Activation of Estrogen Receptor <i>α</i> Enhances Bradykinin Signaling in Peripheral Sensory Neurons of Female Rats

Rowan, Matthew P.; Berg, Kelly A.; Roberts, James L.; Hargreaves, Kenneth M.; Clarke, William P.

doi:10.1124/jpet.114.212977

Cited by 17 publications

(14 citation statements)

References 41 publications

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“…To examine possible mechanisms that would explain the variability in calcium accumulation following ET-1 and BK treatment of sensory neurons, we focused on PLC activation, as it is the first molecular reaction that takes place after activation of ET A R and B 2 R. IP is one metabolite that accumulates in the presence of LiCl after hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and is broadly used as an index of PLC enzymatic activity ( Rowan et al., 2014 ). When IP accumulation was measured in sensory neuron cultures after treatment with ET-1 or BK, significant differences between maximal responses of the agonists were observed ( Figure 3(a) ).…”

Section: Resultsmentioning

confidence: 99%

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Divergence in Endothelin-1- and Bradykinin-Activated Store-Operated Calcium Entry in Afferent Sensory Neurons

et al. 2015

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Endothelin-1 (ET-1) and bradykinin (BK) are endogenous peptides that signal through Gαq/11-protein coupled receptors (GPCRs) to produce nociceptor sensitization and pain. Both peptides activate phospholipase C to stimulate Ca2+ accumulation, diacylglycerol production, and protein kinase C activation and are rapidly desensitized via a G-protein receptor kinase 2-dependent mechanism. However, ET-1 produces a greater response and longer lasting nocifensive behavior than BK in multiple models, indicating a potentially divergent signaling mechanism in primary afferent sensory neurons. Using cultured sensory neurons, we demonstrate significant differences in both Ca2+ influx and Ca2+ release from intracellular stores following ET-1 and BK treatments. As intracellular store depletion may contribute to the regulation of other signaling cascades downstream of GPCRs, we concentrated our investigation on store-operated Ca2+ channels. Using pharmacological approaches, we identified transient receptor potential canonical channel 3 (TRPC3) as a dominant contributor to Ca2+ influx subsequent to ET-1 treatment. On the other hand, BK treatment stimulated Orai1 activation, with only minor input from TRPC3. Taken together, data presented here suggest that ET-1 signaling targets TRPC3, generating a prolonged Ca2+ signal that perpetuates nocifensive responses. In contrast, Orai1 dominates as the downstream target of BK receptor activation and results in transient intracellular Ca2+ increases and abridged nocifensive responses.

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Section: Resultsmentioning

confidence: 99%

“…ET-1- and BK-stimulated inositol monophosphate (IP) accumulation in primary sensory neuronal cultures was measured as previously described ( Rowan et al., 2014 ). Neuronal cultures grown in 96-well plates were labeled with 2 µCi/ml [ 3 H]myoinositol for 24 hr before experiments.…”

Section: Methodsmentioning

confidence: 99%

Divergence in Endothelin-1- and Bradykinin-Activated Store-Operated Calcium Entry in Afferent Sensory Neurons

et al. 2015

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“…6 The nuclei of sensory neurons innervating the uterus are known to express ERs, 15 and ER-dependent signaling modulates a range of processes in peripheral nerves. 29,30 We were, therefore, interested in exploring whether the estrogen-dominated microenvironment could play a role in modulating interactions between macrophages and nerves and what regulatory factors may be involved. By using a migration assay to determine whether neurons could release factors influencing macrophages, we found evidence that addition of CM from DRGs treated with E2 enhanced macrophage migration and that the mRNA concentrations of Ccl-2 and Ccl-3 in DRGs was ER regulated.…”

Section: E2 Mediates a Two-way Dialogue Between Macrophages And Nervesmentioning

confidence: 99%

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Greaves

Temp

Esnal-Zufiurre

et al. 2015

The American Journal of Pathology

143

121

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Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor b, with up to 20% being estrogen receptor a positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1edifferentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brainderived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder. Endometriosis affects 10% of reproductive age women and is associated with persistent pelvic pain. 1 It is defined by the presence of endometrial-like tissue (lesions) found outside the uterus, most commonly on the peritoneum. The mechanisms underlying endometriosis-associated pain are poorly understood, but it has been postulated that estrogen-dependent neuroinflammation may be involved. 2 Notably, the presence of endometrial tissue fragments on the peritoneum elicits an immune response, including recruitment of macrophages, 3 blood vessels, and nerve fibers into the resultant lesions. 4,5 Within the lesions, CD68 þ macrophages have been detected in close association with nerve fibers. 6 Studies investigating macrophage activation and recruitment have revealed that endometriosis-associated macrophages exhibit a phenotype consistent with the alternative end of the macrophage activation spectrum. 7,8 In a mouse model of endometriosis that included cell transfer of polarized macrophages, Bacci et al 7 reported that mice injected with proinflammatory macrophages [macrophage (interferon g)] developed microscopic lesions, but those injected with alternatively activated macrophages [macrophage (IL-4)] developed larger lesions with a well-developed vasculature. Our studies in a mouse model of endometriosis have revealed that macrophages resident in peritoneal lesions can originate from both the peritoneum and the endometrium. 9

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“…Both estrogen receptors (ERs), ER α and ER β , are widely expressed by trigeminal ganglion neurons (Wang et al, 2012;Pavlovic et al, 2017). Estrogen can exert a direct sensitizing effect on trigeminal afferent fibers specifically through ER α (Rowan et al, 2014). Women who suffer migraine with aura have elevated plasma estrogen levels compared with women who have migraine without aura (Nagel-Leiby et al, 1990).…”

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confidence: 99%

Sex-Specific Pharmacotherapy for Migraine: A Narrative Review

Gazerani

Cairns

2020

Front. Neurosci.

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Migraine is a common neurological disorder characterized by recurrent headache episodes that accompany sensory-motor disturbances, such as higher sensitivity to touch and light, extremity heaviness or weakness, and speech or language disabilities. Worldwide, migraine is one of the top 10 causes of disability and hence poses a huge economic burden to society. On average, migraine occurs in 12% of population but its occurrence is sexually dimorphic, as it is two to three times more prevalent in women than in men. This female to male ratio of migraine prevalence is age-and sex hormone-dependent. Advancements in understanding migraine pathogenesis have also revealed an association with both genetics and epigenetics. The severity of migraine, in terms of its attack duration, headache intensity, frequency, and occurrence of migraineassociated symptoms, has generally been reported to be greater in women. Sex differences in migraine disability and comorbidities, such as psychiatric disorders, have also been noted in some population-based studies. However, research on sex-related differences in response to migraine treatments is relatively scarce. Although a general observation is that women consume more medication than men for migraine treatment, strategies for the use of abortive and preventive medications for migraine are generally similar in both sexes. This narrative review summarizes available findings on sexually distinct responses to abortive and prophylactic pharmacotherapy of migraine. Basic experimental data and clinical findings will be presented, and potential mechanisms underlying sex-based responses will be discussed to highlight the importance and value of sex-based treatment in migraine research and practice.

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Activation of Estrogen Receptor α Enhances Bradykinin Signaling in Peripheral Sensory Neurons of Female Rats

Cited by 17 publications

References 41 publications

Divergence in Endothelin-1- and Bradykinin-Activated Store-Operated Calcium Entry in Afferent Sensory Neurons

Divergence in Endothelin-1- and Bradykinin-Activated Store-Operated Calcium Entry in Afferent Sensory Neurons

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Sex-Specific Pharmacotherapy for Migraine: A Narrative Review

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