00) for the targeted photoreceptor. Mice were examined without intervention and following peripheral CGRP (0.1 mg/kg, ip) or vehicle administration every other day for 9 days. A key measure was the asymptotic ratio of time in the high versus low contrast zone.

RCKI mice spent less time in the zone with the higher melanopsin (0.481 ± 0.082, n = 18) or L-cone (0.697 ± 0.113, n = 15) contrast but more time in the zone with the higher S-cone (1.348 ± 0.056, n = 16) contrast. These effects diminished with less relative contrast between the two zones. Furthermore, adding S-cone contrast to melanopsin (0.898 ± 0.122, n = 14) or L-cone (1.158 ± 0.071, n = 45) contrast ameliorated avoidance of these stimuli. Avoidance of ipRGC stimulation was heightened by day 9 of CGRP priming.

The aversion to melanopsin and L-cone stimulation is consistent with ipRGCs responses observed in humans. S-cone stimulation may attenuate ipRGC signals, whereas CGRP may amplify ipRGC signals in migraine-associated photophobia.