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Roads Less Traveled: Sexual Dimorphism and Mast Cell Contributions to Migraine Pathology.

Loewendorf AI, Matynia A, Saribekyan H, Gross N, Csete M, Harrington M - Front Immunol (2016)

Bottom Line: MC-neuron bidirectional communication uniquely positions these cells as potential initiators and/or perpetuators of pain.MCs can secrete nociceptor sensitizing and activating agents, such as serotonin, prostaglandins, histamine, and proteolytic enzymes that can also activate the pain-mediating transient receptor potential vanilloid channels.MCs express receptors for both estrogen and progesterone that induce degranulation upon binding.

View Article: PubMed Central - PubMed

Affiliation: Huntington Medical Research Institutes , Pasadena, CA , USA.

ABSTRACT
Migraine is a common, little understood, and debilitating disease. It is much more prominent in women than in men (~2/3 are women) but the reasons for female preponderance are not clear. Migraineurs frequently experience severe comorbidities, such as allergies, depression, irritable bowel syndrome, and others; many of the comorbidities are more common in females. Current treatments for migraine are not gender specific, and rarely are migraine and its comorbidities considered and treated by the same specialist. Thus, migraine treatments represent a huge unmet medical need, which will only be addressed with greater understanding of its underlying pathophysiology. We discuss the current knowledge about sex differences in migraine and its comorbidities, and focus on the potential role of mast cells (MCs) in both. Sex-based differences in pain recognition and drug responses, fluid balance, and the blood-brain barrier are recognized but their impact on migraine is not well studied. Furthermore, MCs are well recognized for their prominent role in allergies but much less is known about their contributions to pain pathways in general and migraine specifically. MC-neuron bidirectional communication uniquely positions these cells as potential initiators and/or perpetuators of pain. MCs can secrete nociceptor sensitizing and activating agents, such as serotonin, prostaglandins, histamine, and proteolytic enzymes that can also activate the pain-mediating transient receptor potential vanilloid channels. MCs express receptors for both estrogen and progesterone that induce degranulation upon binding. Furthermore, environmental estrogens, such as Bisphenol A, activate MCs in preclinical models but their impact on pain pathways or migraine is understudied. We hope that this discussion will encourage scientists and physicians alike to bridge the knowledge gaps linking sex, MCs, and migraine to develop better, more comprehensive treatments for migraine patients.

No MeSH data available.


Related in: MedlinePlus

Allergy-induced expression of pain receptors that may also occur in migraine and other pain conditions. (A) C-fibers commonly express the ion channel protein transient receptor potential vanilloid 1 (TRPV1), while Aδ cough fibers and Aδ low-threshold mechanosensory fibers do not. Open channels allow cation (sodium and calcium) influx and action potential discharge (151, 152). (B) TRPV1-expression is stimulated by inflammatory eicosanoids, bradykinin, histamine, and others (4). Allergic sensitization with aerosolized allergen induces the expression of TRPV1 channels in both Aβ low-threshold mechanosensory fibers and Aδ cough fibers. In the latter, tracheal endothelium-derived brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) induce expression of TRPV1 mRNA (black arrow, known pathway), while the mechanism of the Aβ low-threshold mechanosensor fiber-capsaicin sensitization is unclear (red arrow, unknown pathway).
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Figure 4: Allergy-induced expression of pain receptors that may also occur in migraine and other pain conditions. (A) C-fibers commonly express the ion channel protein transient receptor potential vanilloid 1 (TRPV1), while Aδ cough fibers and Aδ low-threshold mechanosensory fibers do not. Open channels allow cation (sodium and calcium) influx and action potential discharge (151, 152). (B) TRPV1-expression is stimulated by inflammatory eicosanoids, bradykinin, histamine, and others (4). Allergic sensitization with aerosolized allergen induces the expression of TRPV1 channels in both Aβ low-threshold mechanosensory fibers and Aδ cough fibers. In the latter, tracheal endothelium-derived brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) induce expression of TRPV1 mRNA (black arrow, known pathway), while the mechanism of the Aβ low-threshold mechanosensor fiber-capsaicin sensitization is unclear (red arrow, unknown pathway).

Mentions: Several lines of evidence indicate mast cell involvement in cerebral pain (Figure 2). In electrophysiological studies, MC-derived serotonin, prostaglandin I2, and to a lesser extent, histamine were identified as sensitizing agents of meningeal nociceptors (Figure 4) (133). Interestingly, the usually inflammatory eicosanoid PGD2 and leukotriene C4 did not sensitize meningeal nociceptors (133). Nerve stimulation of rat trigeminal nerve (TN) resulted in increased vascular permeability, MC activation and degranulation in the orofacial area innervated by the trigeminal nucleus (131). Neonatal rats treated with capsaicin to deplete SP have the same MC activation, degranulation, and vascular leakage upon TN stimulation as untreated animals, suggesting that SP-mediated pain signals do not work via MCs (131). On the other hand, NO donor drugs cause enhanced CGRP release in trigeminal pathways, resulting in meningeal arterial vasodilatation and MC degranulation (32).


Roads Less Traveled: Sexual Dimorphism and Mast Cell Contributions to Migraine Pathology.

Loewendorf AI, Matynia A, Saribekyan H, Gross N, Csete M, Harrington M - Front Immunol (2016)

Allergy-induced expression of pain receptors that may also occur in migraine and other pain conditions. (A) C-fibers commonly express the ion channel protein transient receptor potential vanilloid 1 (TRPV1), while Aδ cough fibers and Aδ low-threshold mechanosensory fibers do not. Open channels allow cation (sodium and calcium) influx and action potential discharge (151, 152). (B) TRPV1-expression is stimulated by inflammatory eicosanoids, bradykinin, histamine, and others (4). Allergic sensitization with aerosolized allergen induces the expression of TRPV1 channels in both Aβ low-threshold mechanosensory fibers and Aδ cough fibers. In the latter, tracheal endothelium-derived brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) induce expression of TRPV1 mRNA (black arrow, known pathway), while the mechanism of the Aβ low-threshold mechanosensor fiber-capsaicin sensitization is unclear (red arrow, unknown pathway).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836167&req=5

Figure 4: Allergy-induced expression of pain receptors that may also occur in migraine and other pain conditions. (A) C-fibers commonly express the ion channel protein transient receptor potential vanilloid 1 (TRPV1), while Aδ cough fibers and Aδ low-threshold mechanosensory fibers do not. Open channels allow cation (sodium and calcium) influx and action potential discharge (151, 152). (B) TRPV1-expression is stimulated by inflammatory eicosanoids, bradykinin, histamine, and others (4). Allergic sensitization with aerosolized allergen induces the expression of TRPV1 channels in both Aβ low-threshold mechanosensory fibers and Aδ cough fibers. In the latter, tracheal endothelium-derived brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) induce expression of TRPV1 mRNA (black arrow, known pathway), while the mechanism of the Aβ low-threshold mechanosensor fiber-capsaicin sensitization is unclear (red arrow, unknown pathway).
Mentions: Several lines of evidence indicate mast cell involvement in cerebral pain (Figure 2). In electrophysiological studies, MC-derived serotonin, prostaglandin I2, and to a lesser extent, histamine were identified as sensitizing agents of meningeal nociceptors (Figure 4) (133). Interestingly, the usually inflammatory eicosanoid PGD2 and leukotriene C4 did not sensitize meningeal nociceptors (133). Nerve stimulation of rat trigeminal nerve (TN) resulted in increased vascular permeability, MC activation and degranulation in the orofacial area innervated by the trigeminal nucleus (131). Neonatal rats treated with capsaicin to deplete SP have the same MC activation, degranulation, and vascular leakage upon TN stimulation as untreated animals, suggesting that SP-mediated pain signals do not work via MCs (131). On the other hand, NO donor drugs cause enhanced CGRP release in trigeminal pathways, resulting in meningeal arterial vasodilatation and MC degranulation (32).

Bottom Line: MC-neuron bidirectional communication uniquely positions these cells as potential initiators and/or perpetuators of pain.MCs can secrete nociceptor sensitizing and activating agents, such as serotonin, prostaglandins, histamine, and proteolytic enzymes that can also activate the pain-mediating transient receptor potential vanilloid channels.MCs express receptors for both estrogen and progesterone that induce degranulation upon binding.

View Article: PubMed Central - PubMed

Affiliation: Huntington Medical Research Institutes , Pasadena, CA , USA.

ABSTRACT
Migraine is a common, little understood, and debilitating disease. It is much more prominent in women than in men (~2/3 are women) but the reasons for female preponderance are not clear. Migraineurs frequently experience severe comorbidities, such as allergies, depression, irritable bowel syndrome, and others; many of the comorbidities are more common in females. Current treatments for migraine are not gender specific, and rarely are migraine and its comorbidities considered and treated by the same specialist. Thus, migraine treatments represent a huge unmet medical need, which will only be addressed with greater understanding of its underlying pathophysiology. We discuss the current knowledge about sex differences in migraine and its comorbidities, and focus on the potential role of mast cells (MCs) in both. Sex-based differences in pain recognition and drug responses, fluid balance, and the blood-brain barrier are recognized but their impact on migraine is not well studied. Furthermore, MCs are well recognized for their prominent role in allergies but much less is known about their contributions to pain pathways in general and migraine specifically. MC-neuron bidirectional communication uniquely positions these cells as potential initiators and/or perpetuators of pain. MCs can secrete nociceptor sensitizing and activating agents, such as serotonin, prostaglandins, histamine, and proteolytic enzymes that can also activate the pain-mediating transient receptor potential vanilloid channels. MCs express receptors for both estrogen and progesterone that induce degranulation upon binding. Furthermore, environmental estrogens, such as Bisphenol A, activate MCs in preclinical models but their impact on pain pathways or migraine is understudied. We hope that this discussion will encourage scientists and physicians alike to bridge the knowledge gaps linking sex, MCs, and migraine to develop better, more comprehensive treatments for migraine patients.

No MeSH data available.


Related in: MedlinePlus