PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP

Kuburas, Adisa; Mason, Bianca N.; Hing, Benjamin; Wattiez, Anne‐Sophie; Reis, Alyssa S.; Sowers, Levi P.; Loomis, Cristina Moldovan; Garcı́a-Martı́nez, León F.; Russo, Andrew F.

doi:10.1523/jneurosci.2200-20.2021

Cited by 29 publications

(37 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also showed this both in knockout mice without functional CGRP receptors and by antibody neutralization of CGRP. Our ndings are supported by data from another group using light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP38 (11). These ndings are important as PACAP38 is the only migraine trigger tested in our rodent model to bypass CGRP.…”

Section: Introductionsupporting

confidence: 75%

“…This contrasts with previous observations in mice sensitized by GTN and levcromakalim where CGRP antagonism was highly effective (22). Light aversion in mice as a surrogate for migraine-like photophobia was used to compare CGRP and PACAP38 (11). It showed that one-third of mice did not respond to PACAP38, which was not seen with CGRP.…”

Section: Pacap38 Signaling Pathways Are Distinctcontrasting

confidence: 69%

“…administration dose of 30 mg/kg for anti-PACAP mAb was selected based on previous experiments using this drug showing effect in the light aversion mouse model for migraine-like photophobia (11). The antibody dose corresponded to 8 nmol/mouse, which is approximately threefold excess antibody over exogenous PACAP38 (2.6 nmol) (11). In vitro tests had shown that the anti-PACAP mAb binds both PACAP38 and the other PACAP isoform, PACAP27, with equal a nity (25).…”

Section: Test Compoundsmentioning

confidence: 99%

See 2 more Smart Citations

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

Guo

Ernstsen

Hay‐Schmidt

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Calcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50–60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan. Methods In vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan. Results We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity. Conclusions Based on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.

show abstract

Section: Introductionsupporting

confidence: 75%

Section: Pacap38 Signaling Pathways Are Distinctcontrasting

confidence: 69%

Section: Test Compoundsmentioning

confidence: 99%

See 1 more Smart Citation

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

Guo

Ernstsen

Hay‐Schmidt

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…TRPC5 inhibitors may prove analgesic in all of the following conditions in which LPC is elevated: rheumatoid arthritis (47), osteoarthritis (48), SCD (34), fibromyalgia (49), diabetes (50), multiple sclerosis (47), primary dysmenorrhea (51), lumbar spinal stenosis (52), and migraine (29). Additional support for TRPC5 inhibitors in migraine comes from a recent study in which Trpc5 expression was elevated in TG neurons of mice that developed pituitary adenylate cyclase activating polypeptide (PACAP)induced light aversion (53). Future studies should determine whether TRPC5 is a convergent secondary target for the G protein-coupled peptidergic signaling (CGRP and PACAP) (54) that occurs in patients with migraine.…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice

et al. 2021

View full text Add to dashboard Cite

Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express TRPC5, the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.

show abstract

“…Migraine pathogenesis is multifactorial. The failure of efficacy in the non-responders to current medications suggests that CGRP is not the only cause of migraine and that other neuropeptides are involved; e.g., pituitary adenylate cyclase-activating peptide (PACAP-38) works independently of CGRP or 5-HT 1B/1D/1F receptors (Kuburas et al, 2021 ; Ernstsen et al, 2022 ). In addition, CGRP-based drugs act on the periphery with low penetration across the blood-brain barrier (Edvinsson and Warfvinge, 2019 ); eg., a preclinical study reported that galcanezumab, one of the FDA-approved CGRP antibodies targeting the CGRP peptide, demonstrated limited blood-brain barrier penetration when injected peripherally into rats (Johnson et al, 2019 ).…”

Section: The Current Therapeutics For Migrainementioning

confidence: 99%

Involvement of the cerebellum in migraine

Wang

Tutt

Dorricott

et al. 2022

Front. Syst. Neurosci.

View full text Add to dashboard Cite

Migraine is a disabling neurological disease characterized by moderate or severe headaches and accompanied by sensory abnormalities, e.g., photophobia, allodynia, and vertigo. It affects approximately 15% of people worldwide. Despite advancements in current migraine therapeutics, mechanisms underlying migraine remain elusive. Within the central nervous system, studies have hinted that the cerebellum may play an important sensory integrative role in migraine. More specifically, the cerebellum has been proposed to modulate pain processing, and imaging studies have revealed cerebellar alterations in migraine patients. This review aims to summarize the clinical and preclinical studies that link the cerebellum to migraine. We will first discuss cerebellar roles in pain modulation, including cerebellar neuronal connections with pain-related brain regions. Next, we will review cerebellar symptoms and cerebellar imaging data in migraine patients. Lastly, we will highlight the possible roles of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine symptoms, including preclinical cerebellar studies in animal models of migraine.

show abstract

PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP

Abstract: The contents do not represent the views of VA or the United States Government. We thank Michael Anderson and Kai Wang for help interpreting the inheritance pattern and Johannes Ledolter for help with statistical analysis..

Cited by 29 publications

References 103 publications

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice

Involvement of the cerebellum in migraine

Contact Info

Product

Resources

About