Journal article
PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP
The Journal of neuroscience, Vol.41(21), pp.4697-4715
04/10/2021
DOI: 10.1523/JNEUROSCI.2200-20.2021
PMID: 33846231
Abstract
The neuropeptides CGRP and PACAP have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about a third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex-linked, although there was a trend for greater responses among male mice. RNA-seq analysis of trigeminal ganglia yielded hieriechial clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of the
and
ion channels and glycoprotein hormones and receptors in a subset of male responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice.
The relationship between the neuropeptides CGRP and PACAP in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics.
Details
- Title: Subtitle
- PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP
- Creators
- Adisa Kuburas - Department of Molecular Physiology and BiophysicsBianca N Mason - Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242Benjamin Hing - Department of Molecular Physiology and BiophysicsAnne-Sophie Wattiez - Department of Molecular Physiology and BiophysicsAlyssa S Reis - Department of Molecular Physiology and BiophysicsLevi P Sowers - Center for the Prevention and Treatment of Visual Loss, Veterans Affairs Health Care System, Iowa City, IA 52246Cristina Moldovan Loomis - Alder Biopharmaceuticals, Inc., Bothell, Washington 98011Leon F Garcia-Martinez - Alder Biopharmaceuticals, Inc., Bothell, Washington 98011Andrew F Russo - Center for the Prevention and Treatment of Visual Loss, Veterans Affairs Health Care System, Iowa City, IA 52246
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.41(21), pp.4697-4715
- DOI
- 10.1523/JNEUROSCI.2200-20.2021
- PMID
- 33846231
- NLM abbreviation
- J Neurosci
- eISSN
- 1529-2401
- Publisher
- United States
- Grant note
- name: NIH, award: NS075599, NS098825; name: University of Iowa, Center Support Grant, award: P30EY025580
- Language
- English
- Date published
- 04/10/2021
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Neurology (Pediatrics)
- Record Identifier
- 9984071796802771
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