Biology subjects

Sowers, L. P.

Publications and source records attributed to Sowers, L. P..

4 recordsLinked to original sources

bioRxiv2022

CGRP Administration into the Cerebellum Evokes Migraine-like Behaviors Predominately in Female Mice

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of behavioral tests was done to assess migraine-like behaviors. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. In contrast, significant responses to CGRP were seen only with female mice in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. In male mice, the responses had the same trend as females but did not reach statistical significance. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP in the MN causes light aversion in males, while in females, light aversion is accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine pathophysiology and possibly its prevalence in females.

neuroscience↗

bioRxiv2021

Female mice exhibit a more sensitive automated squint response to pain induced by CGRP and amylin

We developed an automated squint assay using both black C57BL/6J and white CD1 mice that measured the interpalpebral fissure area between the upper and lower eyelids as an objective quantification of pain. In C57BL/6J mice, we observed a squint response to increasing doses of a migraine trigger, the neuropeptide CGRP, including a significant response in female mice at a dose below detection by the manual grimace scale. Using the automated software, both C57BL/6J and CD1 mice lacked a detectable photic blink response. The CGRP-related peptide amylin induced squinting behavior in female mice, but not males. These data demonstrate that an automated squint assay can be used as an objective, real-time continuous-scale measure of pain that provides higher precision and real-time analysis compared to manual grimace assessments.

neuroscience↗

bioRxiv2020

PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP

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 generally 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 pituitary hormones and receptors in a subset of 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. SignificanceThe 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.

neuroscience↗

bioRxiv2020

Multifactorial and closed head impact traumatic brain injuries cause distinct tactile hypersensitivity profiles

Chronic complications of traumatic brain injury (TBI) represent one of the greatest financial burdens and sources of suffering in society today. A substantial number of these patients suffer from post-traumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been under-studied, in large part due to the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of two non-penetrating models of PTH. We show that multifactorial TBI, consisting of aspects of impact, acceleration/deceleration, and blast wave exposure, produces long term tactile hypersensitivity and central sensitization, phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show more severe phenotype with repetitive daily injury for three days, compared to either one or three successive injuries in a single day, providing new insight into patterns of injury that may place patients at greater risk of developing PTH. Importantly, even after recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury had persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide (CGRP) and sodium nitroprusside, a nitric oxide donor. Our results offer new tools for studying PTH, as well as preclinical support for a pathophysiologic role of CGRP in this condition. SummaryTwo models of post-traumatic headache after traumatic brain injury provide novel laboratory tools and insights in relative risks of injury and therapeutic opportunities.

neuroscience↗