Estrogen modulation of the pronociceptive effects of serotonin on female rat trigeminal sensory neurons is timing dependent and dosage dependent and requires estrogen receptor alpha

Kaur, Sukhbir; Hickman, Taylor M; Lopez-Ramirez, Angela; McDonald, Hanna; Lockhart, Lauren M; Darwish, Omar; Averitt, Dayna L.

doi:10.1097/j.pain.0000000000002604

Cited by 5 publications

(2 citation statements)

References 127 publications

(116 reference statements)

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“…It has been reported that ERs distributed widely throughout the central nervous system ( Shughrue and Merchenthaler, 2001 ). Modulation of pain by estrogen has been implicated by an overwhelming number of studies, and ERs’ effects in mediating estrogen function also have been disclosed ( Chen et al, 2021 ; Kaur et al, 2022 ). The actions of estrogen are mediated by two classical ER isoforms, ERα and ERβ ( Kumar et al, 1987 ; Gegenhuber et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Song

Jin

et al. 2023

Front. Cell. Neurosci.

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IntroductionDiscogenic low back pain (DLBP) is the most commonly described form of back pain. Our previous studies indicated that estrogen-dependent DLBP mechanism was mediated by estrogen receptors (ERs) in the intervertebral disc (IVD) tissue, and the IVD degeneration degree is accompanied by downregulation of ERs, particularly ERβ. However, the neuropathological mechanisms underlying ERs modulation of DLBP are still not well understood. In this study, we investigated the antinociceptive effects of selective ERβ agonists on DLBP-related behavior by regulating substance P in spinal cord and dorsal root ganglia.MethodsTwo weeks after ovariectomies, 18-week-old female mice were randomly separated into four groups: control group; DLBP sham surgery plus vehicle group; DLBP plus vehicle group; DLBP plus ERβ-specific agonist diarylpropionitrile (DPN) group. Behavioral data was collected including behavioral measures of axial back pain (grip force and tail suspension tests) and radiating hypersensitivity (mechanical sensitivity and cold sensitivity test). Dual label scanning confocal immunofluorescence microscopy was used to observe spatial colocalization of ERβ and substance P in spinal cord. Substance P changes in spinal cord and dorsal root ganglia were measured by immunohistochemistry and real-time PCR.ResultsERβ activation could improve both axial and radiating behavioral disorders of DLBP. DPN facilitated the decrease of the amount of time in immobility 1 week after agonist administration. At the time point of 3 weeks, DPN group spent significantly less time in immobility than the vehicle group. In the grip strength tests, starting from postoperative week 1-week 3, DPN injection DLBP mice showed more resistance to stretch than the vehicle injection DLBP mice. Significant differences of cold withdrawal latency time were observed between the DLBP plus DPN injection and DLBP vehicle injection groups at 2- and 3-week injection time point. DPN significantly reversed the paw withdrawal threshold of DLBP mice at the time point of 1, 2, and 3 weeks. Substance P colocalized with ERβ in spinal dorsal horn, mainly in laminae I and II, a connection site of pain transmission. Substance P levels in dorsal horn and dorsal root ganglia of DLBP group were distinctly increased compared with that of control and DLBP sham group. DPN therapy could decrease substance P content in the dorsal horn and the dorsal root ganglia of DLBP mice compared with that of vehicle-treated DLBP mice.DiscussionActivation of ERβ is antinociceptive in the DLBP model by controlling substance P in spinal cord and dorsal root ganglia, which might provide a therapeutic target to manage DLBP in the clinic.

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Song

Jin

et al. 2023

Front. Cell. Neurosci.

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“…Also, this study was performed only in male rats. There is strong evidence in the current literature that estrogen and its receptors play a role in the modulation and enhancement of nociceptive behavior and trigeminal neurons sensitivity in rats (Kaur et al., 2022). Since this study aimed to evaluate the effects of FKN signaling blockage in orofacial pain, the effects of estrogen could be a confusing factor for the assessed results.…”

Section: Discussionmentioning

confidence: 99%

Blockage of the fractalkine pathway reduces hyperalgesia and prevents morphological glial alterations—Comparison between inflammatory and neuropathic orofacial pain in male rats

Lisboa,

Pereira,

Alves

et al. 2023

J of Neuroscience Research

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This study aimed to evaluate the effects of inhibitors of the fractalkine pathway in hyperalgesia in inflammatory and neuropathic orofacial pain in male rats and the morphological changes in microglia and satellite glial cells (SGCs). Rats were submitted to zymosan‐induced arthritis of the temporomandibular joint or infraorbital nerve constriction, and treated intrathecally with a P2X7 antagonist, a cathepsin S inhibitor or a p‐38 mitogen‐activated protein kinase (MAPK) inhibitor. Mechanical hyperalgesia was evaluated 4 and 6 h following arthritis induction or 7 and 14 days following nerve ligation. The expression of the receptor CX3CR1, phospho‐p‐38 MAPK, ionized calcium‐binding adapter molecule‐1 (Iba‐1), and glutamine synthetase and the morphological changes in microglia and SGCs were evaluated by confocal microscopy. In both inflammatory and neuropathic models, untreated animals presented a higher expression of CX3CR1 and developed hyperalgesia and up‐regulation of phospho‐p‐38 MAPK, which was prevented by all drugs (p < .05). The number of microglial processes endpoints and the total branch length were lower in the untreated animals, but the overall immunolabeling of Iba‐1 was altered only in neuropathic rats (p < .05). The mean area of SGCs per neuron was significantly altered only in the inflammatory model (p < .05). All morphological alterations were reverted by modulating the fractalkine pathway (p < .05). In conclusion, the blockage of the fractalkine pathway seemed to be a possible therapeutic strategy for inflammatory and neuropathic orofacial pain, reducing mechanical hyperalgesia by impairing the phosphorylation of p‐38 MAPK and reverting morphological alterations in microglia and SGCs.

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Aging is associated with sex-specific alteration in the expression of genes encoding for neuroestradiol synthesis and signaling proteins in the mouse trigeminal somatosensory input

Bautista-Abad,

García-Magro,

Pinto-Benito

et al. 2024

GeroScience

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Pain perception is influenced by sex and aging, with previous studies indicating the involvement of aromatase, the estradiol synthase enzyme, in regulating pain perception. Previous research has established the presence of aromatase in dorsal root ganglia sensory neurons and its role in modulating pain perception. The present study aims to explore the implications of aging and sex on the expression of aromatase and estrogen receptors in the trigeminal ganglion. The study examined mRNA levels of aromatase, ERs, and the androgen receptor (AR) in the trigeminal ganglion of 3-month-old and 27-month-old male and female mice, as well as 3-month-old mice from the four-core genotype (FCG) transgenic model. The latter facilitates the assessment of gonadal hormone and sex chromosome implications for sex-specific traits. Aromatase localization in the ganglion was further assessed through immunohistochemistry. Aromatase immunoreactivity was observed for the first time in sensory neurons within the trigeminal ganglion. Trigeminal ganglion gene expressions were detected for aromatase, ERs, and AR in both sexes. Aromatase, ERβ, and GPER gene expressions were higher in young males versus young females. Analyses of the FCG model indicated that sex differences depended solely on gonadal sex. The aging process induced an enhancement in the expression of aromatase, ERs, and AR genes across both sexes, culminating in a reversal of the previously observed gender-based differences. the potential impact of estrogen synthesis and signaling in the trigeminal ganglion on age and sex differences warrants consideration, particularly in relation to trigeminal sensory functions and pain perception. Graphical abstract Age and gonadal sex influence ERs, AR, and ARO levels in the trigeminal ganglion. Although somatosensory perception shows a decline in the elderly, the incidence of trigeminal neuralgia intensifies in aged adults and is predominantly prevalent in women relative to men. The increased expression of aromatase and estrogen receptors in aged female animals suggests that the modulatory influence that neuroestradiol exerts over the trigeminal somatosensory input, inclusive of pain, undergoes changes in elderly male and female individuals in a sex-specific manner.

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Estrogen modulation of the pronociceptive effects of serotonin on female rat trigeminal sensory neurons is timing dependent and dosage dependent and requires estrogen receptor alpha

Cited by 5 publications

References 127 publications

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Blockage of the fractalkine pathway reduces hyperalgesia and prevents morphological glial alterations—Comparison between inflammatory and neuropathic orofacial pain in male rats

Aging is associated with sex-specific alteration in the expression of genes encoding for neuroestradiol synthesis and signaling proteins in the mouse trigeminal somatosensory input

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