Light-aversion and cephalic allodynia in an intravenous CGRP model of migraine-like behaviour in male and female rats

Background
Photophobia is a common and highly bothersome migraine-associated symptom, where light may cause discomfort and exacerbate headache pain. Calcitonin gene-related peptide (CGRP) may be involved in nociceptive signalling during photophobia. In clinical provocation studies, intravenous CGRP induces both migraine attacks and photophobia. Animal studies attempting to model this have used intraperitoneal or intracranial injections and behavioural tests requiring very high light intensities to provoke light-aversive behaviour, a surrogate for photophobia-like responses. Here, we evaluated the effects of intravenous CGRP on light aversion alongside periorbital sensitivity in naïve rats.

Methods
Male and female Sprague Dawley rats received intravenous injections of 100 µg/kg human αCGRP or saline (n = 6–12/group). After 20 min, light aversion was assessed in an optimized light/dark box (LDB) test. The LDB was optimized by adding bedding material to minimize novelty-related anxiety. Following a washout period, the same rats were re-dosed and tested in either a dim/dark box (DDB) test or an open field test (OFT) to evaluate anxiety in the absence of bright light. Cephalic allodynia, used as an indicator of headache-like pain, was assessed with von Frey measurements.

Results
CGRP-injected rats of both sexes spent significantly less time in the bright compartment of the LDB than controls. This avoidance was absent in the DDB test, and no CGRP-related effect was seen in the OFT, indicating that the effect was light-specific rather than anxiety-based. CGRP also significantly increased periorbital sensitivity, which was not seen following saline injection. Housing conditions and test order influenced outcomes, with female rats seemingly most affected. Grouping animals by treatment and using naïve rats for von Frey appeared to provide the most consistent results.

Conclusions
Intravenous CGRP induced light aversion in both male and female rats, supported by a lack of effect in complementary anxiety tests. The same dose also induced cephalic allodynia, suggestive of headache-like pain. These findings show parallels to clinical provocation studies and highlight the translational potential of this intravenous model for studying migraine-related photophobia-like behaviour. Moreover, the study underscores that housing and test order can strongly influence behavioural outcomes, emphasizing the importance of experimental design in preclinical migraine research.