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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

Principal cephalic pain pathways and meningeal mast cell activation in migraine. Left: the initiation of migraine headache follows activation of nociceptors innervating meningeal blood vessels. Pain information flows from these nociceptors via the trigeminal nerves (TNs) to the trigeminal ganglion (TG), which receives input from the meninges mainly via the ophthalmic branch of the trigeminal nerve (V1), and to a lesser extent from the maxillary (V2) and mandibular (V3) divisions. Pain information is then transmitted to the trigeminocervical complex (TCC), which comprises the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal complex. The occipital cervical nerves (OcNs) sense posterior head and neck pain (common in migraineurs). These pain signals traverse the dorsal root ganglion (DRG) where they also terminate in the TCC. Right: an enlarged view highlighting mast cell activation within the meninges and brain. Activation of meningeal nociceptors leads to the release of vasoactive proinflammatory peptides, such as calcitonin gene-related peptide and substance P from terminal nerve endings (colored circles near terminals), resulting in meningeal BV vasodilatation, and local activation of dural mast cells (MC). Mast cell estrogen receptors ERα and ERβ, and progesterone receptors A (PR-A) and B (PR-B) are located at the plasma membrane or in the nucleus, and mediate mast cell responsiveness to these sex steroids. Following mast cell degranulation by either meningeal nociceptor activation, [or experimental nitroglycerine (NTG) injections], mast cells secrete vasoactive factors (VAF) and cytokines, such as nitric oxide, TNFα, vasoactive intestinal peptide, and histamine (depicted by colored circles) in meninges and brain. Mast cells can also react to neuronal stimuli, including substance P, CGRP, corticotropin-releasing hormone, and histamine. Mast cell degranulation can also lead to disruption of the brain–brain barrier (BBB), which is depicted by astrocytic end feet (blue) and pericytes (green) that directly appose brain capillaries.
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Figure 2: Principal cephalic pain pathways and meningeal mast cell activation in migraine. Left: the initiation of migraine headache follows activation of nociceptors innervating meningeal blood vessels. Pain information flows from these nociceptors via the trigeminal nerves (TNs) to the trigeminal ganglion (TG), which receives input from the meninges mainly via the ophthalmic branch of the trigeminal nerve (V1), and to a lesser extent from the maxillary (V2) and mandibular (V3) divisions. Pain information is then transmitted to the trigeminocervical complex (TCC), which comprises the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal complex. The occipital cervical nerves (OcNs) sense posterior head and neck pain (common in migraineurs). These pain signals traverse the dorsal root ganglion (DRG) where they also terminate in the TCC. Right: an enlarged view highlighting mast cell activation within the meninges and brain. Activation of meningeal nociceptors leads to the release of vasoactive proinflammatory peptides, such as calcitonin gene-related peptide and substance P from terminal nerve endings (colored circles near terminals), resulting in meningeal BV vasodilatation, and local activation of dural mast cells (MC). Mast cell estrogen receptors ERα and ERβ, and progesterone receptors A (PR-A) and B (PR-B) are located at the plasma membrane or in the nucleus, and mediate mast cell responsiveness to these sex steroids. Following mast cell degranulation by either meningeal nociceptor activation, [or experimental nitroglycerine (NTG) injections], mast cells secrete vasoactive factors (VAF) and cytokines, such as nitric oxide, TNFα, vasoactive intestinal peptide, and histamine (depicted by colored circles) in meninges and brain. Mast cells can also react to neuronal stimuli, including substance P, CGRP, corticotropin-releasing hormone, and histamine. Mast cell degranulation can also lead to disruption of the brain–brain barrier (BBB), which is depicted by astrocytic end feet (blue) and pericytes (green) that directly appose brain capillaries.

Mentions: Upon activation, MCs secrete vasoactive mediators and cytokines, including nitric oxide (NO), TNFα, vasoactive intestinal peptide (VIP), and histamine (125–129) (Figures 2 and 3). In turn, MCs react to various neuronal stimuli, such as substance P (SP), CGRP, corticotropin-releasing hormone (CRH), histamine, many of which are also associated with migraine pathophysiology (119, 130).


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)

Principal cephalic pain pathways and meningeal mast cell activation in migraine. Left: the initiation of migraine headache follows activation of nociceptors innervating meningeal blood vessels. Pain information flows from these nociceptors via the trigeminal nerves (TNs) to the trigeminal ganglion (TG), which receives input from the meninges mainly via the ophthalmic branch of the trigeminal nerve (V1), and to a lesser extent from the maxillary (V2) and mandibular (V3) divisions. Pain information is then transmitted to the trigeminocervical complex (TCC), which comprises the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal complex. The occipital cervical nerves (OcNs) sense posterior head and neck pain (common in migraineurs). These pain signals traverse the dorsal root ganglion (DRG) where they also terminate in the TCC. Right: an enlarged view highlighting mast cell activation within the meninges and brain. Activation of meningeal nociceptors leads to the release of vasoactive proinflammatory peptides, such as calcitonin gene-related peptide and substance P from terminal nerve endings (colored circles near terminals), resulting in meningeal BV vasodilatation, and local activation of dural mast cells (MC). Mast cell estrogen receptors ERα and ERβ, and progesterone receptors A (PR-A) and B (PR-B) are located at the plasma membrane or in the nucleus, and mediate mast cell responsiveness to these sex steroids. Following mast cell degranulation by either meningeal nociceptor activation, [or experimental nitroglycerine (NTG) injections], mast cells secrete vasoactive factors (VAF) and cytokines, such as nitric oxide, TNFα, vasoactive intestinal peptide, and histamine (depicted by colored circles) in meninges and brain. Mast cells can also react to neuronal stimuli, including substance P, CGRP, corticotropin-releasing hormone, and histamine. Mast cell degranulation can also lead to disruption of the brain–brain barrier (BBB), which is depicted by astrocytic end feet (blue) and pericytes (green) that directly appose brain capillaries.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Principal cephalic pain pathways and meningeal mast cell activation in migraine. Left: the initiation of migraine headache follows activation of nociceptors innervating meningeal blood vessels. Pain information flows from these nociceptors via the trigeminal nerves (TNs) to the trigeminal ganglion (TG), which receives input from the meninges mainly via the ophthalmic branch of the trigeminal nerve (V1), and to a lesser extent from the maxillary (V2) and mandibular (V3) divisions. Pain information is then transmitted to the trigeminocervical complex (TCC), which comprises the C1 and C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal complex. The occipital cervical nerves (OcNs) sense posterior head and neck pain (common in migraineurs). These pain signals traverse the dorsal root ganglion (DRG) where they also terminate in the TCC. Right: an enlarged view highlighting mast cell activation within the meninges and brain. Activation of meningeal nociceptors leads to the release of vasoactive proinflammatory peptides, such as calcitonin gene-related peptide and substance P from terminal nerve endings (colored circles near terminals), resulting in meningeal BV vasodilatation, and local activation of dural mast cells (MC). Mast cell estrogen receptors ERα and ERβ, and progesterone receptors A (PR-A) and B (PR-B) are located at the plasma membrane or in the nucleus, and mediate mast cell responsiveness to these sex steroids. Following mast cell degranulation by either meningeal nociceptor activation, [or experimental nitroglycerine (NTG) injections], mast cells secrete vasoactive factors (VAF) and cytokines, such as nitric oxide, TNFα, vasoactive intestinal peptide, and histamine (depicted by colored circles) in meninges and brain. Mast cells can also react to neuronal stimuli, including substance P, CGRP, corticotropin-releasing hormone, and histamine. Mast cell degranulation can also lead to disruption of the brain–brain barrier (BBB), which is depicted by astrocytic end feet (blue) and pericytes (green) that directly appose brain capillaries.
Mentions: Upon activation, MCs secrete vasoactive mediators and cytokines, including nitric oxide (NO), TNFα, vasoactive intestinal peptide (VIP), and histamine (125–129) (Figures 2 and 3). In turn, MCs react to various neuronal stimuli, such as substance P (SP), CGRP, corticotropin-releasing hormone (CRH), histamine, many of which are also associated with migraine pathophysiology (119, 130).

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