Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

Patil, Mayur; Belugin, Sergei; Mecklenburg, Jennifer; Wangzhou, Andi; Paige, Candler; Barba-Escobedo, Priscilla A.; Boyd, Jacob T.; Goffin, Vincent; Grattan, David R.; Boehm, Ulrich; Dussor, Gregory; Price, Theodore J.; Akopian, Armen N.

doi:10.1016/j.isci.2019.09.039

Cited by 62 publications

(65 citation statements)

References 79 publications

(138 reference statements)

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“…To do this, we primed the nociceptive pathway with a single injection of exogenous PRL (1μg) I.Pl. (this PRL dosage is active in females but not males (Patil et al, 2019b)) and precipitated hyperalgesic priming with I.T. PGE 2 at 1d post-PRL treatment ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 87%

“…Responsiveness to PRL in sensory neurons is substantially higher in females (>40 fold) than in males (Patil et al, 2013b; Patil et al, 2019b; Patil et al, 2019a), and strictly controlled by E-2 (Diogenes et al, 2006; Patil et al, 2019b). Endogenous and extra-pituitary PRL is elevated in paw and spinal cord after inflammation and surgical injury (Scotland et al, 2011; Patil et al, 2013a).…”

Section: Resultsmentioning

confidence: 99%

“…We were able to administer PGE 2 at 24 h post I.Pl. PRL because 1 μg PRL produces mechanical hypersensitivity for only approximately 3-4 h in females (Patil et al, 2019b). PGE 2 evoked mechanical hypersensitivity was substantially longer lasting in PRL treated female mice compared to vehicle-primed females (2-way ANOVA; F (6, 60) = 6.398; P<0.0001; n=6; Figure 4C ), but this was not the case in male mice (2-way ANOVA; F (4, 40) = 0.2318; P=0.9189; n=5-7; Figure 4B ).…”

Section: Resultsmentioning

confidence: 99%

“…Prolactin (PRL) and its receptor (Prlr) are prime candidates for this potential mechanism, since responsiveness to PRL in a variety of cells, including sensory neurons, is closely regulated by estrogen (Childs et al, 1999; Pi and Voogt, 2002; Diogenes et al, 2006; Belugin et al, 2013). Thus, Prlr signaling sensitizes pain-related ion channels and causes increased excitability in nociceptors specifically in females (Diogenes et al, 2006; Patil et al, 2013b; Liu et al, 2016; Patil et al, 2019b; Patil et al, 2019a). Moreover, Prlr function in female nociceptors is governed by estrogen signaling via a non-genomic pathway that involves sex-specific translation of Prlr mRNA (Patil et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, Prlr signaling sensitizes pain-related ion channels and causes increased excitability in nociceptors specifically in females (Diogenes et al, 2006; Patil et al, 2013b; Liu et al, 2016; Patil et al, 2019b; Patil et al, 2019a). Moreover, Prlr function in female nociceptors is governed by estrogen signaling via a non-genomic pathway that involves sex-specific translation of Prlr mRNA (Patil et al, 2019b). Based on these previous studies, we hypothesized that Prlr signaling might differentially contribute to female-specific regulation of chronic pain that can be assessed by use of the hyperalgesic priming model (Aley et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

Preprint

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Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

Preprint

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Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

Avona

Mason

Burgos-Vega

et al. 2021

Annals of Neurology

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Objective Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female‐specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. Methods Prolactin, CGRP, and receptor antagonists CGRP8‐37 or Δ1‐9‐G129R‐hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back‐labeled trigeminal ganglia (TG) neurons was used to assess PRL‐induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. Results We found that dural PRL produced sustained and long‐lasting migraine‐like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little‐to‐no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8‐37 decreases migraine‐like responses to dural PRL. Reciprocally, Δ1‐9‐G129R‐hPRL attenuates dural CGRP‐induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine‐like responses to dural CGRP. Interpretation This CGRP‐PRL interaction in the meninges is a mechanism by which these peptides could produce female‐selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129–1144

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Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

Mitchell

Cook

Shiers

et al. 2023

J of Comparative Neurology

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Fragile X Mental Retardation Protein (FMRP) regulates activity‐dependent RNA localization and local translation to modulate synaptic plasticity throughout the central nervous system. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS premutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated dorsal root ganglion (DRG) neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation‐dependent nociceptive sensitization. Activity‐dependent, local translation is a key mechanism for enhancing primary nociceptor excitability that promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human DRG and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane‐associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene‐related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.

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Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

Cited by 62 publications

References 79 publications

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

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