Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models - PubMed (original) (raw)
Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models
Amanda Avona et al. J Neurosci. 2019.
Abstract
Migraine is the second leading cause for disability worldwide and the most common neurological disorder. It is also three times more common in women; reasons for this sex difference are not known. Using preclinical behavioral models of migraine, we show that application of calcitonin gene-related peptide (CGRP) to the rat dura mater produces cutaneous periorbital hypersensitivity. Surprisingly, this response was observed only in females; dural CGRP at doses from 1 pg to 3.8 μg produce no responses in males. In females, dural CGRP causes priming to a pH 7.0 solution after animals recover from the initial CGRP-induced allodynia. Dural application of interleukin-6 causes acute responses in males and females but only causes priming to subthreshold dural CGRP (0.1 pg) in females. Intracisternal application of BDNF also causes similar acute hypersensitivity responses in males and females but only priming to subthreshold dural CGRP (0.1 pg) in females. Females were additionally primed to a subthreshold dose of the NO-donor sodium nitroprusside (0.1 mg/kg) following dural CGRP. Finally, the sexually dimorphic responses to dural CGRP were not specific to rats as similar female-specific hypersensitivity responses were seen in mice, where increased grimace responses were also observed. These data are the first to demonstrate that CGRP-induced headache-like behavioral responses at doses up to 3.8 μg are female-specific both acutely and following central and peripheral priming. These data further implicate dural CGRP signaling in the pathophysiology of migraine and propose a model where dural CGRP-based mechanisms contribute to the sexual disparity of this female-biased disorder.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) has long been implicated in the pathophysiology of migraine, and CGRP-based therapeutics are efficacious for the treatment of migraine in humans. However, the location of action for CGRP in migraine remains unclear. We show here that application of CGRP to the cranial meninges causes behavioral responses consistent with headache in preclinical rodent models. Surprisingly, however, these responses are only observed in females. Acute responses to meningeal CGRP are female-specific and sensitization to CGRP after two distinct stimuli are also female-specific. These data implicate the dura mater as a primary location of action for CGRP in migraine and suggest that female-specific mechanisms downstream of CGRP receptor activation contribute to the higher prevalence of migraine in women.
Keywords: CGRP; gender; headache; meningeal innervation; migraine; pain.
Copyright © 2019 the authors.
Figures
Figure 1.
Dural administration of CGRP produces facial hypersensitivity and priming in female, but not in male, rats. Baseline facial withdrawal thresholds were determined before dural stimulation with 100 μ
m
CGRP (A) (n = 10 females, n = 7 males), 0.1 μ
m
CGRP (n = 4 females) (B), or vehicle (n = 5 females, n = 7 males). A dural injection of pH 7.0 SIF was given in all groups at day 5 following either dural CGRP or dural vehicle. Two-way ANOVA followed by Bonferroni post hoc test indicated significant differences in females treated with 100 μ
m
CGRP (F(27,250) = 2.591, p < 0.0001) and in females treated with 0.1 μ
m
CGRP (F(27,250) = 2.591, ****p < 0.0001). These data are represented as means ± SEM. *p < .05, **p < .01, ***p < .001.
Figure 2.
Dural application of CGRP produces facial hypersensitivity in female rats at doses as low as 1 pg. Facial withdrawal thresholds were measured before and following dural stimulation with 0.1 pg CGRP (n = 6), 1 pg CGRP (n = 6), or vehicle pH 7.4 SIF (n = 8). Two-way ANOVA followed by Bonferroni post hoc test revealed significant differences in the 1 pg CGRP-treated group (F(8,85) = 11.07; ****p < 0.0001). These data are represented as means ± SEM.
Figure 3.
Dural application of IL-6 induces priming to dural CGRP in females, but not in males. Facial withdrawal thresholds were measured in female (A) and male (B) rats before and after administration of either 0.1 ng dural IL-6 (n = 10 females, n = 11 males) or vehicle pH 7.4 SIF (n = 9 females, n = 11 males). At 72 h after dural IL-6, all animals received a subthreshold dose of dural CGRP (0.1 pg). Two-way ANOVA indicated a significant effect of CGRP in the IL-6-treated group of females. The significant differences of the means for each group were determined by ANOVA followed by Bonferroni post hoc test (F(9,176) = 7.065; **p < .01, ***p < 0.001, ****p < 0.0001). These data are represented as means ± SEM.
Figure 4.
Intracisternal administration of BDNF induces priming to dural CGRP in females, but not males. Facial withdrawal thresholds were measured in female (A) and male (B) rats before and after either cisternal injection of 1 pg BDNF (n = 6 females, n = 6 males) or vehicle (aCSF, pH 7.4) (n = 6 females, n = 6 males). At 72 h after dural IL-6, when animals had baselined, 0.1 pg CGRP was administered to the dura. Two-way ANOVA indicated a significant effect of CGRP in the BDNF-treated group of females. The significant differences of the means for each group were determined by ANOVA followed by Bonferroni post hoc test (F(9,100) = 7.467). These data are represented as means ± SEM; *p < .05, **p < .01, ****p < 0.0001).
Figure 5.
Dural application of CGRP in mice causes hypersensitivity (A) and grimace (B) in females, but not males. For all animals, von Frey baselines as well as Grimace Score baselines were recorded following dural injection of CGRP (n = 6 females, n = 4 males) or vehicle (n = 4 males); then ANOVA with Bonferroni post hoc test showed significant differences in withdrawal thresholds female-treated group (F(20,121) = 4.466; **p < 0.01, ****p < 0.0001) as well as significant grimacing (F(16,99) = 2.033; *p < .05, **p < 0.01, ****p < 0.0001).
Figure 6.
Dural application of CGRP primes female rats to a subthreshold nitric oxide donor. Facial withdrawal thresholds were measured in females before and after either 1 pg CGRP (n = 9) or vehicle pH 7.4 SIF (n = 7) applied to the dura. At 24 h following dural CGRP or dural vehicle, all rats were given 0.1 mg/kg SNP (i.p.). Two-way ANOVA indicated significant effects of SNP in the CGRP-treated group with no response to SNP in the vehicle-treated group. Significant differences in the means of each group were determined by ANOVA followed by Bonferroni post hoc test (F(6,98) = 9.171). These data are represented as means ± SEM; ***p < .001, ****p < .0001).
Figure 7.
Intraplantar administration of CGRP results in hypersensitivity of the hindpaw in females, but not males. Facial and paw withdrawal thresholds for males (A, C) and females (B, D) were tested before and following injection of 1 pg CGRP (n = 9 females, n = 10 males) or vehicle (1× PBS, pH 7.4) (n = 9 females, n = 10 males). Two-way ANOVA followed by Bonferroni post hoc test indicated significant hindpaw allodynia in the hindpaws of CGRP-treated females (F(4,80) = 5.103; **p < 0.01, ***p < 0.001). No significant facial hypersensitivity was observed following intraplantar CGRP administration. These data are represented as means ± SEM to the end of this paragraph.
Comment in
- Female-Specific Effects of CGRP Suggest Limited Efficacy of New Migraine Treatments in Males.
Moehring F, Sadler KE. Moehring F, et al. J Neurosci. 2019 Nov 13;39(46):9062-9064. doi: 10.1523/JNEUROSCI.1254-19.2019. J Neurosci. 2019. PMID: 31723033 Free PMC article. No abstract available.
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